Science.gov

Sample records for affect neuronal excitability

  1. Maternal care differentially affects neuronal excitability and synaptic plasticity in the dorsal and ventral hippocampus.

    PubMed

    Nguyen, Huy-Binh; Bagot, Rosemary C; Diorio, Josie; Wong, Tak Pan; Meaney, Michael J

    2015-06-01

    Variations in early life maternal care modulate hippocampal development to program distinct emotional-cognitive phenotypes that persist into adulthood. Adult rat offspring that received low compared with high levels of maternal licking and grooming (low LG offspring) in early postnatal life show reduced long term potentiation (LTP) and impaired hippocampal-dependent memory, suggesting a 'detrimental' maternal effect on neural development. However, these studies focused uniquely on the dorsal hippocampus. Emerging evidence suggests a distinct role of the ventral hippocampus in mediating aggression, anxiety, and fear-memory formation, which are enhanced in low LG offspring. We report that variations in maternal care in the rat associate with opposing effects on hippocampal function in the dorsal and ventral hippocampus. Reduced pup licking associated with suppressed LTP formation in the dorsal hippocampus, but enhanced ventral hippocampal LTP. Ventral hippocampal neurons in low LG offspring fired action potentials at lower threshold voltages that were of larger amplitude and faster rise rate in comparison with those in high LG offspring. Furthermore, recordings of excitatory postsynaptic potential-to-spike coupling (E-S coupling) revealed an increase in excitability of ventral hippocampal CA1 neurons in low LG offspring. These effects do not associate with changes in miniature excitatory postsynaptic currents or paired-pulse facilitation, suggesting a specific effect of maternal care on intrinsic excitability. These findings suggest region-specific influences of maternal care in shaping neural development and synaptic plasticity. PMID:25598429

  2. Maternal Care Differentially Affects Neuronal Excitability and Synaptic Plasticity in the Dorsal and Ventral Hippocampus

    PubMed Central

    Nguyen, Huy-Binh; Bagot, Rosemary C; Diorio, Josie; Wong, Tak Pan; Meaney, Michael J

    2015-01-01

    Variations in early life maternal care modulate hippocampal development to program distinct emotional–cognitive phenotypes that persist into adulthood. Adult rat offspring that received low compared with high levels of maternal licking and grooming (low LG offspring) in early postnatal life show reduced long term potentiation (LTP) and impaired hippocampal-dependent memory, suggesting a ‘detrimental' maternal effect on neural development. However, these studies focused uniquely on the dorsal hippocampus. Emerging evidence suggests a distinct role of the ventral hippocampus in mediating aggression, anxiety, and fear-memory formation, which are enhanced in low LG offspring. We report that variations in maternal care in the rat associate with opposing effects on hippocampal function in the dorsal and ventral hippocampus. Reduced pup licking associated with suppressed LTP formation in the dorsal hippocampus, but enhanced ventral hippocampal LTP. Ventral hippocampal neurons in low LG offspring fired action potentials at lower threshold voltages that were of larger amplitude and faster rise rate in comparison with those in high LG offspring. Furthermore, recordings of excitatory postsynaptic potential-to-spike coupling (E-S coupling) revealed an increase in excitability of ventral hippocampal CA1 neurons in low LG offspring. These effects do not associate with changes in miniature excitatory postsynaptic currents or paired-pulse facilitation, suggesting a specific effect of maternal care on intrinsic excitability. These findings suggest region-specific influences of maternal care in shaping neural development and synaptic plasticity. PMID:25598429

  3. Radiation-induced impairment of neuronal excitability

    SciTech Connect

    Pellmar, T.C.; Tolliver, J.M.; Neel, K.L.

    1988-01-01

    Radiation causes a decrease in the synaptically evoked activity of CA1 hippocampal pyramidal cells. This effect is dose and dose-rate dependent. Hydrogen peroxide, which produces hydroxyl free radicals when combined with FE + 2, produces similar damage. In contrast, the radioprotectant, dithiothreitol, increases the excitability of hippocampal neurons. These studies indicate that radiation can directly affect the function of central neurons.

  4. [Ambient modulation of neuronal excitability].

    PubMed

    Chen, Yi-Zhang

    2016-08-25

    Although the modulation of synaptic activity plays an important role in the modulation of neuronal excitability, the significance of the ambient modulation (AM) of neuronal excitability should be emphasized. The AM refers to the alterations of membrane potential of neuron resulted from distinct neural activities, such as the tonic inhibition and excitation through activation of extra-synaptic receptors, the paracrine actions of nearby neural and non-neural cells, endocrinal actions of blood borne hormones and other active chemical substances. The AM of neuronal excitability may have important bearings on distinct brain functions, such as the regulation and switching of cortical states, the appearance of chaotic and vague feelings, which are usually the characteristic features in many mental and neural disorders. PMID:27546499

  5. scn1bb, a zebrafish ortholog of SCN1B expressed in excitable and non-excitable cells, affects motor neuron axon morphology and touch sensitivity

    PubMed Central

    Fein, Amanda J.; Wright, Melissa A.; Slat, Emily A.; Ribera, Angeles B.; Isom, Lori L.

    2009-01-01

    Voltage-gated Na+ channels initiate and propagate action potentials in excitable cells. Mammalian Na+ channels are composed of one pore-forming α subunit and two β subunits. SCN1B encodes the Na+ channel β1 subunit that modulates channel gating and voltage-dependence, regulates channel cell surface expression, and functions as a cell adhesion molecule (CAM). We recently identified scn1ba, a zebrafish ortholog of SCN1B. Here we report that zebrafish express a second β1-like paralog, scn1bb. In contrast to the restricted expression of scn1ba mRNA in excitable cells, we detected scn1bb transcripts and protein in several ectodermal derivatives including neurons, glia, the lateral line, peripheral sensory structures, and tissues derived from other germ layers such as the pronephros. As expected for β1 subunits, elimination of Scn1bb protein in vivo by morpholino knock-down reduced Na+ current amplitudes in Rohon-Beard neurons of zebrafish embryos, consistent with effects observed in heterologous systems. Further, after Scn1bb knock-down, zebrafish embryos displayed defects in Rohon-Beard mediated touch sensitivity, demonstrating the significance of Scn1bb modulation of Na+ current to organismal behavior. In addition to effects associated with Na+ current modulation, Scn1bb knockdown produced phenotypes consistent with CAM functions. In particular, morpholino knock-down led to abnormal development of ventrally-projecting spinal neuron axons, defasciculation of the olfactory nerve, and increased hair cell number in the inner ear. We propose that, in addition to modulation of electrical excitability, Scn1bb plays critical developmental roles by functioning as a CAM in the zebrafish embryonic nervous system. PMID:19020043

  6. Dopamine modulates excitability of basolateral amygdala neurons in vitro.

    PubMed

    Kröner, Sven; Rosenkranz, J Amiel; Grace, Anthony A; Barrionuevo, German

    2005-03-01

    The amygdala plays a role in affective behaviors, which are modulated by the dopamine (DA) innervation of the basolateral amygdala complex (BLA). Although in vivo studies indicate that activation of DA receptors alters BLA neuronal activity, it is unclear whether DA exerts direct effects on BLA neurons or whether it acts via indirect effects on BLA afferents. Using whole cell patch-clamp recordings in rat brain slices, we investigated the site and mechanisms through which DA regulates the excitability of BLA neurons. Dopamine enhanced the excitability of BLA projection neurons in response to somatic current injections via a postsynaptic effect. Dopamine D1 receptor activation increased excitability and evoked firing, whereas D2 receptor activation increased input resistance. Current- and voltage-clamp experiments in projection neurons showed that D1 receptor activation enhanced excitability by modulating a 4-aminopyridine- and alpha-dendrotoxin-sensitive, slowly inactivating K+ current. Furthermore, DA and D1 receptor activation increased evoked firing in fast-spiking BLA interneurons. Consistent with a postsynaptic modulation of interneuron excitability, DA also increased the frequency of spontaneous inhibitory postsynaptic currents recorded in projection neurons without changing release of GABA. These data demonstrate that DA exerts direct effects on BLA projection neurons and indirect actions via modulation of interneurons that may work in concert to enhance the neuronal response to large, suprathreshold inputs, while suppressing weaker inputs. PMID:15537813

  7. Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability.

    PubMed

    Murase, Sachiko; Lantz, Crystal L; Kim, Eunyoung; Gupta, Nitin; Higgins, Richard; Stopfer, Mark; Hoffman, Dax A; Quinlan, Elizabeth M

    2016-07-01

    In early postnatal development, naturally occurring cell death, dendritic outgrowth, and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here, we demonstrate that deletion of the extracellular proteinase matrix metalloproteinase-9 (MMP-9) affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons but decreases dendritic length and complexity. Parallel changes in neuronal morphology are observed in primary visual cortex and persist into adulthood. Individual CA1 neurons in MMP-9(-/-) mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significantly increases spontaneous neuronal activity in awake MMP-9(-/-) mice and enhances response to acute challenge by the excitotoxin kainate. Our data document a novel role for MMP-9-dependent proteolysis: the regulation of several aspects of circuit maturation to constrain excitability throughout life. PMID:26093382

  8. Matrix Metalloproteinase-9 regulates neuronal circuit development and excitability

    PubMed Central

    Murase, Sachiko; Lantz, Crystal; Kim, Eunyoung; Gupta, Nitin; Higgins, Richard; Stopfer, Mark; Hoffman, Dax A.; Quinlan, Elizabeth M.

    2015-01-01

    In early postnatal development, naturally occurring cell death, dendritic outgrowth and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here we demonstrate that deletion of the extracellular proteinase MMP-9 affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons, but decreases dendritic length and complexity while dendritic spine density is unchanged. Parallel changes in neuronal morphology are observed in primary visual cortex, and persist into adulthood. Individual CA1 neurons in MMP-9−/− mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significant increases spontaneous neuronal activity in awake MMP-9−/− mice and enhances response to acute challenge by the excitotoxin kainate. Thus MMP-9-dependent proteolysis regulates several aspects of circuit maturation to constrain excitability throughout life. PMID:26093382

  9. Persistent histamine excitation of glutamatergic preoptic neurons.

    PubMed

    Tabarean, Iustin V

    2012-01-01

    Thermoregulatory neurons of the median preoptic nucleus (MnPO) represent a target at which histamine modulates body temperature. The mechanism by which histamine excites a population of MnPO neurons is not known. In this study it was found that histamine activated a cationic inward current and increased the intracellular Ca(2+) concentration, actions that had a transient component as well as a sustained one that lasted for tens of minutes after removal of the agonist. The sustained component was blocked by TRPC channel blockers. Single-cell reverse transcription-PCR analysis revealed expression of TRPC1, TRPC5 and TRPC7 subunits in neurons excited by histamine. These studies also established the presence of transcripts for the glutamatergic marker Vglut2 and for the H1 histamine receptor in neurons excited by histamine. Intracellular application of antibodies directed against cytoplasmic sites of the TRPC1 or TRPC5 channel subunits decreased the histamine-induced inward current. The persistent inward current and elevation in intracellular Ca(2+) concentration could be reversed by activating the PKA pathway. This data reveal a novel mechanism by which histamine induces persistent excitation and sustained intracellular Ca(2+) elevation in glutamatergic MnPO neurons. PMID:23082195

  10. Persistent Histamine Excitation of Glutamatergic Preoptic Neurons

    PubMed Central

    Tabarean, Iustin V.

    2012-01-01

    Thermoregulatory neurons of the median preoptic nucleus (MnPO) represent a target at which histamine modulates body temperature. The mechanism by which histamine excites a population of MnPO neurons is not known. In this study it was found that histamine activated a cationic inward current and increased the intracellular Ca2+ concentration, actions that had a transient component as well as a sustained one that lasted for tens of minutes after removal of the agonist. The sustained component was blocked by TRPC channel blockers. Single-cell reverse transcription-PCR analysis revealed expression of TRPC1, TRPC5 and TRPC7 subunits in neurons excited by histamine. These studies also established the presence of transcripts for the glutamatergic marker Vglut2 and for the H1 histamine receptor in neurons excited by histamine. Intracellular application of antibodies directed against cytoplasmic sites of the TRPC1 or TRPC5 channel subunits decreased the histamine-induced inward current. The persistent inward current and elevation in intracellular Ca2+ concentration could be reversed by activating the PKA pathway. This data reveal a novel mechanism by which histamine induces persistent excitation and sustained intracellular Ca2+ elevation in glutamatergic MnPO neurons. PMID:23082195

  11. Vibrational resonance in excitable neuronal systems

    NASA Astrophysics Data System (ADS)

    Yu, Haitao; Wang, Jiang; Liu, Chen; Deng, Bin; Wei, Xile

    2011-12-01

    In this paper, we investigate the effect of a high-frequency driving on the dynamical response of excitable neuronal systems to a subthreshold low-frequency signal by numerical simulation. We demonstrate the occurrence of vibrational resonance in spatially extended neuronal networks. Different network topologies from single small-world networks to modular networks of small-world subnetworks are considered. It is shown that an optimal amplitude of high-frequency driving enhances the response of neuron populations to a low-frequency signal. This effect of vibrational resonance of neuronal systems depends extensively on the network structure and parameters, such as the coupling strength between neurons, network size, and rewiring probability of single small-world networks, as well as the number of links between different subnetworks and the number of subnetworks in the modular networks. All these parameters play a key role in determining the ability of the network to enhance the outreach of the localized subthreshold low-frequency signal. Considering that two-frequency signals are ubiquity in brain dynamics, we expect the presented results could have important implications for the weak signal detection and information propagation across neuronal systems.

  12. Natural antisense transcripts regulate the neuronal stress response and excitability

    PubMed Central

    Zheng, Xingguo; Valakh, Vera; DiAntonio, Aaron; Ben-Shahar, Yehuda

    2014-01-01

    Neurons regulate ionic fluxes across their plasma membrane to maintain their excitable properties under varying environmental conditions. However, the mechanisms that regulate ion channels abundance remain poorly understood. Here we show that pickpocket 29 (ppk29), a gene that encodes a Drosophila degenerin/epithelial sodium channel (DEG/ENaC), regulates neuronal excitability via a protein-independent mechanism. We demonstrate that the mRNA 3′UTR of ppk29 affects neuronal firing rates and associated heat-induced seizures by acting as a natural antisense transcript (NAT) that regulates the neuronal mRNA levels of seizure (sei), the Drosophila homolog of the human Ether-à-go-go Related Gene (hERG) potassium channel. We find that the regulatory impact of ppk29 mRNA on sei is independent of the sodium channel it encodes. Thus, our studies reveal a novel mRNA dependent mechanism for the regulation of neuronal excitability that is independent of protein-coding capacity. DOI: http://dx.doi.org/10.7554/eLife.01849.001 PMID:24642409

  13. Diverse precerebellar neurons share similar intrinsic excitability.

    PubMed

    Kolkman, Kristine E; McElvain, Lauren E; du Lac, Sascha

    2011-11-16

    The cerebellum dedicates a majority of the brain's neurons to processing a wide range of sensory, motor, and cognitive signals. Stereotyped circuitry within the cerebellar cortex suggests that similar computations are performed throughout the cerebellum, but little is known about whether diverse precerebellar neurons are specialized for the nature of the information they convey. In vivo recordings indicate that firing responses to sensory or motor stimuli vary dramatically across different precerebellar nuclei, but whether this reflects diverse synaptic inputs or differentially tuned intrinsic excitability has not been determined. We targeted whole-cell patch-clamp recordings to neurons in eight precerebellar nuclei which were retrogradely labeled from different regions of the cerebellum in mice. Intrinsic physiology was compared across neurons in the medial vestibular, external cuneate, lateral reticular, prepositus hypoglossi, supragenual, Roller/intercalatus, reticularis tegmenti pontis, and pontine nuclei. Within the firing domain, precerebellar neurons were remarkably similar. Firing faithfully followed temporally modulated inputs, could be sustained at high rates, and was a linear function of input current over a wide range of inputs and firing rates. Pharmacological analyses revealed common expression of Kv3 currents, which were essential for a wide linear firing range, and of SK (small-conductance calcium-activated potassium) currents, which were essential for a wide linear input range. In contrast, membrane properties below spike threshold varied considerably within and across precerebellar nuclei, as evidenced by variability in postinhibitory rebound firing. Our findings indicate that diverse precerebellar neurons perform similar scaling computations on their inputs but may be differentially tuned to synaptic inhibition. PMID:22090493

  14. Learning intrinsic excitability in medium spiny neurons

    PubMed Central

    Scheler, Gabriele

    2014-01-01

    We present an unsupervised, local activation-dependent learning rule for intrinsic plasticity (IP) which affects the composition of ion channel conductances for single neurons in a use-dependent way. We use a single-compartment conductance-based model for medium spiny striatal neurons in order to show the effects of parameterization of individual ion channels on the neuronal membrane potential-curent relationship (activation function). We show that parameter changes within the physiological ranges are sufficient to create an ensemble of neurons with significantly different activation functions. We emphasize that the effects of intrinsic neuronal modulation on spiking behavior require a distributed mode of synaptic input and can be eliminated by strongly correlated input. We show how modulation and adaptivity in ion channel conductances can be utilized to store patterns without an additional contribution by synaptic plasticity (SP). The adaptation of the spike response may result in either "positive" or "negative" pattern learning. However, read-out of stored information depends on a distributed pattern of synaptic activity to let intrinsic modulation determine spike response. We briefly discuss the implications of this conditional memory on learning and addiction. PMID:25520776

  15. Perineuronal Nets Enhance the Excitability of Fast-Spiking Neurons.

    PubMed

    Balmer, Timothy S

    2016-01-01

    Perineuronal nets (PNNs) are specialized complexes of extracellular matrix molecules that surround the somata of fast-spiking neurons throughout the vertebrate brain. PNNs are particularly prevalent throughout the auditory brainstem, which transmits signals with high speed and precision. It is unknown whether PNNs contribute to the fast-spiking ability of the neurons they surround. Whole-cell recordings were made from medial nucleus of the trapezoid body (MNTB) principal neurons in acute brain slices from postnatal day 21 (P21) to P27 mice. PNNs were degraded by incubating slices in chondroitinase ABC (ChABC) and were compared to slices that were treated with a control enzyme (penicillinase). ChABC treatment did not affect the ability of MNTB neurons to fire at up to 1000 Hz when driven by current pulses. However, f-I (frequency-intensity) curves constructed by injecting Gaussian white noise currents superimposed on DC current steps showed that ChABC treatment reduced the gain of spike output. An increase in spike threshold may have contributed to this effect, which is consistent with the observation that spikes in ChABC-treated cells were delayed relative to control-treated cells. In addition, parvalbumin-expressing fast-spiking cortical neurons in >P70 slices that were treated with ChABC also had reduced excitability and gain. The development of PNNs around somata of fast-spiking neurons may be essential for fast and precise sensory transmission and synaptic inhibition in the brain. PMID:27570824

  16. Perineuronal Nets Enhance the Excitability of Fast-Spiking Neurons

    PubMed Central

    2016-01-01

    Perineuronal nets (PNNs) are specialized complexes of extracellular matrix molecules that surround the somata of fast-spiking neurons throughout the vertebrate brain. PNNs are particularly prevalent throughout the auditory brainstem, which transmits signals with high speed and precision. It is unknown whether PNNs contribute to the fast-spiking ability of the neurons they surround. Whole-cell recordings were made from medial nucleus of the trapezoid body (MNTB) principal neurons in acute brain slices from postnatal day 21 (P21) to P27 mice. PNNs were degraded by incubating slices in chondroitinase ABC (ChABC) and were compared to slices that were treated with a control enzyme (penicillinase). ChABC treatment did not affect the ability of MNTB neurons to fire at up to 1000 Hz when driven by current pulses. However, f–I (frequency–intensity) curves constructed by injecting Gaussian white noise currents superimposed on DC current steps showed that ChABC treatment reduced the gain of spike output. An increase in spike threshold may have contributed to this effect, which is consistent with the observation that spikes in ChABC-treated cells were delayed relative to control-treated cells. In addition, parvalbumin-expressing fast-spiking cortical neurons in >P70 slices that were treated with ChABC also had reduced excitability and gain. The development of PNNs around somata of fast-spiking neurons may be essential for fast and precise sensory transmission and synaptic inhibition in the brain. PMID:27570824

  17. Sleep Interacts with Aβ to Modulate Intrinsic Neuronal Excitability

    PubMed Central

    Tabuchi, Masashi; Lone, Shahnaz R.; Liu, Sha; Liu, Qili; Zhang, Julia; Spira, Adam P.; Wu, Mark N.

    2015-01-01

    SUMMARY Background Emerging data suggest an important relationship between sleep and Alzheimer’s Disease (AD), but how poor sleep promotes the development of AD remains unclear. Results Here, using a Drosophila model of AD, we provide evidence suggesting that changes in neuronal excitability underlie the effects of sleep loss on AD pathogenesis. β-amyloid (Aβ) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases Aβ burden. Moreover, enhancing sleep reduces Aβ deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on Aβ, and decreasing neuronal activity blocks the elevated Aβ accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as Aβ expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates Aβ–induced hyperexcitability and suggest that defects in specific K+ currents underlie the hyperexcitability caused by sleep loss and Aβ expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to Aβ-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan. Conclusions Our findings directly link sleep loss to changes in neuronal excitability and Aβ accumulation and further suggest that neuronal hyperexcitability is an important mediator of Aβ toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of Aβ, a key pathogenic step in the development of AD. PMID:25754641

  18. Excitable neurons, firing threshold manifolds and canards.

    PubMed

    Mitry, John; McCarthy, Michelle; Kopell, Nancy; Wechselberger, Martin

    2013-01-01

    We investigate firing threshold manifolds in a mathematical model of an excitable neuron. The model analyzed investigates the phenomenon of post-inhibitory rebound spiking due to propofol anesthesia and is adapted from McCarthy et al. (SIAM J. Appl. Dyn. Syst. 11(4):1674-1697, 2012). Propofol modulates the decay time-scale of an inhibitory GABAa synaptic current. Interestingly, this system gives rise to rebound spiking within a specific range of propofol doses. Using techniques from geometric singular perturbation theory, we identify geometric structures, known as canards of folded saddle-type, which form the firing threshold manifolds. We find that the position and orientation of the canard separatrix is propofol dependent. Thus, the speeds of relevant slow synaptic processes are encoded within this geometric structure. We show that this behavior cannot be understood using a static, inhibitory current step protocol, which can provide a single threshold for rebound spiking but cannot explain the observed cessation of spiking for higher propofol doses. We then compare the analyses of dynamic and static synaptic inhibition, showing how the firing threshold manifolds of each relate, and why a current step approach is unable to fully capture the behavior of this model. PMID:23945278

  19. Neuronal excitability: voltage-dependent currents and synaptic transmission.

    PubMed

    Rutecki, P A

    1992-04-01

    Neuronal membrane excitability and the synaptic connections among neurons produce behavior and cognition. The intracellular compartment of neurons is negatively charged relative to the extracellular space, and this charge, as well as current flow, is produced by ions. From the perspective of charged ions, the lipid bilayer of the neuronal membrane acts as a capacitor, and transmembrane glycoprotein pores or channels act as resistors. The open and closed states of ionic channels determine the membrane potential. At equilibrium, the lowest resistance or greatest permeability is for potassium, and the resting membrane potential is close to the equilibrium potential for potassium. When a channel is opened, permeable ions diffuse down their electrochemical gradients and the membrane potential is changed. Channels are gated (opened or closed) by voltage, neurotransmitters, and second messengers. The neuron integrates synaptic potentials produced by transmitter-gated channel activity and either generates a subthreshold potential, or a suprathreshold depolarization that generates an action potential or a burst of action potentials. Action potential generation is mediated by a large, brief sodium influx that is followed by activation of a voltage-dependent potassium eflux. The pattern of action potential firing is dependent on the interaction of a repertoire of voltage-dependent ion conductances. The action potential is the main signaling mechanism to activate synaptic transmission at axon terminals. Synaptic transmission is graded depending on the amount of calcium entering the presynaptic terminal. The number of action potentials, or the shape of the action potential, will determine the amount of calcium entering the terminal and the efficacy of synaptic transmission. Presynaptic ion channels may also be controlled by neurotransmitters or modulators and affect synaptic transmission by altering the amount of calcium influx. PMID:1375602

  20. Which Neurons Will Be the Engram - Activated Neurons and/or More Excitable Neurons?

    PubMed Central

    Kim, Ji-il; Cho, Hye-Yeon; Han, Jin-Hee

    2016-01-01

    During past decades, the formation and storage principle of memory have received much attention in the neuroscience field. Although some studies have attempted to demonstrate the nature of the engram, elucidating the memory engram allocation mechanism was not possible because of the limitations of existing methods, which cannot specifically modulate the candidate neuronal population. Recently, the development of new techniques, which offer ways to mark and control specific populations of neurons, may accelerate solving this issue. Here, we review the recent advances, which have provided substantial evidence showing that both candidates (neuronal population that is activated by learning, and that has increased CREB level/excitability at learning) satisfy the criteria of the engram, which are necessary and sufficient for memory expression. PMID:27122991

  1. Excitation BolsTORs motor neurons in ALS mice.

    PubMed

    Mattson, Mark P

    2013-10-01

    It is unclear why motor neurons selectively degenerate in amyotrophic lateral sclerosis (ALS). Saxena et al. (2013) demonstrate that excitation of motor neurons can prevent their demise in a mouse model of inherited ALS by a mechanism involving the mTOR pathway. PMID:24094096

  2. Dynamic DNA methylation regulates neuronal intrinsic membrane excitability.

    PubMed

    Meadows, Jarrod P; Guzman-Karlsson, Mikael C; Phillips, Scott; Brown, Jordan A; Strange, Sarah K; Sweatt, J David; Hablitz, John J

    2016-01-01

    Epigenetic modifications, such as DNA cytosine methylation, contribute to the mechanisms underlying learning and memory by coordinating adaptive gene expression and neuronal plasticity. Transcription-dependent plasticity regulated by DNA methylation includes synaptic plasticity and homeostatic synaptic scaling. Memory-related plasticity also includes alterations in intrinsic membrane excitability mediated by changes in the abundance or activity of ion channels in the plasma membrane, which sets the threshold for action potential generation. We found that prolonged inhibition of DNA methyltransferase (DNMT) activity increased intrinsic membrane excitability of cultured cortical pyramidal neurons. Knockdown of the cytosine demethylase TET1 or inhibition of RNA polymerase blocked the increased membrane excitability caused by DNMT inhibition, suggesting that this effect was mediated by subsequent cytosine demethylation and de novo transcription. Prolonged DNMT inhibition blunted the medium component of the after-hyperpolarization potential, an effect that would increase neuronal excitability, and was associated with reduced expression of the genes encoding small-conductance Ca(2+)-activated K(+) (SK) channels. Furthermore, the specific SK channel blocker apamin increased neuronal excitability but was ineffective after DNMT inhibition. Our results suggested that DNMT inhibition enables transcriptional changes that culminate in decreased expression of SK channel-encoding genes and decreased activity of SK channels, thus providing a mechanism for the regulation of neuronal intrinsic membrane excitability by dynamic DNA cytosine methylation. This study has implications for human neurological and psychiatric diseases associated with dysregulated intrinsic excitability. PMID:27555660

  3. Neuronal excitability level transition induced by electrical stimulation

    NASA Astrophysics Data System (ADS)

    Florence, G.; Kurths, J.; Machado, B. S.; Fonoff, E. T.; Cerdeira, H. A.; Teixeira, M. J.; Sameshima, K.

    2014-12-01

    In experimental studies, electrical stimulation (ES) has been applied to induce neuronal activity or to disrupt pathological patterns. Nevertheless, the underlying mechanisms of these activity pattern transitions are not clear. To study these phenomena, we simulated a model of the hippocampal region CA1. The computational simulations using different amplitude levels and duration of ES revealed three states of neuronal excitability: burst-firing mode, depolarization block and spreading depression wave. We used the bifurcation theory to analyse the interference of ES in the cellular excitability and the neuronal dynamics. Understanding this process would help to improve the ES techniques to control some neurological disorders.

  4. Neuron absorption study and mid-IR optical excitations

    NASA Astrophysics Data System (ADS)

    Guo, Dingkai; Chen, Xing; Vadala, Shilpa; Leach, Jennie; Kostov, Yordan; Bewley, William W.; Kim, Chul-Soo; Kim, Mijin; Canedy, Chadwick L.; Merritt, Charles D.; Vurgaftman, Igor; Meyer, Jerry R.; Choa, Fow-Sen

    2012-02-01

    Neuronal optical excitation can provide non-contacting tools to explore brain circuitry and a durable stimulation interface for cardiac pacing and visual as well as auditory sensory neuronal stimulation. To obtain accurate absorption spectra, we scan the transmission of neurons in cell culture medium, and normalize it by subtracting out the absorption spectrum of the medium alone. The resulting spectra show that the main neuronal absorption peaks are in the 3000- 6000nm band, although there is a smaller peak near 1450nm. By coupling the output of a 3μm interband cascade laser (ICL) into a mid-IR fluorozirconate fiber, we can effectively deliver more than 1J/cm2 photon intensity to the excitation site for neuronal stimulation.

  5. Dietary cholesterol modulates the excitability of rabbit hippocampal CA1 pyramidal neurons

    PubMed Central

    Wang, Desheng; Schreurs, Bernard G.

    2010-01-01

    Previous work has shown high dietary cholesterol can affect learning and memory including rabbit eyeblink conditioning and this effect may be due to increased membrane cholesterol and enhanced hippocampal amyloid beta production. This study investigated whether dietary cholesterol modulates rabbit hippocampal CA1 neuron membrane properties known to be involved in rabbit eyeblink conditioning. Whole-cell current clamp recordings in hippocampal neurons from rabbits fed 2% cholesterol or normal chow for 8 weeks revealed changes including decreased after-hyperpolarization amplitudes (AHPs) – an index of membrane excitability shown to be important for rabbit eyeblink conditioning. This index was reversed by adding copper to drinking water – a dietary manipulation that can retard rabbit eyeblink conditioning. Evidence of cholesterol effects on membrane excitability was provided by application of methyl-β-cyclodextrin, a compound that reduces membrane cholesterol, which increased the excitability of hippocampal CA1 neurons. PMID:20639007

  6. Neuritin Up-regulates Kv4.2 α-Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway*

    PubMed Central

    Yao, Jin-jing; Zhao, Qian-Ru; Liu, Dong-Dong; Chow, Chi-Wing; Mei, Yan-Ai

    2016-01-01

    Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca2+/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca2+ and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4−/− mice but not in Nfatc2−/− mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4−/− mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions. PMID:27307045

  7. Neuritin Up-regulates Kv4.2 α-Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway.

    PubMed

    Yao, Jin-Jing; Zhao, Qian-Ru; Liu, Dong-Dong; Chow, Chi-Wing; Mei, Yan-Ai

    2016-08-12

    Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca(2+)/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca(2+) and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4(-/-) mice but not in Nfatc2(-/-) mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4(-/-) mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions. PMID:27307045

  8. Diverse impact of acute and long-term extracellular proteolytic activity on plasticity of neuronal excitability

    PubMed Central

    Wójtowicz, Tomasz; Brzdąk, Patrycja; Mozrzymas, Jerzy W.

    2015-01-01

    Learning and memory require alteration in number and strength of existing synaptic connections. Extracellular proteolysis within the synapses has been shown to play a pivotal role in synaptic plasticity by determining synapse structure, function, and number. Although synaptic plasticity of excitatory synapses is generally acknowledged to play a crucial role in formation of memory traces, some components of neural plasticity are reflected by nonsynaptic changes. Since information in neural networks is ultimately conveyed with action potentials, scaling of neuronal excitability could significantly enhance or dampen the outcome of dendritic integration, boost neuronal information storage capacity and ultimately learning. However, the underlying mechanism is poorly understood. With this regard, several lines of evidence and our most recent study support a view that activity of extracellular proteases might affect information processing in neuronal networks by affecting targets beyond synapses. Here, we review the most recent studies addressing the impact of extracellular proteolysis on plasticity of neuronal excitability and discuss how enzymatic activity may alter input-output/transfer function of neurons, supporting cognitive processes. Interestingly, extracellular proteolysis may alter intrinsic neuronal excitability and excitation/inhibition balance both rapidly (time of minutes to hours) and in long-term window. Moreover, it appears that by cleavage of extracellular matrix (ECM) constituents, proteases may modulate function of ion channels or alter inhibitory drive and hence facilitate active participation of dendrites and axon initial segments (AISs) in adjusting neuronal input/output function. Altogether, a picture emerges whereby both rapid and long-term extracellular proteolysis may influence some aspects of information processing in neurons, such as initiation of action potential, spike frequency adaptation, properties of action potential and dendritic

  9. Inflection, canards and excitability threshold in neuronal models.

    PubMed

    Desroches, M; Krupa, M; Rodrigues, S

    2013-10-01

    A technique is presented, based on the differential geometry of planar curves, to evaluate the excitability threshold of neuronal models. The aim is to determine regions of the phase plane where solutions to the model equations have zero local curvature, thereby defining a zero-curvature (inflection) set that discerns between sub-threshold and spiking electrical activity. This transition can arise through a Hopf bifurcation, via the so-called canard explosion that happens in an exponentially small parameter variation, and this is typical for a large class of planar neuronal models (FitzHugh-Nagumo, reduced Hodgkin-Huxley), namely, type II neurons (resonators). This transition can also correspond to the crossing of the stable manifold of a saddle equilibrium, in the case of type I neurons (integrators). We compute inflection sets and study how well they approximate the excitability threshold of these neuron models, that is, both in the canard and in the non-canard regime, using tools from invariant manifold theory and singularity theory. With the latter, we investigate the topological changes that inflection sets undergo upon parameter variation. Finally, we show that the concept of inflection set gives a good approximation of the threshold in both the so-called resonator and integrator neuronal cases. PMID:22945512

  10. Spinal motor neuron excitability during the cutaneous silent period.

    PubMed

    Leis, A A; Stĕtkárová, I; Berić, A; Stokić, D S

    1995-12-01

    The physiologic mechanisms generating the cutaneous silent period (CSP) remain uncertain. It is not known whether the CSP occurs because of inexcitability of the spinal motor neuron. We therefore, assessed excitability of the motor neuron during the CSP using F-wave responses. H-reflexes were also elicited during the CSP. Electrical stimulation to the fifth digit produced the CSP in the voluntarily contracting abductor pollicis brevis muscle (APB). Median nerve stimulation at the wrist elicited control F or H responses during isometric APB contraction (condition 1) and in resting muscle (condition 2). Control amplitudes were compared to those elicited in the midst of the CSP. In Condition 1, F-wave amplitudes and frequency during the CSP were unchanged compared with controls. However, F-waves were increased in amplitude and frequency during the CSP (P < 0.001) relative to responses elicited in resting muscle (condition 2). H-reflexes during the CSP were suppressed (P < 0.001) compared with controls elicited during contraction (condition 1), but facilitated relative to the resting state (condition 2) in which no H-reflexes were elicitable. We conclude that spinal motor neurons remain excitable to antidromic volleys at the same time that the corticospinal volley is inhibited to produce the CSP. Moreover, motor neuron excitability appears to be increased during the CSP compared to the relaxed state. PMID:7477071

  11. Nonlinear Dynamics of Neuronal Excitability, Oscillations, and Coincidence Detection

    PubMed Central

    RINZEL, JOHN; HUGUET, GEMMA

    2014-01-01

    We review some widely studied models and firing dynamics for neuronal systems, both at the single cell and network level, and dynamical systems techniques to study them. In particular, we focus on two topics in mathematical neuroscience that have attracted the attention of mathematicians for decades: single-cell excitability and bursting. We review the mathematical framework for three types of excitability and onset of repetitive firing behavior in single-neuron models and their relation with Hodgkin’s classification in 1948 of repetitive firing properties. We discuss the mathematical dissection of bursting oscillations using fast/slow analysis and demonstrate the approach using single-cell and mean-field network models. Finally, we illustrate the properties of Type III excitability in which case repetitive firing for constant or slow inputs is absent. Rather, firing is in response only to rapid enough changes in the stimulus. Our case study involves neuronal computations for sound localization for which neurons in the auditory brain stem perform extraordinarily precise coincidence detection with submillisecond temporal resolution. PMID:25392560

  12. Extracellular pH regulates excitability of vomeronasal sensory neurons.

    PubMed

    Cichy, Annika; Ackels, Tobias; Tsitoura, Chryssanthi; Kahan, Anat; Gronloh, Nina; Söchtig, Melanie; Engelhardt, Corinna H; Ben-Shaul, Yoram; Müller, Frank; Spehr, Jennifer; Spehr, Marc

    2015-03-01

    The mouse vomeronasal organ (VNO) plays a critical role in semiochemical detection and social communication. Vomeronasal stimuli are typically secreted in various body fluids. Following direct contact with urine deposits or other secretions, a peristaltic vascular pump mediates fluid entry into the recipient's VNO. Therefore, while vomeronasal sensory neurons (VSNs) sample various stimulatory semiochemicals dissolved in the intraluminal mucus, they might also be affected by the general physicochemical properties of the "solvent." Here, we report cycle stage-correlated variations in urinary pH among female mice. Estrus-specific pH decline is observed exclusively in urine samples from sexually experienced females. Moreover, patch-clamp recordings in acute VNO slices reveal that mouse VSNs reliably detect extracellular acidosis. Acid-evoked responses share the biophysical and pharmacological hallmarks of the hyperpolarization-activated current Ih. Mechanistically, VSN acid sensitivity depends on a pH-induced shift in the voltage-dependence of Ih activation that causes the opening of HCN channels at rest, thereby increasing VSN excitability. Together, our results identify extracellular acidification as a potent activator of vomeronasal Ih and suggest HCN channel-dependent vomeronasal gain control of social chemosignaling. Our data thus reveal a potential mechanistic basis for stimulus pH detection in rodent chemosensory communication. PMID:25740530

  13. Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation

    PubMed Central

    Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

    2015-01-01

    One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors. DOI: http://dx.doi.org/10.7554/eLife.09275.001 PMID:26208338

  14. Microglia Control Neuronal Network Excitability via BDNF Signalling

    PubMed Central

    2013-01-01

    Microglia-neuron interactions play a crucial role in several neurological disorders characterized by altered neural network excitability, such as epilepsy and neuropathic pain. While a series of potential messengers have been postulated as substrates of the communication between microglia and neurons, including cytokines, purines, prostaglandins, and nitric oxide, the specific links between messengers, microglia, neuronal networks, and diseases have remained elusive. Brain-derived neurotrophic factor (BDNF) released by microglia emerges as an exception in this riddle. Here, we review the current knowledge on the role played by microglial BDNF in controlling neuronal excitability by causing disinhibition. The efforts made by different laboratories during the last decade have collectively provided a robust mechanistic paradigm which elucidates the mechanisms involved in the synthesis and release of BDNF from microglia, the downstream TrkB-mediated signals in neurons, and the biophysical mechanism by which disinhibition occurs, via the downregulation of the K+-Cl− cotransporter KCC2, dysrupting Cl−homeostasis, and hence the strength of GABAA- and glycine receptor-mediated inhibition. The resulting altered network activity appears to explain several features of the associated pathologies. Targeting the molecular players involved in this canonical signaling pathway may lead to novel therapeutic approach for ameliorating a wide array of neural dysfunctions. PMID:24089642

  15. Excitation and depression of cortical neurones by 5-hydroxytryptamine

    PubMed Central

    Roberts, M. H. T.; Straughan, D. W.

    1967-01-01

    1. 5-Hydroxytryptamine (5-HT) and various 5-HT antagonists have been applied micro-electrophoretically from multibarrelled micropipettes into the environment of single neurones in the post-sigmoid and suprasylvian gyri of the cat cerebral cortex. 2. In unanaesthetized animals (encéphale isolé) a high proportion of neurones (30%) were excited by 5-HT. This excitation usually had a rapid onset and was seen both in spontaneously active neurones and in otherwise quiescent neurones in which firing was induced by L-glutamate. Some neurones were so sensitive that the uncontrolled diffusion from micropipettes was sufficient to excite them. More cells were excited by 5-HT applied as a cation from solutions of the bimaleate salt than when solutions of the creatinine sulphate salt were used. 3. In a high proportion of cells (33%) spontaneous firing or amino acid excitation was depressed by 5-HT. 4. A mixed effect was seen in a small proportion (6%) of the cells tested; usually 5-HT caused an excitation initially which was followed by a depression. In other cells, desensitization occurred, and the excitatory effect of 5-HT was diminished or lost. 5. When glutamate was used to excite otherwise quiescent cells, there was a significant increase in the number of cells excited by 5-HT and a significant decrease in the number of cells unaffected compared with spontaneously active cells. 6. The micro-electrophoretic application of D-lysergic diethylamide (LSD 25), 2-brom LSD (BOL 148), methysergide (UML 491), or 2′- (3-dimethylaminopropylthio)cinnamanilide (SQ 10643) temporarily prevented excitation by 5-HT in half the cells tested. LSD and SQ 10643 were particularly potent in this respect. This antagonism of 5-HT excitation could still be seen when excitation of the cell by L-glutamate or acetylcholine (ACh) was unaffected. 7. The depression induced by 5-HT was not prevented by the application of known 5-HT antagonists in the majority of the cells tested (93%). In two cells

  16. Non-linear leak currents affect mammalian neuron physiology

    PubMed Central

    Huang, Shiwei; Hong, Sungho; De Schutter, Erik

    2015-01-01

    In their seminal works on squid giant axons, Hodgkin, and Huxley approximated the membrane leak current as Ohmic, i.e., linear, since in their preparation, sub-threshold current rectification due to the influence of ionic concentration is negligible. Most studies on mammalian neurons have made the same, largely untested, assumption. Here we show that the membrane time constant and input resistance of mammalian neurons (when other major voltage-sensitive and ligand-gated ionic currents are discounted) varies non-linearly with membrane voltage, following the prediction of a Goldman-Hodgkin-Katz-based passive membrane model. The model predicts that under such conditions, the time constant/input resistance-voltage relationship will linearize if the concentration differences across the cell membrane are reduced. These properties were observed in patch-clamp recordings of cerebellar Purkinje neurons (in the presence of pharmacological blockers of other background ionic currents) and were more prominent in the sub-threshold region of the membrane potential. Model simulations showed that the non-linear leak affects voltage-clamp recordings and reduces temporal summation of excitatory synaptic input. Together, our results demonstrate the importance of trans-membrane ionic concentration in defining the functional properties of the passive membrane in mammalian neurons as well as other excitable cells. PMID:26594148

  17. Purines and neuronal excitability: links to the ketogenic diet.

    PubMed

    Masino, S A; Kawamura, M; Ruskin, D N; Geiger, J D; Boison, D

    2012-07-01

    ATP and adenosine are purines that play dual roles in cell metabolism and neuronal signaling. Acting at the A(1) receptor (A(1)R) subtype, adenosine acts directly on neurons to inhibit excitability and is a powerful endogenous neuroprotective and anticonvulsant molecule. Previous research showed an increase in ATP and other cell energy parameters when an animal is administered a ketogenic diet, an established metabolic therapy to reduce epileptic seizures, but the relationship among purines, neuronal excitability and the ketogenic diet was unclear. Recent work in vivo and in vitro tested the specific hypothesis that adenosine acting at A(1)Rs is a key mechanism underlying the success of ketogenic diet therapy and yielded direct evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Specifically, an in vitro mimic of a ketogenic diet revealed an A(1)R-dependent metabolic autocrine hyperpolarization of hippocampal neurons. In parallel, applying the ketogenic diet in vivo to transgenic mouse models with spontaneous electrographic seizures revealed that intact A(1)Rs are necessary for the seizure-suppressing effects of the diet. This is the first direct in vivo evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Other predictions of the relationship between purines and the ketogenic diet are discussed. Taken together, recent research on the role of purines may offer new opportunities for metabolic therapy and insight into its underlying mechanisms. PMID:21880467

  18. Estragole blocks neuronal excitability by direct inhibition of Na+ channels

    PubMed Central

    Silva-Alves, K.S.; Ferreira-da-Silva, F.W.; Peixoto-Neves, D.; Viana-Cardoso, K.V.; Moreira-Júnior, L.; Oquendo, M.B.; Oliveira-Abreu, K.; Albuquerque, A.A.C.; Coelho-de-Souza, A.N.; Leal-Cardoso, J.H.

    2013-01-01

    Estragole is a volatile terpenoid, which occurs naturally as a constituent of the essential oils of many plants. It has several pharmacological and biological activities. The objective of the present study was to investigate the mechanism of action of estragole on neuronal excitability. Intact and dissociated dorsal root ganglion neurons of rats were used to record action potential and Na+ currents with intracellular and patch-clamp techniques, respectively. Estragole blocked the generation of action potentials in cells with or without inflexions on their descendant (repolarization) phase (Ninf and N0 neurons, respectively) in a concentration-dependent manner. The resting potentials and input resistances of Ninf and N0 cells were not altered by estragole (2, 4, and 6 mM). Estragole also inhibited total Na+ current and tetrodotoxin-resistant Na+ current in a concentration-dependent manner (IC50 of 3.2 and 3.6 mM, respectively). Kinetic analysis of Na+ current in the presence of 4 mM estragole showed a statistically significant reduction of fast and slow inactivation time constants, indicating an acceleration of the inactivation process. These data demonstrate that estragole blocks neuronal excitability by direct inhibition of Na+ channel conductance activation. This action of estragole is likely to be relevant to the understanding of the mechanisms of several pharmacological effects of this substance. PMID:24345915

  19. Heat pulse excitability of vestibular hair cells and afferent neurons.

    PubMed

    Rabbitt, Richard D; Brichta, Alan M; Tabatabaee, Hessam; Boutros, Peter J; Ahn, JoongHo; Della Santina, Charles C; Poppi, Lauren A; Lim, Rebecca

    2016-08-01

    In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse) and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (ΔT ≈ 0.25°C per pulse). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each infrared heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with Q10 ≈ 2. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise (dT/dt) and an inward conduction current driven by ΔT An iberiotoxin-sensitive inhibitory conduction current was also evoked by ΔT, rising in <3 ms and decaying with a time constant of ∼24 ms. The inhibitory component dominated whole cell currents in 50% of hair cells at -68 mV and in 67% of hair cells at -60 mV. Responses were quantified and described on the basis of first principles of thermodynamics. Results identify key molecular targets underlying heat pulse excitability in vestibular sensory organs and provide quantitative methods for rational application of optical heat pulses to examine protein biophysics and manipulate cellular excitability. PMID:27226448

  20. Suppression of voltage-gated Na(+) channels and neuronal excitability by imperatorin.

    PubMed

    Wu, King-Chuen; Chen, Yi-Hung; Cheng, Ka-Shun; Kuo, Yueh-Hsiung; Yang, Chin-Tsang; Wong, Kar-Lok; Tu, Yuan-Kun; Chan, Paul; Leung, Yuk-Man

    2013-12-01

    Imperatorin is a naturally occurring furocoumarin compound isolated from plants such as Angelica archangelica and Cnidium monnieri. It has multiple pharmacological effects including anticonvulsant effects. Here we determined the effects of imperatorin on voltage-gated Na(+) channels (VGSC) using whole-cell patch clamp techniques in differentiated neuronal NG108-15 cells. We showed that imperatorin inhibited VGSC; such inhibition did not show state-dependence. Imperatorin caused a left shift in the steady-state inactivation curve without affecting activation gating. The inhibition of VGSC by imperatorin displayed a mild frequency-dependence. Imperatorin was also shown to inhibit VGSC and action potential amplitude without affecting voltage-gated K(+) channels in rat hippocampal CA1 neurons. In conclusion, our results suggest that imperatorin dampens neuronal excitability by inhibiting VGSC. PMID:24113522

  1. Increased excitability of both principle neurons and interneurons during associative learning

    PubMed Central

    Oh, M. Matthew; Disterhoft, John F.

    2015-01-01

    In this review, we highlight several studies indicating that modulation of intrinsic neuronal excitability is a key for successful memory formation. Specifically, we will focus our discussion on our hypothesis that the postburst afterhyperpolarization (AHP: a key regulator of intrinsic excitability) is an essential cellular mechanism used by both principle and inhibitory neurons to change their neuronal activity as memory is formed. In addition, we propose that these intrinsic excitability changes occur first in principle neurons, followed by changes in inhibitory neurons; thus maintaining the balance of network activity among neurons for successful encoding and read-out of memory. PMID:24946769

  2. An FPGA-Based Silicon Neuronal Network with Selectable Excitability Silicon Neurons.

    PubMed

    Li, Jing; Katori, Yuichi; Kohno, Takashi

    2012-01-01

    This paper presents a digital silicon neuronal network which simulates the nerve system in creatures and has the ability to execute intelligent tasks, such as associative memory. Two essential elements, the mathematical-structure-based digital spiking silicon neuron (DSSN) and the transmitter release based silicon synapse, allow us to tune the excitability of silicon neurons and are computationally efficient for hardware implementation. We adopt mixed pipeline and parallel structure and shift operations to design a sufficient large and complex network without excessive hardware resource cost. The network with 256 full-connected neurons is built on a Digilent Atlys board equipped with a Xilinx Spartan-6 LX45 FPGA. Besides, a memory control block and USB control block are designed to accomplish the task of data communication between the network and the host PC. This paper also describes the mechanism of associative memory performed in the silicon neuronal network. The network is capable of retrieving stored patterns if the inputs contain enough information of them. The retrieving probability increases with the similarity between the input and the stored pattern increasing. Synchronization of neurons is observed when the successful stored pattern retrieval occurs. PMID:23269911

  3. Connectivity, excitability and activity patterns in neuronal networks

    NASA Astrophysics Data System (ADS)

    le Feber, Joost; Stoyanova, Irina I.; Chiappalone, Michela

    2014-06-01

    Extremely synchronized firing patterns such as those observed in brain diseases like epilepsy may result from excessive network excitability. Although network excitability is closely related to (excitatory) connectivity, a direct measure for network excitability remains unavailable. Several methods currently exist for estimating network connectivity, most of which are related to cross-correlation. An example is the conditional firing probability (CFP) analysis which calculates the pairwise probability (CFPi,j) that electrode j records an action potential at time t = τ, given that electrode i recorded a spike at t = 0. However, electrode i often records multiple spikes within the analysis interval, and CFP values are biased by the on-going dynamic state of the network. Here we show that in a linear approximation this bias may be removed by deconvoluting CFPi,j with the autocorrelation of i (i.e. CFPi,i), to obtain the single pulse response (SPRi,j)—the average response at electrode j to a single spike at electrode i. Thus, in a linear system SPRs would be independent of the dynamic network state. Nonlinear components of synaptic transmission, such as facilitation and short term depression, will however still affect SPRs. Therefore SPRs provide a clean measure of network excitability. We used carbachol and ghrelin to moderately activate cultured cortical networks to affect their dynamic state. Both neuromodulators transformed the bursting firing patterns of the isolated networks into more dispersed firing. We show that the influence of the dynamic state on SPRs is much smaller than the effect on CFPs, but not zero. The remaining difference reflects the alteration in network excitability. We conclude that SPRs are less contaminated by the dynamic network state and that mild excitation may decrease network excitability, possibly through short term synaptic depression.

  4. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

    PubMed Central

    Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.; Kuo, Chay T.; Wadiche, Jacques I.; Overstreet-Wadiche, Linda

    2016-01-01

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations. PMID:27095423

  5. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

    DOE PAGESBeta

    Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.; Kuo, Chay T.; Wadiche, Jacques I.; Overstreet-Wadiche, Linda

    2016-04-20

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spikemore » due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Here, our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations.« less

  6. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons.

    PubMed

    Dieni, Cristina V; Panichi, Roberto; Aimone, James B; Kuo, Chay T; Wadiche, Jacques I; Overstreet-Wadiche, Linda

    2016-01-01

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations. PMID:27095423

  7. Excitation and Modulation of TRPA1, TRPV1, and TRPM8 Channel-expressing Sensory Neurons by the Pruritogen Chloroquine*

    PubMed Central

    Than, Jonathan Y.-X. L.; Li, Lin; Hasan, Raquibul; Zhang, Xuming

    2013-01-01

    The sensations of pain, itch, and cold often interact with each other. Pain inhibits itch, whereas cold inhibits both pain and itch. TRPV1 and TRPA1 channels transduce pain and itch, whereas TRPM8 transduces cold. The pruritogen chloroquine (CQ) was reported to excite TRPA1, leading to the sensation of itch. It is unclear how CQ excites and modulates TRPA1+, TRPV1+, and TRPM8+ neurons and thus affects the sensations of pain, itch, and cold. Here, we show that only 43% of CQ-excited dorsal root ganglion neurons expressed TRPA1; as expected, the responses of these neurons were completely prevented by the TRPA1 antagonist HC-030031. The remaining 57% of CQ-excited neurons did not express TRPA1, and excitation was not prevented by either a TRPA1 or TRPV1 antagonist but was prevented by the general transient receptor potential canonical (TRPC) channel blocker BTP2 and the selective TRPC3 inhibitor Pyr3. Furthermore, CQ caused potent sensitization of TRPV1 in 51.9% of TRPV1+ neurons and concomitant inhibition of TRPM8 in 48.8% of TRPM8+ dorsal root ganglion neurons. Sensitization of TRPV1 is caused mainly by activation of the phospholipase C-PKC pathway following activation of the CQ receptor MrgprA3. By contrast, inhibition of TRPM8 is caused by a direct action of activated Gαq independent of the phospholipase C pathway. Our data suggest the involvement of the TRPC3 channel acting together with TRPA1 to mediate CQ-induced itch. CQ not only elicits itch by directly exciting itch-encoding neurons but also exerts previously unappreciated widespread actions on pain-, itch-, and cold-sensing neurons, leading to enhanced pain and itch. PMID:23508958

  8. Nicotine excites corticotropin-releasing hormone mRNA-expressing neuron in the hypothalamic paraventricular nucleus in vitro in rats.

    PubMed

    Cui, Bai-Ri; Zhang, Bin-Bin; Chu, Chun-Ping; Cui, Xun; Qiu, De-Lai

    2016-05-25

    Nicotine is known to modulate the activity of the hypothalamic-pituitary-adrenal axis by stimulating corticotropin-releasing hormone (CRH) release from the hypothalamic paraventricular nucleus (PVN). However, the mechanism by which nicotine affects the hypothalamic-pituitary-adrenal axis by modulating PVN CRH neuronal activity is currently unclear. Here, we examined the effects of nicotine on PVN CRH-mRNA-expressing neurons in vitro in rats by whole-cell patch-clamp recordings, biocytin staining, and single-cell reverse transcription-multiplex PCR techniques. Of the 146 PVN putative parvocellular neurons, 17.1% (25/146) coexpressed GAPDH mRNA and CRH mRNA. Under current-clamp recording conditions, application of nicotine (1 μM) induced excitation in 92% (23/25) PVN CRH-mRNA-expressing neurons, which showed a significant increase in the spike firing rate accompanied by a depolarization of the membrane potential. Nicotine induced an increase in the spike firing rate of PVN CRH-mRNA-expressing neurons in a concentration-dependent manner. The half-effective concentration (EC50) of nicotine for increasing the spike firing rate of PVN CRH-mRNA-expressing neurons was 1.6 μM. Extracellular application of ionotropic glutamate receptor antagonist kynurenic acid (1 mM) abolished the nicotine-induced excitation of PVN CRH-mRNA-expressing neurons. Moreover, application of nicotine induced a significant increase in the spontaneous excitatory postsynaptic currents frequency, but without significantly altering the spontaneous excitatory postsynaptic currents amplitude of the CRH-mRNA-expressing neurons. Biocytin staining confirmed that the nicotine-sensitive CRH-mRNA-expressing neurons were located in the PVN parvocellular division. These results indicated that extracellular administration of nicotine indirectly excited PVN CRH-mRNA-expressing neurons, suggesting that nicotine modulated PVN CRH secretion by enhancement of both the presynaptic action potential drive and

  9. Rare variants in neuronal excitability genes influence risk for bipolar disorder

    PubMed Central

    Ament, Seth A.; Szelinger, Szabolcs; Glusman, Gustavo; Ashworth, Justin; Hou, Liping; Akula, Nirmala; Shekhtman, Tatyana; Badner, Judith A.; Brunkow, Mary E.; Mauldin, Denise E.; Stittrich, Anna-Barbara; Rouleau, Katherine; Detera-Wadleigh, Sevilla D.; Nurnberger, John I.; Gershon, Elliot S.; Schork, Nicholas; Price, Nathan D.; Gelinas, Richard; Hood, Leroy; Craig, David; McMahon, Francis J.; Kelsoe, John R.; Roach, Jared C.; Kelsoe, John R.; Greenwood, Tiffany A.; Nievergelt, Caroline M.; Shilling, Paul D.; Shekhtman, Tatyana; Roach, Jared C.; Ament, Seth A.; Hood, Leroy; Nurnberger, John I.; Edenberg, Howard J.; Foroud, Tatiana; Koller, Daniel L.; Gershon, Elliot S.; Badner, Judith A.; Liu, Chunyu; Scheftner, William A.; Lawson, William B.; Coryell, William; Potash, James B.; Rice, John; Byerley, William; McMahon, Francis J.; Hou, Liping; Berrettini, Wade H.; Zandi, Peter P.; McInnis, Melvin G.; Craig, David W.; Szelinger, Szabolcs; Schulze, Thomas G.; Schork, Nicholas J.; Quarless, Danjuma

    2015-01-01

    We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5′ and 3′ UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD. PMID:25730879

  10. Centrifugal inhibitory processes affecting neurones in the cat cochlear nucleus

    PubMed Central

    Comis, S. D.

    1970-01-01

    1. Stimulation of the lateral part of the olivary S-segment in the cat inhibited neurones in the ipsilateral cochlear nucleus. A smaller number of neurones located in the ventral division of the cochlear nucleus were excited. 2. It is suggested that inhibition in the ipsilateral cochlear nucleus may be mediated directly by fibres making synaptic connexions on the cochlear nucleus neurones, or indirectly by inhibitory fibres acting at the cochlea. 3. The direct inhibitory process at the cochlear nucleus is unaffected by strychnine, whereas the inhibitory process at the cochlea is abolished by strychnine. 4. A cochlear nucleus neurone can be influenced simultaneously by excitatory and inhibitory processes. ImagesFig. 1 PMID:5499823

  11. Computational modeling of optogenetic neuronal excitation under complex illumination conditions using a Matlab-Neuron interface (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Yona, Guy; Weissler, Yonatan; Meitav, Nizan; Guzi, Eliran; Rifold, Dafna D.; Kahn, Itamar; Shoham, Shy

    2016-03-01

    Optogenetics has in recent years become a central tool in neuroscience research. Creating a realistic model of optogenetic neuronal excitation is of crucial importance for controlling the activation levels of various neuronal populations in different depths, predicting experimental results and designing the optical systems. However, current approaches to modeling light propagation through rodents' brain tissue suffer from major shortcomings and comprehensive modeling of local illumination levels together with other important factors governing excitation (i.e., cellular morphology, channel dynamics and expression), are still lacking. To address this challenge we introduce a new simulation tool for optogenetic neuronal excitation under complex and realistic illumination conditions that implements a detailed physical model for light scattering (in MATLAB) together with neuron morphology and channelrhodopsin-2 model (in NEURON). These two disparate simulation environments were interconnected using a newly developed generic interface termed 'NeuroLab'. Applying this method, we show that in a layer-V cortical neuron, the relative contribution of the apical dendrites to neuronal excitation is considerably greater than that of the soma or basal dendrites, when illuminated from the surface.

  12. Reduced Hyperpolarization-Activated Current Contributes to Enhanced Intrinsic Excitability in Cultured Hippocampal Neurons from PrP−/− Mice

    PubMed Central

    Fan, Jing; Stemkowski, Patrick L.; Gandini, Maria A.; Black, Stefanie A.; Zhang, Zizhen; Souza, Ivana A.; Chen, Lina; Zamponi, Gerald W.

    2016-01-01

    Genetic ablation of cellular prion protein (PrPC) has been linked to increased neuronal excitability and synaptic activity in the hippocampus. We have previously shown that synaptic activity in hippocampi of PrP-null mice is increased due to enhanced N-methyl-D-aspartate receptor (NMDAR) function. Here, we focused on the effect of PRNP gene knock-out (KO) on intrinsic neuronal excitability, and in particular, the underlying ionic mechanism in hippocampal neurons cultured from P0 mouse pups. We found that the absence of PrPC profoundly affected the firing properties of cultured hippocampal neurons in the presence of synaptic blockers. The membrane impedance was greater in PrP-null neurons, and this difference was abolished by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker ZD7288 (100 μM). HCN channel activity appeared to be functionally regulated by PrPC. The amplitude of voltage sag, a characteristic of activating HCN channel current (Ih), was decreased in null mice. Moreover, Ih peak current was reduced, along with a hyperpolarizing shift in activation gating and slower kinetics. However, neither HCN1 nor HCN2 formed a biochemical complex with PrPC. These results suggest that the absence of PrP downregulates the activity of HCN channels through activation of a cell signaling pathway rather than through direct interactions. This in turn contributes to an increase in membrane impedance to potentiate neuronal excitability. PMID:27047338

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

    PubMed Central

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

    2013-01-01

    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. PMID:24173561

  14. Hydrogen peroxide modulates neuronal excitability and membrane properties in ventral horn neurons of the rat spinal cord.

    PubMed

    Ohashi, Masayuki; Hirano, Toru; Watanabe, Kei; Shoji, Hirokazu; Ohashi, Nobuko; Baba, Hiroshi; Endo, Naoto; Kohno, Tatsuro

    2016-09-01

    Hydrogen peroxide (H2O2), a reactive oxygen species, is an important signaling molecule for synaptic and neuronal activity in the central nervous system; it is produced excessively in brain ischemia and spinal cord injury. Although H2O2-mediated modulations of synaptic transmission have been reported in ventral horn (VH) neurons of the rat spinal cord, the effects of H2O2 on neuronal excitability and membrane properties remain poorly understood. Accordingly, the present study investigated such effects using a whole-cell patch-clamp technique. The bath-application of H2O2 decreased neuronal excitability accompanied by decreased input resistance, firing frequency, and action potential amplitude and by increased rheobase. These H2O2-mediated changes were induced by activation of extrasynaptic, but not synaptic, GABAA receptors. Indeed, GABAergic tonic currents were enhanced by H2O2. On the other hand, the amplitude of medium and slow afterhyperpolarization (mAHP and sAHP), which plays important roles in controlling neuronal excitability and is mediated by small-conductance calcium-activated potassium (SK) channels, was significantly decreased by H2O2. When extrasynaptic GABAA receptors were completely blocked, these decreases of mAHP and sAHP persisted, and H2O2 increased excitability, suggesting that H2O2 per se might have the potential to increase neuronal excitability via decreased SK channel conductance. These findings indicate that activating extrasynaptic GABAA receptors or SK channels may attenuate acute neuronal damage caused by H2O2-induced hyperexcitability and therefore represent a novel therapeutic target for the prevention and treatment of H2O2-induced motor neuron disorders. PMID:27343829

  15. Excitation of type II anterior caudate neurons by stimulation of dopamine D3 receptors.

    PubMed

    Piercey, M F; Hyslop, D K; Hoffmann, W E

    1997-07-11

    Previous studies have demonstrated that both direct- and indirect-acting dopamine (DA) receptor agonists excite type II neurons in the anterior caudate (CN) by stimulation of DA receptors belonging to the D2 receptor subfamily (D2, D3, D4 receptor subtypes). In the present study, pramipexole, a D3-preferring DA agonist effective in treating Parkinson's disease, excited type II anterior CN neurons. As with other direct-acting agonists, excitation of the CN neurons occurred only at doses above those that silenced DA neurons in the substantia nigra pars compacta (SNPC). Although more potent than pramipexole in inhibiting SNPC cells, PNU-91356A, a D2-preferring agonist, did not excite type II CN cells. The D3-preferring antagonist (+)-AJ76 was weaker than haloperidol, a D2-preferring antagonist, in reversing the effects of amphetamine on firing rates in dopaminergic neurons in both the SNPC and the CN. However, in relationship to its potency in the SNPC, (+)-AJ76 was more potent than haloperidol in the CN. PNU-101387, a selective D4 antagonist, did not alter amphetamine-induced stimulation of type II CN neurons. We conclude that DA agonists may excite type II anterior CN neurons via D3 receptor activation. The stimulation of these neurons may contribute to the anti-parkinsonian effects of pramipexole. PMID:9262154

  16. Pet-1 Switches Transcriptional Targets Postnatally to Regulate Maturation of Serotonin Neuron Excitability

    PubMed Central

    Wyler, Steven C.; Spencer, W. Clay; Green, Noah H.; Rood, Benjamin D.; Crawford, LaTasha; Craige, Caryne; Gresch, Paul; McMahon, Douglas G.; Beck, Sheryl G.

    2016-01-01

    Newborn neurons enter an extended maturation stage, during which they acquire excitability characteristics crucial for development of presynaptic and postsynaptic connectivity. In contrast to earlier specification programs, little is known about the regulatory mechanisms that control neuronal maturation. The Pet-1 ETS (E26 transformation-specific) factor is continuously expressed in serotonin (5-HT) neurons and initially acts in postmitotic precursors to control acquisition of 5-HT transmitter identity. Using a combination of RNA sequencing, electrophysiology, and conditional targeting approaches, we determined gene expression patterns in maturing flow-sorted 5-HT neurons and the temporal requirements for Pet-1 in shaping these patterns for functional maturation of mouse 5-HT neurons. We report a profound disruption of postmitotic expression trajectories in Pet-1−/− neurons, which prevented postnatal maturation of 5-HT neuron passive and active intrinsic membrane properties, G-protein signaling, and synaptic responses to glutamatergic, lysophosphatidic, and adrenergic agonists. Unexpectedly, conditional targeting revealed a postnatal stage-specific switch in Pet-1 targets from 5-HT synthesis genes to transmitter receptor genes required for afferent modulation of 5-HT neuron excitability. 5-HT1a autoreceptor expression depended transiently on Pet-1, thus revealing an early postnatal sensitive period for control of 5-HT excitability genes. Chromatin immunoprecipitation followed by sequencing revealed that Pet-1 regulates 5-HT neuron maturation through direct gene activation and repression. Moreover, Pet-1 directly regulates the 5-HT neuron maturation factor Engrailed 1, which suggests Pet-1 orchestrates maturation through secondary postmitotic regulatory factors. The early postnatal switch in Pet-1 targets uncovers a distinct neonatal stage-specific function for Pet-1, during which it promotes maturation of 5-HT neuron excitability. SIGNIFICANCE STATEMENT The

  17. Excitement and synchronization of small-world neuronal networks with short-term synaptic plasticity.

    PubMed

    Han, Fang; Wiercigroch, Marian; Fang, Jian-An; Wang, Zhijie

    2011-10-01

    Excitement and synchronization of electrically and chemically coupled Newman-Watts (NW) small-world neuronal networks with a short-term synaptic plasticity described by a modified Oja learning rule are investigated. For each type of neuronal network, the variation properties of synaptic weights are examined first. Then the effects of the learning rate, the coupling strength and the shortcut-adding probability on excitement and synchronization of the neuronal network are studied. It is shown that the synaptic learning suppresses the over-excitement, helps synchronization for the electrically coupled network but impairs synchronization for the chemically coupled one. Both the introduction of shortcuts and the increase of the coupling strength improve synchronization and they are helpful in increasing the excitement for the chemically coupled network, but have little effect on the excitement of the electrically coupled one. PMID:21956933

  18. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons

    PubMed Central

    Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Padilla, Stephanie L; Palmiter, Richard D

    2016-01-01

    Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1ARH) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1ARH neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1ARH neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1ARH neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1ARH neurons. We propose that Kiss1ARH neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function. DOI: http://dx.doi.org/10.7554/eLife.16246.001 PMID:27549338

  19. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons.

    PubMed

    Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Padilla, Stephanie L; Palmiter, Richard D; Kelly, Martin J; Rønnekleiv, Oline K

    2016-01-01

    Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1(ARH)) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1(ARH) neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1(ARH) neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1(ARH) neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1(ARH) neurons. We propose that Kiss1(ARH) neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function. PMID:27549338

  20. Modelling Feedback Excitation, Pacemaker Properties and Sensory Switching of Electrically Coupled Brainstem Neurons Controlling Rhythmic Activity

    PubMed Central

    Hull, Michael J.; Soffe, Stephen R.; Willshaw, David J.; Roberts, Alan

    2016-01-01

    What cellular and network properties allow reliable neuronal rhythm generation or firing that can be started and stopped by brief synaptic inputs? We investigate rhythmic activity in an electrically-coupled population of brainstem neurons driving swimming locomotion in young frog tadpoles, and how activity is switched on and off by brief sensory stimulation. We build a computational model of 30 electrically-coupled conditional pacemaker neurons on one side of the tadpole hindbrain and spinal cord. Based on experimental estimates for neuron properties, population sizes, synapse strengths and connections, we show that: long-lasting, mutual, glutamatergic excitation between the neurons allows the network to sustain rhythmic pacemaker firing at swimming frequencies following brief synaptic excitation; activity persists but rhythm breaks down without electrical coupling; NMDA voltage-dependency doubles the range of synaptic feedback strengths generating sustained rhythm. The network can be switched on and off at short latency by brief synaptic excitation and inhibition. We demonstrate that a population of generic Hodgkin-Huxley type neurons coupled by glutamatergic excitatory feedback can generate sustained asynchronous firing switched on and off synaptically. We conclude that networks of neurons with NMDAR mediated feedback excitation can generate self-sustained activity following brief synaptic excitation. The frequency of activity is limited by the kinetics of the neuron membrane channels and can be stopped by brief inhibitory input. Network activity can be rhythmic at lower frequencies if the neurons are electrically coupled. Our key finding is that excitatory synaptic feedback within a population of neurons can produce switchable, stable, sustained firing without synaptic inhibition. PMID:26824331

  1. Modelling Feedback Excitation, Pacemaker Properties and Sensory Switching of Electrically Coupled Brainstem Neurons Controlling Rhythmic Activity.

    PubMed

    Hull, Michael J; Soffe, Stephen R; Willshaw, David J; Roberts, Alan

    2016-01-01

    What cellular and network properties allow reliable neuronal rhythm generation or firing that can be started and stopped by brief synaptic inputs? We investigate rhythmic activity in an electrically-coupled population of brainstem neurons driving swimming locomotion in young frog tadpoles, and how activity is switched on and off by brief sensory stimulation. We build a computational model of 30 electrically-coupled conditional pacemaker neurons on one side of the tadpole hindbrain and spinal cord. Based on experimental estimates for neuron properties, population sizes, synapse strengths and connections, we show that: long-lasting, mutual, glutamatergic excitation between the neurons allows the network to sustain rhythmic pacemaker firing at swimming frequencies following brief synaptic excitation; activity persists but rhythm breaks down without electrical coupling; NMDA voltage-dependency doubles the range of synaptic feedback strengths generating sustained rhythm. The network can be switched on and off at short latency by brief synaptic excitation and inhibition. We demonstrate that a population of generic Hodgkin-Huxley type neurons coupled by glutamatergic excitatory feedback can generate sustained asynchronous firing switched on and off synaptically. We conclude that networks of neurons with NMDAR mediated feedback excitation can generate self-sustained activity following brief synaptic excitation. The frequency of activity is limited by the kinetics of the neuron membrane channels and can be stopped by brief inhibitory input. Network activity can be rhythmic at lower frequencies if the neurons are electrically coupled. Our key finding is that excitatory synaptic feedback within a population of neurons can produce switchable, stable, sustained firing without synaptic inhibition. PMID:26824331

  2. Learning Enhances Intrinsic Excitability in a Subset of Lateral Amygdala Neurons

    ERIC Educational Resources Information Center

    Sehgal, Megha; Ehlers, Vanessa L.; Moyer, James R., Jr.

    2014-01-01

    Learning-induced modulation of neuronal intrinsic excitability is a metaplasticity mechanism that can impact the acquisition of new memories. Although the amygdala is important for emotional learning and other behaviors, including fear and anxiety, whether learning alters intrinsic excitability within the amygdala has received very little…

  3. Enhanced excitability of hippocampal mossy fibers and CA3 neurons under dietary zinc deficiency.

    PubMed

    Takeda, Atsushi; Yamada, Kohei; Minami, Akira; Nagano, Tetsuo; Oku, Naoto

    2005-02-01

    On the basis of the evidence that susceptibility to kainate-induced seizures is enhanced by zinc deficiency and that glutamate concentrations in hippocampal extracellular fluid are excessively increased during seizures, excitability of hippocampal mossy fibers and CA3 neurons was examined using hippocampal slices, which were prepare from mice fed a zinc-deficient diet for 4 weeks. The spatio-temporal dynamics of zinc and calcium was monitored using their indicators, membrane-impermeable ZnAF-2 and membrane-permeable fura-2 AM, respectively. When the molecular layer of dentate gyrus was stimulated with 100mM KCl for 1s, the increased percentages of extracellular zinc in the stratum lucidum and CA3 pyramidal cell layer were higher in zinc-deficient mice than in the control mice, implying that glutamate release from the mossy fibers of the dentate granular cells is enhanced by zinc deficiency. Judging from the increased percentages, however, the amount of zinc released was estimated to be less in zinc-deficient mice. On the other hand, the basal calcium concentrations in the stratum lucidum and CA3 pyramidal cell layer detected with fura-2 were higher in zinc-deficient mice than in the control mice, indicating that hippocampal calcium homeostasis is affected by zinc deficiency. Furthermore, the increased percentage of intracellular calcium in the stratum lucidum by stimulation with high K+ was enhanced by the zinc deficiency. The alteration of hippocampal calcium homeostasis seems to enhance excitability of dentate granular cells in zinc deficiency, following by an enhanced excitability of postsynaptic structures in CA3 neurons. PMID:15716032

  4. Self-excited relaxation oscillations in networks of impulse neurons

    NASA Astrophysics Data System (ADS)

    Glyzin, S. D.; Kolesov, A. Yu; Rozov, N. Kh

    2015-06-01

    This paper addresses the problem of mathematical modelling of neuron activity. New classes of singularly perturbed differential-difference equations with Volterra-type delay are proposed and used to describe how single neurons and also neural networks function with various kinds of connections (electrical or chemical). Special asymptotic methods are developed which make it possible to analyse questions of the existence and stability of relaxation periodic motions in such systems. Bibliography: 56 titles.

  5. Regulation of excitability in tonic firing substantia gelatinosa neurons of the spinal cord by small-conductance Ca(2+)-activated K(+) channels.

    PubMed

    Yang, Kun

    2016-06-01

    The excitability of substantia gelatinosa (SG) neurons in the spinal dorsal horn determines the processing of nociceptive information from the periphery to the central nervous system. Small conductance Ca(2+)-activated K(+) (SK) channels on neurons supply strong negative feedback control on neuronal excitability by affecting afterhyperpolarization (AHP). However, the role of SK channels in regulating tonic-firing SG neuron excitability remains elusive. In the present study, whole-cell recordings were conducted in SG neurons from acute spinal cord slices of adult rats. The SK channel opener 1-ethyl-2-benzimidazolinone (1-EBIO) attenuated spike discharges and increased AHP amplitudes; this effect was mimicked by a high Ca(2+) external solution. Systemic administration of 1-EBIO attenuated the thermal-induced nociception behavior. Conversely, the inhibition of SK channels with apamin, a specific SK channel inhibitor, increased neuronal excitability and decreased the AHP amplitudes; this effect was mimicked by a Ca(2+)-free external solution. Apamin increased excitatory synaptic transmission by increasing the amplitudes of evoked excitatory postsynaptic potentials (eEPSPs). This facilitation depended on N-methyl-d-aspartate (NMDA) receptors, extracellular Mg(2+) and intracellular Ca(2+). Voltage-gated Ca(2+) channels (VGCCs) were also involved in the apamin-induced effects. Strikingly, 1-EBIO action on decreasing excitability persisted in the presence of apamin, indicating that 1-EBIO manipulates SK channels via a pathway rather than via apamin-sensitive SK channels. The data reveal a previously uncharacterized mechanism for manipulating SG neuronal excitability by Ca(2+) conductances via both apamin-sensitive and apamin-insensitive pathways. Because SG neurons in the dorsal horn are involved in regulating nociception, manipulating neuronal excitability via SK channels indicates a potential therapeutic target. PMID:26777279

  6. Self-organization of synchronous activity propagation in neuronal networks driven by local excitation.

    PubMed

    Bayati, Mehdi; Valizadeh, Alireza; Abbassian, Abdolhossein; Cheng, Sen

    2015-01-01

    Many experimental and theoretical studies have suggested that the reliable propagation of synchronous neural activity is crucial for neural information processing. The propagation of synchronous firing activity in so-called synfire chains has been studied extensively in feed-forward networks of spiking neurons. However, it remains unclear how such neural activity could emerge in recurrent neuronal networks through synaptic plasticity. In this study, we investigate whether local excitation, i.e., neurons that fire at a higher frequency than the other, spontaneously active neurons in the network, can shape a network to allow for synchronous activity propagation. We use two-dimensional, locally connected and heterogeneous neuronal networks with spike-timing dependent plasticity (STDP). We find that, in our model, local excitation drives profound network changes within seconds. In the emergent network, neural activity propagates synchronously through the network. This activity originates from the site of the local excitation and propagates through the network. The synchronous activity propagation persists, even when the local excitation is removed, since it derives from the synaptic weight matrix. Importantly, once this connectivity is established it remains stable even in the presence of spontaneous activity. Our results suggest that synfire-chain-like activity can emerge in a relatively simple way in realistic neural networks by locally exciting the desired origin of the neuronal sequence. PMID:26089794

  7. Brain-derived neurotrophic factor differentially modulates excitability of two classes of hippocampal output neurons.

    PubMed

    Graves, A R; Moore, S J; Spruston, N; Tryba, A K; Kaczorowski, C C

    2016-08-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampus-dependent learning and memory. Canonically, this has been ascribed to an enhancing effect on neuronal excitability and synaptic plasticity in the CA1 region. However, it is the pyramidal neurons in the subiculum that form the primary efferent pathways conveying hippocampal information to other areas of the brain, and yet the effect of BDNF on these neurons has remained unexplored. We present new data that BDNF regulates neuronal excitability and cellular plasticity in a much more complex manner than previously suggested. Subicular pyramidal neurons can be divided into two major classes, which have different electrophysiological and morphological properties, different requirements for the induction of plasticity, and different extrahippocampal projections. We found that BDNF increases excitability in one class of subicular pyramidal neurons yet decreases excitability in the other class. Furthermore, while endogenous BDNF was necessary for the induction of synaptic plasticity in both cell types, BDNF enhanced intrinsic plasticity in one class of pyramidal neurons yet suppressed intrinsic plasticity in the other. Taken together, these data suggest a novel role for BDNF signaling, as it appears to dynamically and bidirectionally regulate the output of hippocampal information to different regions of the brain. PMID:27146982

  8. Brain-derived neurotrophic factor differentially modulates excitability of two classes of hippocampal output neurons

    PubMed Central

    Graves, A. R.; Moore, S. J.; Spruston, N.; Tryba, A. K.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampus-dependent learning and memory. Canonically, this has been ascribed to an enhancing effect on neuronal excitability and synaptic plasticity in the CA1 region. However, it is the pyramidal neurons in the subiculum that form the primary efferent pathways conveying hippocampal information to other areas of the brain, and yet the effect of BDNF on these neurons has remained unexplored. We present new data that BDNF regulates neuronal excitability and cellular plasticity in a much more complex manner than previously suggested. Subicular pyramidal neurons can be divided into two major classes, which have different electrophysiological and morphological properties, different requirements for the induction of plasticity, and different extrahippocampal projections. We found that BDNF increases excitability in one class of subicular pyramidal neurons yet decreases excitability in the other class. Furthermore, while endogenous BDNF was necessary for the induction of synaptic plasticity in both cell types, BDNF enhanced intrinsic plasticity in one class of pyramidal neurons yet suppressed intrinsic plasticity in the other. Taken together, these data suggest a novel role for BDNF signaling, as it appears to dynamically and bidirectionally regulate the output of hippocampal information to different regions of the brain. PMID:27146982

  9. Presynaptic Excitation via GABAB Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression.

    PubMed

    Zhang, Juen; Tan, Lubin; Ren, Yuqi; Liang, Jingwen; Lin, Rui; Feng, Qiru; Zhou, Jingfeng; Hu, Fei; Ren, Jing; Wei, Chao; Yu, Tao; Zhuang, Yinghua; Bettler, Bernhard; Wang, Fengchao; Luo, Minmin

    2016-07-28

    Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABAB presynaptic excitation. Ablating these neurons or inactivating their GABAB receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABAB receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABAB mediates excitation by amplifying presynaptic Ca(2+) entry through Cav2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABAB mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABAB receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders. PMID:27426949

  10. Changes in neuronal excitability serve as a mechanism of long-term memory for operant conditioning

    PubMed Central

    Mozzachiodi, Riccardo; Lorenzetti, Fred D.; Baxter, Douglas A.; Byrne, John H.

    2016-01-01

    Learning can lead to changes in the intrinsic excitability of neurons. However, it is unclear to what extent these changes persist and what role they play in the expression of memory. Here, we report that in vitro analogues of operant conditioning produce a long-term (24 h) increase in the excitability of an identified neuron (B51) critical for the expression of feeding in Aplysia. This increase in excitability, which is cAMP dependent, contributes to the associative modification of the feeding circuitry, providing a mechanism for long-term memory storage. PMID:18776897

  11. Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis.

    PubMed

    Nardelli, Paul; Vincent, Jacob A; Powers, Randall; Cope, Tim C; Rich, Mark M

    2016-08-01

    The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5s) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced

  12. Kisspeptin and Gonadotropin-Releasing Hormone Neuronal Excitability: Molecular Mechanisms Driven by 17β-Estradiol.

    PubMed

    Rønnekleiv, Oline K; Zhang, Chunguang; Bosch, Martha A; Kelly, Martin J

    2015-01-01

    Kisspeptin is a neuropeptide that signals via a Gαq-coupled receptor, GPR54, in gonadotropin-releasing hormone (GnRH) neurons and is essential for pubertal maturation and fertility. Kisspeptin depolarizes and excites GnRH neurons primarily through the activation of canonical transient receptor potential (TRPC) channels and the inhibition of K+ channels. The gonadal steroid 17β-estradiol (E2) upregulates not only kisspeptin (Kiss1) mRNA but also increases the excitability of the rostral forebrain Kiss1 neurons. In addition, a primary postsynaptic action of E2 on GnRH neurons is to upregulate the expression of channel transcripts that orchestrate the downstream signaling of kisspeptin in GnRH neurons. These include not only TRPC4 channels but also low-voltage-activated T-type calcium channels and high-voltage-activated L-, N- and R-type calcium channel transcripts. Moreover, E2 has direct membrane-initiated actions to alter the excitability of GnRH neurons by enhancing ATP-sensitive potassium channel activity, which is critical for maintaining GnRH neurons in a hyperpolarized state for the recruitment of T-type calcium channels that are important for burst firing. Therefore, E2 modulates the excitability of GnRH neurons as well as of Kiss1 neurons by altering the expression and/or function of ion channels; moreover, kisspeptin provides critical excitatory input to GnRH neurons to facilitate burst firing activity and peptide release. PMID:25612870

  13. Kisspeptin and GnRH Neuronal Excitability: Molecular Mechanisms Driven by 17β-Estradiol

    PubMed Central

    Rønnekleiv, Oline K.; Zhang, Chunguang; Bosch, Martha A.; Kelly, Martin J.

    2014-01-01

    Kisspeptin is a neuropeptide that signals via a Gαq-coupled receptor, GPR54, in gonadotropin-releasing hormone (GnRH) neurons and is essential for pubertal maturation and fertility. Kisspeptin depolarizes and excites GnRH neurons primarily through the activation of canonical transient receptor potential (TRPC) channels and inhibition of K+ channels. The gonadal steroid 17β-estradiol (E2) up-regulates not only kisspeptin (Kiss1) mRNA, but also increases the excitability of the rostral forebrain Kiss1 neurons. In addition, a primary postsynaptic action of E2 on GnRH neurons is to up-regulate the expression of channel transcripts that orchestrate the downstream signaling of kisspeptin in GnRH neurons. These include not only TRPC4 channels, but also low voltage-activated T-type calcium channels and high voltage-activated L-, N- and R-type calcium channel transcripts. Moreover, E2 has direct membrane-initiated actions to alter the excitability of GnRH neurons by enhancing ATP-sensitive potassium (KATP) channel activity, which is critical for maintaining GnRH neurons in a hyperpolarized state for recruitment of T-type calcium channels that are important for burst firing. Therefore, E2 modulates the excitability of GnRH neurons as well as Kiss1 neurons by altering the expression and/or function of ion channels; and kisspeptin provides critical excitatory input to GnRH neurons to facilitate burst firing activity and peptide release. PMID:25612870

  14. Insulin Excites Anorexigenic Proopiomelanocortin Neurons via Activation of Canonical Transient Receptor Potential Channels

    PubMed Central

    Qiu, Jian; Zhang, Chunguang; Borgquist, Amanda; Nestor, Casey C; Smith, Arik W.; Bosch, Martha A.; Ku, Stephen; Wagner, Edward J.; Rønnekleiv, Oline K.; Kelly, Martin J.

    2014-01-01

    SUMMARY Proopiomelanocortin (POMC) neurons within the hypothalamic arcuate nucleus are vital anorexigenic neurons. Although both the leptin receptor and insulin receptor are coupled to activation of phosphatidylinositide3-kinase (PI3K) in POMC neurons, they are thought to have disparate actions on POMC excitability. Using whole-cell recording and selective pharmacological tools, we have found that similar to leptin, purified insulin depolarized POMC, and adjacent kisspeptin neurons via activation of TRPC5 channels, which are highly expressed in these neurons. In contrast, insulin hyperpolarized and inhibited NPY/AgRP neurons via activation of KATP channels. Moreover, Zn2+, which is found in insulin formulations at nanomolar concentrations, inhibited POMC neurons via activation of KATP channels. Finally as predicted, insulin given intracerebroventrically robustly inhibited food intake and activated c-fos expression in arcuate POMC neurons. Our results show that purified insulin excites POMC neurons in the arcuate nucleus, which we propose is a major mechanism by which insulin regulates energy homeostasis. PMID:24703699

  15. Retinoic acid affects calcium signaling in adult molluscan neurons.

    PubMed

    Vesprini, Nicholas D; Dawson, Taylor F; Yuan, Ye; Bruce, Doug; Spencer, Gaynor E

    2015-01-01

    Retinoic acid, the active metabolite of vitamin A, is important for nervous system development, regeneration, as well as cognitive functions of the adult central nervous system. These central nervous system functions are all highly dependent on neuronal activity. Retinoic acid has previously been shown to induce changes in the firing properties and action potential waveforms of adult molluscan neurons in a dose- and isomer-dependent manner. In this study, we aimed to determine the cellular pathways by which retinoic acid might exert such effects, by testing the involvement of pathways previously shown to be affected by retinoic acid. We demonstrated that the ability of all-trans retinoic acid (atRA) to induce electrophysiological changes in cultured molluscan neurons was not prevented by inhibitors of protein synthesis, protein kinase A or phospholipase C. However, we showed that atRA was capable of rapidly reducing intracellular calcium levels in the same dose- and isomer-dependent manner as shown previously for changes in neuronal firing. Moreover, we also demonstrated that the transmembrane ion flux through voltage-gated calcium channels was rapidly modulated by retinoic acid. In particular, the peak current density was reduced and the inactivation rate was increased in the presence of atRA, over a similar time course as the changes in cell firing and reductions in intracellular calcium. These studies provide further evidence for the ability of atRA to induce rapid effects in mature neurons. PMID:25343782

  16. Exogenous gangliosides may affect methylation mechanisms in neuronal cell cultures

    SciTech Connect

    Ferret, B.; Hubsch, A.; Dreyfus, H.; Massarelli, R. )

    1991-02-01

    Primary neurons in culture from chick embryo cerebral hemispheres were treated with a mixture of gangliosides added to the growth medium (final concentration: 10(-5)M and 10(-8)M) from the 3rd to the 6th day in vitro. Under these conditions methylation processes measured with (3H) and (35S) methionine and (3H)ethanolamine as precursors showed an increased methylation of (3H)ethanolamine containing phospholipids, a correspondent increased conversion of these compounds to (3H)choline containing phospholipids, and a general increased methylation of trichloroacetic acid precipitable macromolecules containing labeled methionine. A small increase in protein synthesis was observed after incubation of neurons with (3H)- and (35S)methionine. This was confirmed after electrophoretic separation of a protein extract with increased 3H- and 35S-labeling in protein bands with moecular weights between 50 and 60 KDaltons. A protein band of about 55 KDaltons appeared to be preferentially labelled when (3H) methionine was the precursor. The treatment with gangliosides increased the incorporation of (methyl-3H) label after incubation of neurons with (3H) methionine, into total DNA and decreased that of total RNA. The treatment of neurons in culture with exogenous gangliosides hence affects differently methylation processes, a finding which may confirm the involvement of gangliosides on the intracellular mediation of neuronal information mechanisms.

  17. Coherence-Resonance-Induced Neuronal Firing near a Saddle-Node and Homoclinic Bifurcation Corresponding to Type-I Excitability

    NASA Astrophysics Data System (ADS)

    Jia, Bing; Gu, Hua-Guang; Li, Yu-Ye

    2011-09-01

    Excitability is an essential characteristic of excitable media such as nervous and cardiac systems. Different types of neuronal excitability are related to different bifurcation structures. We simulate the coherence resonance effect near a saddle-node and homoclinic bifurcation corresponding to type-I excitability in a theoretical neuron model, and recognize the obvious features of the corresponding firing pattern. Similar firing patterns are discovered in rat hippocampal CA1 pyramidal neurons. The results are not only helpful for understanding the dynamics of the saddle-node bifurcation and type-I excitability in a realistic nervous system, but also provide a practical indicator to identify types of excitability and bifurcation.

  18. Regulation of neuronal excitability by release of proteins from glial cells

    PubMed Central

    Igelhorst, Birte A.; Niederkinkhaus, Vanessa; Karus, Claudia; Lange, Maren D.; Dietzel, Irmgard D.

    2015-01-01

    Effects of glial cells on electrical isolation and shaping of synaptic transmission between neurons have been extensively studied. Here we present evidence that the release of proteins from astrocytes as well as microglia may regulate voltage-activated Na+ currents in neurons, thereby increasing excitability and speed of transmission in neurons kept at distance from each other by specialized glial cells. As a first example, we show that basic fibroblast growth factor and neurotrophin-3, which are released from astrocytes by exposure to thyroid hormone, influence each other to enhance Na+ current density in cultured hippocampal neurons. As a second example, we show that the presence of microglia in hippocampal cultures can upregulate Na+ current density. The effect can be boosted by lipopolysaccharides, bacterial membrane-derived stimulators of microglial activation. Comparable effects are induced by the exposure of neuron-enriched hippocampal cultures to tumour necrosis factor-α, which is released from stimulated microglia. Taken together, our findings suggest that release of proteins from various types of glial cells can alter neuronal excitability over a time course of several days. This explains changes in neuronal excitability occurring in states of thyroid hormone imbalance and possibly also in seizures triggered by infectious diseases. PMID:26009773

  19. Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability

    PubMed Central

    Dell'Orco, James M.; Wasserman, Aaron H.; Chopra, Ravi; Ingram, Melissa A. C.; Hu, Yuan-Shih; Singh, Vikrant; Wulff, Heike; Opal, Puneet; Orr, Harry T.

    2015-01-01

    Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. SIGNIFICANCE STATEMENT In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated

  20. The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain

    PubMed Central

    Gehman, Lauren T.; Stoilov, Peter; Maguire, Jamie; Damianov, Andrey; Lin, Chia-Ho; Shiue, Lily; Ares, Manuel; Mody, Istvan; Black, Douglas L.

    2011-01-01

    The Rbfox family of RNA binding proteins regulates alternative splicing of many important neuronal transcripts but their role in neuronal physiology is not clear1. We show here that central nervous system (CNS)-specific deletion of the Rbfox1 gene results in heightened susceptibility to spontaneous and kainic acid-induced seizures. Electrophysiological recording reveals a corresponding increase in neuronal excitability in the dentate gyrus of the knockout mice. Whole transcriptome analyses identify multiple splicing changes in the Rbfox1−/− brain with few changes in overall transcript abundance. These splicing changes alter proteins that mediate synaptic transmission and membrane excitation, some of which are implicated in human epilepsy. Thus, Rbfox1 directs a genetic program required in the prevention of neuronal hyperexcitation and seizures. The Rbfox1 knockout mice provide a new model to study the post-transcriptional regulation of synaptic function. PMID:21623373

  1. Monitoring the excitability of neocortical efferent neurons to direct activation by extracellular current pulses.

    PubMed

    Swadlow, H A

    1992-08-01

    and is thought to reflect excitability changes associated with EPSPs. Examination of such subliminal responses revealed subthreshold synaptic inputs that were not revealed by examination of all-or-none action potentials. In contrast to the specificity of the short-latency threshold decrease, a long-lasting increase in JSCP threshold was seen in virtually all neurons after stimulation of each of the afferent pathways tested. This increase in threshold usually began 20-40 ms after stimulation, lasted for 100-200 ms, and is thought to reflect excitability changes associated with a long-lasting inhibitory postsynaptic potential (IPSP) seen in many cortical neurons. 4. Many neurons in primary somatosensory cortex of rat, cat, and rabbit have no demonstrable receptive fields.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1527578

  2. Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus.

    PubMed Central

    Lledo, P M; Tremblay, P; DeArmond, S J; Prusiner, S B; Nicoll, R A

    1996-01-01

    We recorded in the CA1 region from hippocampal slices of prion protein (PrP) gene knockout mice to investigate whether the loss of the normal form of prion protein (PrPC) affects neuronal excitability as well as synaptic transmission in the central nervous system. No deficit in synaptic inhibition was found using field potential recordings because (i) responses induced by stimulation in stratum radiatum consisted of a single population spike in PrP gene knockout mice similar to that recorded from control mice and (ii) the plot of field excitatory postsynaptic potential slope versus the population spike amplitude showed no difference between the two groups of mice. Intracellular recordings also failed to detect any difference in cell excitability and the reversal potential for inhibitory postsynaptic potentials. Analysis of the kinetics of inhibitory postsynaptic current revealed no modification. Finally, we examined whether synaptic plasticity was altered and found no difference in long-term potentiation between control and PrP gene knockout mice. On the basis of our findings, we propose that the loss of the normal form of prion protein does not alter the physiology of the CA1 region of the hippocampus. PMID:8637886

  3. Mice Deficient for Prion Protein Exhibit Normal Neuronal Excitability and Synaptic Transmission in the Hippocampus

    NASA Astrophysics Data System (ADS)

    Lledo, Pierre-Marie; Tremblay, Patrick; Dearmond, Stephen J.; Prusiner, Stanley B.; Nicoll, Roger A.

    1996-03-01

    We recorded in the CA1 region from hippocampal slices of prion protein (PrP) gene knockout mice to investigate whether the loss of the normal form of prion protein (PrPC) affects neuronal excitability as well as synaptic transmission in the central nervous system. No deficit in synaptic inhibition was found using field potential recordings because (i) responses induced by stimulation in stratum radiatum consisted of a single population spike in PrP gene knockout mice similar to that recorded from control mice and (ii) the plot of field excitatory postsynaptic potential slope versus the population spike amplitude showed no difference between the two groups of mice. Intracellular recordings also failed to detect any difference in cell excitability and the reversal potential for inhibitory postsynaptic potentials. Analysis of the kinetics of inhibitory postsynaptic current revealed no modification. Finally, we examined whether synaptic plasticity was altered and found no difference in long-term potentiation between control and PrP gene knockout mice. On the basis of our findings, we propose that the loss of the normal form of prion protein does not alter the physiology of the CA1 region of the hippocampus.

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

    PubMed

    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 Adar(5G1) 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 Adar(5G1) 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 Adar(5G1) 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

  5. Exogenous brain-derived neurotrophic factor relieves pain symptoms of diabetic rats by reducing excitability of dorsal root ganglion neurons.

    PubMed

    Li, Lei; Yu, Ting; Yu, Liling; Li, Haijun; Liu, Yongjuan; Wang, Dongqin

    2016-08-01

    Diabetic peripheral neuropathy (DPN) is a common complication of diabetes lacking of effective treatments. Enhanced excitability of dorsal root ganglion (DRG) neuron plays a crucial role in the progression of diabetic neuropathic hyperalgesia. Brain-derived neurotrophic factor (BDNF) is known as a neuromodulator of nociception, but whether and how BDNF modulates the excitability of DRG neurons in the development of DPN remain to be clarified. This study investigated the role of exogenous BDNF and its high-affinity tropomyosin receptor kinase B (TrkB) in rats with streptozotocin-induced diabetic neuropathic pain. The results showed that continued intrathecal administration of BDNF to diabetic rats dramatically alleviated mechanical and thermal hyperalgesia, as well as inhibited hyperexcitability of DRG neurons. These effects were blocked by pretreatment with TrkB Fc (a synthetic fusion protein consisting of the extracellular ligand-binding domain of the TrkB receptor). The expression of BDNF and TrkB was upregulated in the DRG of diabetic rats. Intrathecal administration of BDNF did not affect this upregulation. These data provide novel information that exogenous BDNF relieved pain symptoms of diabetic rats by reducing hyperexcitability of DRG neurons and might be the potential treatment of painful diabetic neuropathy. PMID:26441011

  6. Balance between Excitation and Inhibition Controls the Temporal Organization of Neuronal Avalanches

    NASA Astrophysics Data System (ADS)

    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.

  7. Human cerebrospinal fluid increases the excitability of pyramidal neurons in the in vitro brain slice

    PubMed Central

    Bjorefeldt, Andreas; Andreasson, Ulf; Daborg, Jonny; Riebe, Ilse; Wasling, Pontus; Zetterberg, Henrik; Hanse, Eric

    2015-01-01

    The composition of brain extracellular fluid is shaped by a continuous exchange of substances between the cerebrospinal fluid (CSF) and interstitial fluid. The CSF is known to contain a wide range of endogenous neuromodulatory substances, but their collective influence on neuronal activity has been poorly investigated. We show here that replacing artificial CSF (aCSF), routinely used for perfusion of brain slices in vitro, with human CSF (hCSF) powerfully boosts spontaneous firing of CA1, CA3 and layer 5 pyramidal neurons in the rat brain slice. CA1 pyramidal neurons in hCSF display lowered firing thresholds, more depolarized resting membrane potentials and reduced input resistance, mimicking properties of pyramidal neurons recorded in vivo. The increased excitability of CA1 pyramidal neurons was completely occluded by intracellular application of GTPγS, suggesting that endogenous neuromodulators in hCSF act on G-protein coupled receptors to enhance excitability. We found no increase in spontaneous inhibitory synaptic transmission by hCSF, indicating a differential effect on glutamatergic and GABAergic neurons. Our findings highlight a previously unknown function of the CSF in promoting spontaneous excitatory activity, and may help to explain differences observed in the activity of pyramidal neurons recorded in vivo and in vitro. PMID:25556798

  8. TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury

    PubMed Central

    2011-01-01

    Background Neuronal hyperexcitability is a crucial phenomenon underlying spontaneous and evoked pain. In invertebrate nociceptors, the S-type leak K+ channel (analogous to TREK-1 in mammals) plays a critical role of in determining neuronal excitability following nerve injury. Few data are available on the role of leak K2P channels after peripheral axotomy in mammals. Results Here we describe that rat sciatic nerve axotomy induces hyperexcitability of L4-L5 DRG sensory neurons and decreases TRESK (K2P18.1) expression, a channel with a major contribution to total leak current in DRGs. While the expression of other channels from the same family did not significantly change, injury markers ATF3 and Cacna2d1 were highly upregulated. Similarly, acute sensory neuron dissociation (in vitro axotomy) produced marked hyperexcitability and similar total background currents compared with neurons injured in vivo. In addition, the sanshool derivative IBA, which blocked TRESK currents in transfected HEK293 cells and DRGs, increased intracellular calcium in 49% of DRG neurons in culture. Most IBA-responding neurons (71%) also responded to the TRPV1 agonist capsaicin, indicating that they were nociceptors. Additional evidence of a biological role of TRESK channels was provided by behavioral evidence of pain (flinching and licking), in vivo electrophysiological evidence of C-nociceptor activation following IBA injection in the rat hindpaw, and increased sensitivity to painful pressure after TRESK knockdown in vivo. Conclusions In summary, our results clearly support an important role of TRESK channels in determining neuronal excitability in specific DRG neurons subpopulations, and show that axonal injury down-regulates TRESK channels, therefore contributing to neuronal hyperexcitability. PMID:21527011

  9. PYRETHROID MODULATION OF SPONTANEOUS NEURONAL EXCITABILITY AND NEUROTRANSMISSION IN HIPPOCAMPAL NEURONS IN CULTURE

    EPA Science Inventory

    Pyrethroid insecticides have potent actions on voltage-gated sodium channels, inhibiting inactivation and increasing channel open times. These are thought to underlie, at least in part, the clinical symptoms of pyrethroid intoxication. However, disruption of neuronal activity at ...

  10. Excitability and responsiveness of rat barrel cortex neurons in the presence and absence of spontaneous synaptic activity in vivo

    PubMed Central

    Altwegg-Boussac, Tristan; Chavez, Mario; Mahon, Séverine; Charpier, Stéphane

    2014-01-01

    The amplitude and temporal dynamics of spontaneous synaptic activity in the cerebral cortex vary as a function of brain states. To directly assess the impact of different ongoing synaptic activities on neocortical function, we performed in vivo intracellular recordings from barrel cortex neurons in rats under two pharmacological conditions generating either oscillatory or tonic synaptic drive. Cortical neurons membrane excitability and firing responses were compared, in the same neurons, before and after complete suppression of background synaptic drive following systemic injection of a high dose of anaesthetic. Compared to the oscillatory state, the tonic pattern resulted in a more depolarized and less fluctuating membrane potential (Vm), a lower input resistance (Rm) and steeper relations of firing frequency versus injected current (F–I). Whatever their temporal dynamics, suppression of background synaptic activities increased mean Vm, without affecting Rm, and induced a rightward shift of F–I curves. Both types of synaptic drive generated a high variability in current-induced firing rate and patterns in cortical neurons, which was much reduced after removal of spontaneous activity. These findings suggest that oscillatory and tonic synaptic patterns differentially facilitate the input–output function of cortical neurons but result in a similar moment-to-moment variability in spike responses to incoming depolarizing inputs. PMID:24732430

  11. Mutations in the Drosophila pushover gene confer increased neuronal excitability and spontaneous synaptic vesicle fusion

    SciTech Connect

    Richards, S.; Hillman, T.; Stern, M.

    1996-04-01

    We describe the identification of a gene called pushover (push), which affects both behavior and synaptic transmission at the neuromuscular junction. Adults carrying either of two mutations in push exhibit sluggishness, uncoordination, a defective escape response, and male sterility. Larvae defective in push exhibit increased release of transmitter at the neuromuscular junction. In particular, the frequency of spontaneous transmitter release and the amount of transmitter release evoked by nerve stimulation are each increased two- to threefold in push mutants at the lowest external [(Ca{sup 2+})] tested (0.15 mM). Furthermore, these mutants are more sensitive than wild type to application of the potassium channel-blocking drug quinidine: following quinidine application, push mutants, but not wild-type, display repetitive firing of the motor axon, leading to repetitive muscle postsynaptic potentials. The push gene thus might affect both neuronal excitability and the transmitter release process. Complementation tests and recombinational mapping suggest that the push mutations are allelic to a previously identified P-element-induced mutation, which also causes behavorial abnormalities and male sterility. 43 refs., 5 figs., 1 tab.

  12. Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

    ERIC Educational Resources Information Center

    Kaczorowski, Catherine C.; Disterhoft, John F.

    2009-01-01

    Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

  13. Morphology and Intrinsic Excitability of Regenerating Sensory and Motor Neurons Grown on a Line Micropattern

    PubMed Central

    Benzina, Ouafa; Cloitre, Thierry; Martin, Marta; Raoul, Cédric; Gergely, Csilla; Scamps, Frédérique

    2014-01-01

    Axonal regeneration is one of the greatest challenges in severe injuries of peripheral nerve. To provide the bridge needed for regeneration, biological or synthetic tubular nerve constructs with aligned architecture have been developed. A key point for improving axonal regeneration is assessing the effects of substrate geometry on neuronal behavior. In the present study, we used an extracellular matrix-micropatterned substrate comprising 3 µm wide lines aimed to physically mimic the in vivo longitudinal axonal growth of mice peripheral sensory and motor neurons. Adult sensory neurons or embryonic motoneurons were seeded and processed for morphological and electrical activity analyses after two days in vitro. We show that micropattern-guided sensory neurons grow one or two axons without secondary branching. Motoneurons polarity was kept on micropattern with a long axon and small dendrites. The micro-patterned substrate maintains the growth promoting effects of conditioning injury and demonstrates, for the first time, that neurite initiation and extension could be differentially regulated by conditioning injury among DRG sensory neuron subpopulations. The micro-patterned substrate impacts the excitability of sensory neurons and promotes the apparition of firing action potentials characteristic for a subclass of mechanosensitive neurons. The line pattern is quite relevant for assessing the regenerative and developmental growth of sensory and motoneurons and offers a unique model for the analysis of the impact of geometry on the expression and the activity of mechanosensitive channels in DRG sensory neurons. PMID:25329060

  14. Enhanced excitability of guinea pig inferior mesenteric ganglion neurons during and following recovery from chemical colitis.

    PubMed

    Linden, David R

    2012-11-01

    Postganglionic sympathetic neurons in the prevertebral ganglia (PVG) provide ongoing inhibitory tone to the gastrointestinal tract and receive innervation from mechanosensory intestinofugal afferent neurons primarily located in the colon and rectum. This study tests the hypothesis that colitis alters the excitability of PVG neurons. Intracellular recording techniques were used to evaluate changes in the electrical properties of inferior mesenteric ganglion (IMG) neurons in the trinitrobenzene sulfonic acid (TNBS) and acetic acid models of guinea pig colitis. Visceromotor IMG neurons were hyperexcitable 12 and 24 h, but not 6 h, post-TNBS during "acute" inflammation. Hyperexcitability persisted at 6 days post-TNBS during "chronic" inflammation, as well as at 56 days post-TNBS when colitis had resolved. In contrast, there was only a modest decrease in the current required to elicit an action potential at 24 h after acetic acid administration. Vasomotor neurons from inflamed preparations exhibited normal excitability. The excitatory effects of XE-991, a blocker of the channel that contributes to the M-type potassium current, and heteropodatoxin-2, a blocker of the channel that contributes to the A-type potassium current, were unchanged in TNBS-inflamed preparations, suggesting that these currents did not contribute to hyperexcitability. Riluzole, an inhibitor of persistent sodium currents, caused tonic visceromotor neurons to accommodate to sustained current pulses, regardless of the inflammatory state of the preparation, and restored a normal rheobase in neurons from TNBS-inflamed preparations but did not alter the rheobase of control preparations, suggesting that enhanced activity of voltage-gated sodium channels may contribute to colitis-induced hyperexcitability. Collectively, these data indicate that enhanced sympathetic drive as a result of hyperexcitable visceromotor neurons may contribute to small bowel dysfunction during colitis. PMID:22961805

  15. Excitation of tuberoinfundibular dopamine neurons by oxytocin: crosstalk in the control of lactation.

    PubMed

    Briffaud, Virginie; Williams, Paul; Courty, Justine; Broberger, Christian

    2015-03-11

    Milk production in the nursing mother is induced by the hormone prolactin. Its release from the anterior pituitary is generally under tonic inhibition by neuroendocrine tuberoinfundibular dopamine (TIDA) neurons of the arcuate nucleus. Successful nursing, however, requires not only production but also ejection of breast milk. This function is supported by the hormone oxytocin. Here we explored the possibility that interaction between these functionally complementary hormones is mediated by TIDA neurons. First, whole-cell patch-clamp recordings were performed on prepubertal male rat hypothalamic slices, where TIDA neurons can be identified by a robust and rhythmic membrane potential oscillation. Oxytocin induced a switch of this rhythmic activity to tonic discharge through a depolarization involving direct actions on TIDA neurons. The depolarization is sensitive to blockade of the oxytocin receptor and is mediated by a voltage-dependent inward current. This inward current has two components: a canonical transient receptor potential-like conductance in the low-voltage range, and in the high-voltage range, a Ca(2+)-dependent component. Finally, whole-cell and loose-patch recordings were also performed on slices from virgin and lactating female rats to evaluate the relevance of these findings for nursing. In these preparations, oxytocin was found to excite TIDA neurons, identified by their expression of tyrosine hydroxylase. These findings suggest that oxytocin can modulate prolactin secretion by exciting TIDA neurons, and that this may serve as a feedforward inhibition of prolactin release. PMID:25762669

  16. Cell-Specific Fine-Tuning of Neuronal Excitability by Differential Expression of Modulator Protein Isoforms

    PubMed Central

    Jepson, James; Sheldon, Amanda; Shahidullah, Mohammad; Fei, Hong; Koh, Kyunghee

    2013-01-01

    SLOB (SLOWPOKE-binding protein) modulates the Drosophila SLOWPOKE calcium-activated potassium channel. We have shown previously that SLOB deletion or RNAi knockdown decreases excitability of neurosecretory pars intercerebralis (PI) neurons in the adult Drosophila brain. In contrast, we found that SLOB deletion/knockdown enhances neurotransmitter release from motor neurons at the fly larval neuromuscular junction, suggesting an increase in excitability. Because two prominent SLOB isoforms, SLOB57 and SLOB71, modulate SLOWPOKE channels in opposite directions in vitro, we investigated whether divergent expression patterns of these two isoforms might underlie the differential modulation of excitability in PI and motor neurons. By performing detailed in vitro and in vivo analysis, we found strikingly different modes of regulatory control by the slob57 and slob71 promoters. The slob71, but not slob57, promoter contains binding sites for the Hunchback and Mirror transcriptional repressors. Furthermore, several core promoter elements that are absent in the slob57 promoter coordinately drive robust expression of a luciferase vector by the slob71 promoter in vitro. In addition, we visualized the expression patterns of the slob57 and slob71 promoters in vivo and found clear spatiotemporal differences in promoter activity. SLOB57 is expressed prominently in adult PI neurons, whereas larval motor neurons exclusively express SLOB71. In contrast, at the larval neuromuscular junction, SLOB57 expression appears to be restricted mainly to a subset of glial cells. Our results illustrate how the use of alternative transcriptional start sites within an ion channel modulator locus coupled with functionally relevant alternative splicing can be used to fine-tune neuronal excitability in a cell-specific manner. PMID:24133277

  17. The effects of prolonged intracortical microstimulation on the excitability of pyramidal tract neurons in the cat.

    PubMed

    McCreery, Douglas B; Agnew, William F; Bullara, Leo A

    2002-01-01

    This study was conducted to examine the excitability changes induced in cerebral cortical neurons during prolonged microstimulation with a spatially dense microelectrodes array. The arrays of 16 iridium microelectrodes were implanted chronically into the postcruciate gyrus of cats. Neuronal responses characteristic of single pyramidal tract axons (ULRs) were recorded in the medullary pyramid. 7 h of pulsing of individual electrodes at 50 Hz and at 4 nC/ph induced little or no change in the ULRs' electrical thresholds. The thresholds also were quite stable when 4 of the 16 microelectrodes were pulsed on each of 14 consecutive days. However, when all 16 microelectrodes were pulsed for 7 h at 4 nC/ph, the threshold of approximately half of the ULRs became elevated. Recovery of excitability required 2-18 days. Prolonged sequential (interleaved) pulsing of the 16 microelectrodes induced less depression of excitability than did simultaneous pulsing, but only when the stimulus amplitude was low (12 A, 1.8 nC/ph). Stimulation at a higher amplitude (15 nC/ph) induced much more depression of excitability. These findings imply that multiple processes mediate the stimulation-induced depression of neuronal excitability. The data also demonstrate that the depression can be reduced by employing a stimulus regimen in which the inherent spatial resolution of the array is maximized (sequential pulsing at an amplitude in which there is minimal overlap of the effective current fields). PMID:11874134

  18. Modulators of Calcium Influx Regulate Membrane Excitability in Rat Dorsal Root Ganglion Neurons

    PubMed Central

    Lirk, Philipp; Poroli, Mark; Rigaud, Marcel; Fuchs, Andreas; Fillip, Patrick; Huang, Chun-Yuan; Ljubkovic, Marko; Sapunar, Damir; Hogan, Quinn

    2009-01-01

    Background Chronic neuropathic pain resulting from neuronal damage remains difficult to treat, in part due to incomplete understanding of underlying cellular mechanisms. We have previously shown that inward Ca2+ flux (ICa) across the sensory neuron plasmalemma is decreased in a rodent model of chronic neuropathic pain, but the direct consequence of this loss of ICa on function of the sensory neuron has not been defined. We therefore examined the extent to which altered membrane properties after nerve injury, especially increased excitability that may contribute to chronic pain, are attributable to diminished Ca2+ entry. Methods Intracellular microelectrode measurements were obtained from A-type neurons of dorsal root ganglia excised from control rats and those with neuropathic pain behavior following spinal nerve ligation. Recording conditions were varied to suppress or promote ICa while biophysical parameters and excitability were determined. Results Both lowered external bath Ca2+ concentration and blockade of ICa with bath cadmium diminished the duration and area of the afterhyperpolarization (AHP), accompanied by decreased current threshold for action potential (AP) initiation and increased repetitive firing during sustained depolarization. Reciprocally, elevated bath Ca2+ increased the AHP and suppressed repetitive firing. Voltage sag during neuronal hyperpolarization, indicative of the cation-nonselective H-current, diminished with lowered bath Ca2+, cadmium application, or chelation of intracellular Ca2+. Additional recordings with selective blockers of ICa subtypes showed that N-, P/Q, L-, and R-type currents each contribute to generation of the AHP, and that blockade of any of these as well as the T-type current slows the AP upstroke, prolongs the AP duration, and (except for L-type current) decreases the current threshold for AP initiation. Conclusions Taken together, our findings show that suppression of ICa decreases the AHP, reduces the

  19. Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels

    PubMed Central

    2014-01-01

    Background Inorganic polyphosphate (polyP) is a highly charged polyanion capable of interacting with a number of molecular targets. This signaling molecule is released into the extracellular matrix by central astrocytes and by peripheral platelets during inflammation. While the release of polyP is associated with both induction of blood coagulation and astrocyte extracellular signaling, the role of secreted polyP in regulation of neuronal activity remains undefined. Here we test the hypothesis that polyP is an important participant in neuronal signaling. Specifically, we investigate the ability of neurons to release polyP and to induce neuronal firing, and clarify the underlying molecular mechanisms of this process by studying the action of polyP on voltage gated channels. Results Using patch clamp techniques, and primary hippocampal and dorsal root ganglion cell cultures, we demonstrate that polyP directly influences neuronal activity, inducing action potential generation in both PNS and CNS neurons. Mechanistically, this is accomplished by shifting the voltage sensitivity of NaV channel activation toward the neuronal resting membrane potential, the block KV channels, and the activation of CaV channels. Next, using calcium imaging we found that polyP stimulates an increase in neuronal network activity and induces calcium influx in glial cells. Using in situ DAPI localization and live imaging, we demonstrate that polyP is naturally present in synaptic regions and is released from the neurons upon depolarization. Finally, using a biochemical assay we demonstrate that polyP is present in synaptosomes and can be released upon their membrane depolarization by the addition of potassium chloride. Conclusions We conclude that polyP release leads to increased excitability of the neuronal membrane through the modulation of voltage gated ion channels. Together, our data establishes that polyP could function as excitatory neuromodulator in both the PNS and CNS. PMID:24886461

  20. Dynorphin activation of kappa opioid receptor reduces neuronal excitability in the paraventricular nucleus of mouse thalamus.

    PubMed

    Chen, Zhiheng; Tang, Yamei; Tao, Huai; Li, Cunyan; Zhang, Xianghui; Liu, Yong

    2015-10-01

    It has been reported that kappa opioid receptor (KOR) is expressed in the paraventricular nucleus of thalamus (PVT), a brain region associated with arousal, drug reward and stress. Although intra-PVT infusion of KOR agonist was found to inhibit drug-seeking behavior, it is still unclear whether endogenous KOR agonists directly regulate PVT neuron activity. Here, we investigated the effect of the endogenous KOR agonist dynorphin-A (Dyn-A) on the excitability of mouse PVT neurons at different developmental ages. We found Dyn-A strongly inhibited PVT neurons through a direct postsynaptic hyperpolarization. Under voltage-clamp configuration, Dyn-A evoked an obvious outward current in majority of neurons tested in anterior PVT (aPVT) but only in minority of neurons in posterior PVT (pPVT). The Dyn-A current was abolished by KOR antagonist nor-BNI, Ba(2+) and non-hydrolyzable GDP analogue GDP-β-s, indicating that Dyn-A activates KOR and opens G-protein-coupled inwardly rectifying potassium channels in PVT neurons. More interestingly, by comparing Dyn-A currents in aPVT neurons of mice at various ages, we found Dyn-A evoked significant larger current in aPVT neurons from mice around prepuberty and early puberty stage. In addition, KOR activation by Dyn-A didn't produce obvious desensitization, while mu opioid receptor (MOR) activation induced obvious desensitization of mu receptor itself and also heterologous desensitization of KOR in PVT neurons. Together, our findings indicate that Dyn-A activates KOR and inhibits aPVT neurons in mice at various ages especially around puberty, suggesting a possible role of KOR in regulating aPVT-related brain function including stress response and drug-seeking behavior during adolescence. PMID:26056031

  1. Opening of pannexin- and connexin-based channels increases the excitability of nodose ganglion sensory neurons.

    PubMed

    Retamal, Mauricio A; Alcayaga, Julio; Verdugo, Christian A; Bultynck, Geert; Leybaert, Luc; Sáez, Pablo J; Fernández, Ricardo; León, Luis E; Sáez, Juan C

    2014-01-01

    Satellite glial cells (SGCs) are the main glia in sensory ganglia. They surround neuronal bodies and form a cap that prevents the formation of chemical or electrical synapses between neighboring neurons. SGCs have been suggested to establish bidirectional paracrine communication with sensory neurons. However, the molecular mechanism involved in this cellular communication is unknown. In the central nervous system (CNS), astrocytes present connexin43 (Cx43) hemichannels and pannexin1 (Panx1) channels, and the opening of these channels allows the release of signal molecules, such as ATP and glutamate. We propose that these channels could play a role in glia-neuron communication in sensory ganglia. Therefore, we studied the expression and function of Cx43 and Panx1 in rat and mouse nodose-petrosal-jugular complexes (NPJcs) using confocal immunofluorescence, molecular and electrophysiological techniques. Cx43 and Panx1 were detected in SGCs and in sensory neurons, respectively. In the rat and mouse, the electrical activity of vagal nerve increased significantly after nodose neurons were exposed to a Ca(2+)/Mg(2+)-free solution, a condition that increases the open probability of Cx hemichannels. This response was partially mimicked by a cell-permeable peptide corresponding to the last 10 amino acids of Cx43 (TAT-Cx43CT). Enhanced neuronal activity was reduced by Cx hemichannel, Panx1 channel and P2X7 receptor blockers. Moreover, the role of Panx1 was confirmed in NPJc, because in those from Panx1 knockout mice showed a reduced increase of neuronal activity induced by Ca(2+)/Mg(2+)-free extracellular conditions. The data suggest that Cx hemichannels and Panx channels serve as paracrine communication pathways between SGCs and neurons by modulating the excitability of sensory neurons. PMID:24999316

  2. Opening of pannexin- and connexin-based channels increases the excitability of nodose ganglion sensory neurons

    PubMed Central

    Retamal, Mauricio A.; Alcayaga, Julio; Verdugo, Christian A.; Bultynck, Geert; Leybaert, Luc; Sáez, Pablo J.; Fernández, Ricardo; León, Luis E.; Sáez, Juan C.

    2014-01-01

    Satellite glial cells (SGCs) are the main glia in sensory ganglia. They surround neuronal bodies and form a cap that prevents the formation of chemical or electrical synapses between neighboring neurons. SGCs have been suggested to establish bidirectional paracrine communication with sensory neurons. However, the molecular mechanism involved in this cellular communication is unknown. In the central nervous system (CNS), astrocytes present connexin43 (Cx43) hemichannels and pannexin1 (Panx1) channels, and the opening of these channels allows the release of signal molecules, such as ATP and glutamate. We propose that these channels could play a role in glia-neuron communication in sensory ganglia. Therefore, we studied the expression and function of Cx43 and Panx1 in rat and mouse nodose-petrosal-jugular complexes (NPJcs) using confocal immunofluorescence, molecular and electrophysiological techniques. Cx43 and Panx1 were detected in SGCs and in sensory neurons, respectively. In the rat and mouse, the electrical activity of vagal nerve increased significantly after nodose neurons were exposed to a Ca2+/Mg2+-free solution, a condition that increases the open probability of Cx hemichannels. This response was partially mimicked by a cell-permeable peptide corresponding to the last 10 amino acids of Cx43 (TAT-Cx43CT). Enhanced neuronal activity was reduced by Cx hemichannel, Panx1 channel and P2X7 receptor blockers. Moreover, the role of Panx1 was confirmed in NPJc, because in those from Panx1 knockout mice showed a reduced increase of neuronal activity induced by Ca2+/Mg2+-free extracellular conditions. The data suggest that Cx hemichannels and Panx channels serve as paracrine communication pathways between SGCs and neurons by modulating the excitability of sensory neurons. PMID:24999316

  3. Acute lipopolysaccharide exposure facilitates epileptiform activity via enhanced excitatory synaptic transmission and neuronal excitability in vitro

    PubMed Central

    Gao, Fei; Liu, Zhiqiang; Ren, Wei; Jiang, Wen

    2014-01-01

    Growing evidence indicates brain inflammation has been involved in the genesis of seizures. However, the direct effect of acute inflammation on neuronal circuits is not well known. Lipopolysaccharide (LPS) has been used extensively to stimulate brain inflammatory responses both in vivo and in vitro. Here, we observed the contribution of inflammation induced by 10 μg/mL LPS to the excitability of neuronal circuits in acute hippocampal slices. When slices were incubated with LPS for 30 minutes, significant increased concentration of tumor necrosis factor α and interleukin 1β were detected by enzyme-linked immunosorbent assay. In electrophysiological recordings, we found that frequency of epileptiform discharges and spikes per burst increased 30 minutes after LPS application. LPS enhanced evoked excitatory postsynaptic currents but did not modify evoked inhibitory postsynaptic currents. In addition, exposure to LPS enhanced the excitability of CA1 pyramidal neurons, as demonstrated by a decrease in rheobase and an increase in action potential frequency elicited by depolarizing current injection. Our observations suggest that acute inflammation induced by LPS facilitates epileptiform activity in vitro and that enhancement of excitatory synaptic transmission and neuronal excitability may contribute to this facilitation. These results may provide new clues for treating seizures associated with brain inflammatory disease. PMID:25170268

  4. Intrinsic excitability state of local neuronal population modulates signal propagation in feed-forward neural networks.

    PubMed

    Han, Ruixue; Wang, Jiang; Yu, Haitao; Deng, Bin; Wei, Xilei; Qin, Yingmei; Wang, Haixu

    2015-04-01

    Reliable signal propagation across distributed brain areas is an essential requirement for cognitive function, and it has been investigated extensively in computational studies where feed-forward network (FFN) is taken as a generic model. But it is still unclear how distinct local network states, which are intrinsically generated by synaptic interactions within each layer, would affect the ability of FFN to transmit information. Here we investigate the impact of such network states on propagating transient synchrony (synfire) and firing rate by a combination of numerical simulations and analytical approach. Specifically, local network dynamics is attributed to the competition between excitatory and inhibitory neurons within each layer. Our results show that concomitant with different local network states, the performance of signal propagation differs dramatically. For both synfire propagation and firing rate propagation, there exists an optimal local excitability state, respectively, that optimizes the performance of signal propagation. Furthermore, we find that long-range connections strongly change the dependence of spiking activity propagation on local network state and propose that these two factors work jointly to determine information transmission across distributed networks. Finally, a simple mean field approach that bridges response properties of long-range connectivity and local subnetworks is utilized to reveal the underlying mechanism. PMID:25933656

  5. Intrinsic excitability state of local neuronal population modulates signal propagation in feed-forward neural networks

    NASA Astrophysics Data System (ADS)

    Han, Ruixue; Wang, Jiang; Yu, Haitao; Deng, Bin; Wei, Xilei; Qin, Yingmei; Wang, Haixu

    2015-04-01

    Reliable signal propagation across distributed brain areas is an essential requirement for cognitive function, and it has been investigated extensively in computational studies where feed-forward network (FFN) is taken as a generic model. But it is still unclear how distinct local network states, which are intrinsically generated by synaptic interactions within each layer, would affect the ability of FFN to transmit information. Here we investigate the impact of such network states on propagating transient synchrony (synfire) and firing rate by a combination of numerical simulations and analytical approach. Specifically, local network dynamics is attributed to the competition between excitatory and inhibitory neurons within each layer. Our results show that concomitant with different local network states, the performance of signal propagation differs dramatically. For both synfire propagation and firing rate propagation, there exists an optimal local excitability state, respectively, that optimizes the performance of signal propagation. Furthermore, we find that long-range connections strongly change the dependence of spiking activity propagation on local network state and propose that these two factors work jointly to determine information transmission across distributed networks. Finally, a simple mean field approach that bridges response properties of long-range connectivity and local subnetworks is utilized to reveal the underlying mechanism.

  6. 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

  7. Analysis of Dominant Mutations Affecting Muscle Excitation in Caenorhabditis Elegans

    PubMed Central

    Reiner, D. J.; Weinshenker, D.; Thomas, J. H.

    1995-01-01

    We examined mutations that disrupt muscle activation in Caenorhabditis elegans. Fifteen of 17 of these genes were identified previously and we describe new mutations in three of them. We also describe mutations in two new genes, exp-3 and exp-4. We assessed the degree of defect in pharyngeal, body-wall, egg-laying, and enteric muscle activation in animals mutant for each gene. Mutations in all 17 genes are semidominant and, in cases that could be tested, appear to be gain-of-function. Based on their phenotypes, the genes fall into three broad categories: mutations in 11 genes cause defective muscle activation, mutations in four genes cause hyperactivated muscle, and mutations in two genes cause defective activation in some muscle types and hyperactivation in others. In all testable cases, the mutations blocked response to pharmacological activators of egg laying, but did not block muscle activation by irradiation with a laser microbeam. The data suggest that these mutations affect muscle excitation, but not the capacity of the muscle fibers to contract. For most of the genes, apparent loss-of-function mutants have a grossly wild-type phenotype. These observations suggest that there is a large group of genes that function in muscle excitation that can be identified primarily by dominant mutations. PMID:8582640

  8. 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.

  9. Vasopressin indirectly excites dorsal raphe serotonin neurons through activation of the vasopressin1A receptor.

    PubMed

    Rood, B D; Beck, S G

    2014-02-28

    The neuropeptide vasopressin (AVP; arginine-vasopressin) is produced in a handful of brain nuclei located in the hypothalamus and extended amygdala and is released both peripherally as a hormone and within the central nervous system as a neurotransmitter. Central projections have been associated with a number of functions including regulation of physiological homeostasis, control of circadian rhythms, and modulation of social behavior. The AVP neurons located in the bed nucleus of the stria terminalis and medial amygdala (i.e., extended amygdala) in particular have been associated with affiliative social behavior in multiple species. It was recently demonstrated that in the mouse AVP projections emanating from extended amygdala neurons innervate a number of forebrain and midbrain brain regions including the dorsal raphe nucleus (DR), the site of origin of most forebrain-projecting serotonin neurons. Based on the presence of AVP fibers in the DR, we hypothesized that AVP would alter the physiology of serotonin neurons via AVP 1A receptor (V1AR) activation. Using whole-cell electrophysiology techniques, we found that AVP increased the frequency and amplitude of excitatory post-synaptic currents (EPSCs) in serotonin neurons of male mice. The indirect stimulation of serotonin neurons was AMPA/kainate receptor dependent and blocked by the sodium channel blocker tetrodotoxin, suggesting an effect of AVP on glutamate neurons. Further, the increase in EPSC frequency induced by AVP was blocked by selective V1AR antagonists. Our data suggest that AVP had an excitatory influence on serotonin neurons. This work highlights a new target (i.e., V1AR) for manipulating serotonin neuron excitability. In light of our data, we propose that some of the diverse effects of AVP on physiology and behavior, including social behavior, may be due to activation of the DR serotonin system. PMID:24345477

  10. Abrupt and gradual transitions between low and hyperexcited firing frequencies in neuronal models with fast synaptic excitation: A comparative study

    NASA Astrophysics Data System (ADS)

    Rotstein, Horacio G.

    2013-12-01

    Hyperexcitability of neuronal networks is one of the hallmarks of epileptic brain seizure generation, and results from a net imbalance between excitation and inhibition that promotes excessive abnormal firing frequencies. The transition between low and high firing frequencies as the levels of recurrent AMPA excitation change can occur either gradually or abruptly. We used modeling, numerical simulations, and dynamical systems tools to investigate the biophysical and dynamic mechanisms that underlie these two identified modes of transition in recurrently connected neurons via AMPA excitation. We compare our results and demonstrate that these two modes of transition are qualitatively different and can be linked to different intrinsic properties of the participating neurons.

  11. Activity-dependent serotonergic excitation of callosal projection neurons in the mouse prefrontal cortex

    PubMed Central

    Stephens, Emily K.; Avesar, Daniel; Gulledge, Allan T.

    2014-01-01

    Layer 5 pyramidal neurons (L5PNs) in the mouse prefrontal cortex respond to serotonin (5-HT) according to their long-distance axonal projections; 5-HT1A (1A) receptors mediate inhibitory responses in corticopontine (CPn) L5PNs, while 5-HT2A (2A) receptors can enhance action potential (AP) output in callosal/commissural (COM) L5PNs, either directly (in “COM-excited” neurons), or following brief 1A-mediated inhibition (in “COM-biphasic” neurons). Here we compare the impact of 5-HT on the excitability of CPn and COM L5PNs experiencing variable excitatory drive produced by current injection (DC current or simulated synaptic current) or with exogenous glutamate. 5-HT delivered at resting membrane potentials, or paired with subthreshold depolarizing input, hyperpolarized CPn and COM-biphasic L5PNs and failed to promote AP generation in COM-excited L5PNs. Conversely, when paired with suprathreshold excitatory drive generating multiple APs, 5-HT suppressed AP output in CPn L5PNs, enhanced AP generation in COM-excited L5PNs, and generated variable responses in COM-biphasic L5PNs. While COM-excited neurons failed to respond to 5-HT in the presence of a 2A receptor antagonist, 32% of CPn neurons exhibited 2A-dependent excitation following blockade of 1A receptors. The presence of pharmacologically revealed 2A receptors in CPn L5PNs was correlated with the duration of 1A-mediated inhibition, yet biphasic excitatory responses to 5-HT were never observed, even when 5-HT was paired with strong excitatory drive. Our results suggest that 2A receptors selectively amplify the output of COM L5PNs experiencing suprathreshold excitatory drive, while shaping the duration of 1A-mediated inhibition in a subset of CPn L5PNs. Activity-dependent serotonergic excitation of COM L5PNs, combined with 1A-mediated inhibition of CPn and COM-biphasic L5PNs, may facilitate executive function by focusing network activity within cortical circuits subserving the most appropriate behavioral output

  12. Transportation in the Interstitial Space of the Brain Can Be Regulated by Neuronal Excitation

    NASA Astrophysics Data System (ADS)

    Shi, Chunyan; Lei, Yiming; Han, Hongbin; Zuo, Long; Yan, Junhao; He, Qingyuan; Yuan, Lan; Liu, Huipo; Xu, Ge; Xu, Weiguo

    2015-12-01

    The transportation of substances in the interstitial space (ISS) is crucial for the maintenance of brain homeostasis, however its link to neuronal activity remains unclear. Here, we report a marked reduction in substance transportation in the ISS after neuronal excitation. Using a tracer-based method, water molecules in the interstitial fluid (ISF) could be specifically visualized in magnetic resonance (MR) imaging. We first observed the flow of ISF in the thalamus and caudate nucleus of a rat. The ISF flow was then modulated using a painful stimulation model. We demonstrated that the flow of ISF slowed significantly following neuronal activity in the thalamus. This reduction in ISF flow continued for hours and was not accompanied by slow diffusion into the ISS. This observation suggests that the transportation of substances into the ISS can be regulated with a selective external stimulation.

  13. Transportation in the Interstitial Space of the Brain Can Be Regulated by Neuronal Excitation

    PubMed Central

    Shi, Chunyan; Lei, Yiming; Han, Hongbin; Zuo, Long; Yan, Junhao; He, Qingyuan; Yuan, Lan; Liu, Huipo; Xu, Ge; Xu, Weiguo

    2015-01-01

    The transportation of substances in the interstitial space (ISS) is crucial for the maintenance of brain homeostasis, however its link to neuronal activity remains unclear. Here, we report a marked reduction in substance transportation in the ISS after neuronal excitation. Using a tracer-based method, water molecules in the interstitial fluid (ISF) could be specifically visualized in magnetic resonance (MR) imaging. We first observed the flow of ISF in the thalamus and caudate nucleus of a rat. The ISF flow was then modulated using a painful stimulation model. We demonstrated that the flow of ISF slowed significantly following neuronal activity in the thalamus. This reduction in ISF flow continued for hours and was not accompanied by slow diffusion into the ISS. This observation suggests that the transportation of substances into the ISS can be regulated with a selective external stimulation. PMID:26631412

  14. Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity

    PubMed Central

    Kuba, Hiroshi; Yamada, Rei; Ishiguro, Go; Adachi, Ryota

    2015-01-01

    Structural plasticity of the axon initial segment (AIS), the trigger zone of neurons, is a powerful means for regulating neuronal activity. Here, we show that AIS plasticity is not limited to structural changes; it also occurs as changes in ion-channel expression, which substantially augments the efficacy of regulation. In the avian cochlear nucleus, depriving afferent inputs by removing cochlea elongated the AIS, and simultaneously switched the dominant Kv channels at the AIS from Kv1.1 to Kv7.2. Due to the slow activation kinetics of Kv7.2, the redistribution of the Kv channels reduced the shunting conductance at the elongated AIS during the initiation of action potentials and effectively enhanced the excitability of the deprived neurons. The results indicate that the functional plasticity of the AIS works cooperatively with the structural plasticity and compensates for the loss of afferent inputs to maintain the homeostasis of auditory circuits after hearing loss by cochlea removal. PMID:26581625

  15. Developmental changes in membrane excitability and morphology of neurons in the nucleus angularis of the chicken

    PubMed Central

    Fukui, Iwao; Ohmori, Harunori

    2003-01-01

    In order to understand how sound intensity information is extracted and processed in the auditory nuclei, we investigated the neuronal excitability in the nucleus angularis (NA) of the chicken (P0–5) and the chicken embryo (E16–21). In embryos, neurons fired basically in three patterns in response to current injections: the onset pattern (19 %), the tonic pattern (52 %) and the pause pattern (29 %). After hatching, neurons fired either in the tonic pattern (83 %) or in the onset pattern (17 %). In both pre- and post-hatch periods, multiple firing neurons (tonic and pause) increased the maximum rate of rise of the action potential 2.6-fold, the fall 3.9-fold, and the maximum firing frequency 4-fold, and shifted the threshold potential to be more negative. After hatching, the firing frequency of tonic neurons reached a maximum at about 650 Hz. Application of TEA (1 mm) reduced the firing frequency, broadened action potentials and reduced the maximum rate of fall, but the threshold current was not changed. Dendrotoxin-I (DTX, 100 nm) reduced the threshold current. Application of DTX induced the onset neuron to fire repetitively. Branching patterns of auditory nerve fibres (ANFs) in NA were visualized by labelling with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (Di-I) placed within the cochlea. Di-I placed near the apex of the cochlea labelled the ventral part of the NA, and Di-I placed in the base labelled the dorso-lateral part. Tonic neurons labelled with biocytin extended dendrites in parallel with the projection of ANFs in the nucleus after hatching. ANF activity of a limited range of characteristic sound frequencies is thought to be extracted by tonic neurons and encoded into firing frequencies proportional to the strength of the input. PMID:12576492

  16. Reaction-diffusion waves in neuronal tissue and the window of cortical excitability

    NASA Astrophysics Data System (ADS)

    Dahlem, M. A.; Müller, S. C.

    2004-07-01

    Spreading depression (SD) is a dynamic wave phenomenon occurring in all gray matter regions of the central nervous systems (CNS). It is characterized by a sudden breakdown of neuronal activity and accompanied by a massive influx and efflux of ions across the membrane of neurons. The retina is a constituent of the CNS in which one can easily observe the dynamic behavior of the SD wave fronts, because SD changes the optical properties of the tissue. There is ample evidence that SD belongs to the self-organization processes due to the coupling of reaction with diffusion in excitable medium. It is assumed that the occurrence of SD is associated with some neurological symptoms of migraine with aura. A frequently reported aura symptom is a traveling visual blind region (scotoma) with a preceding figure of scintillating line segments. The characteristic form and development of the scotoma suggests that the underlying phenomenon is a wave propagating through the primary visual cortex, most likely the cortical spreading depression. In this article we discuss similarities between SD waves and the migraine aura on the basis of properties of reaction-diffusion waves known from other excitable media. In particular, the propagation velocities, the shape and the dynamics of the waves are compared with each other. We find that the assumption of the neuronal tissue to be in a state of only weak excitability explains some properties of the migraine aura, such as the confined appearance and its propagation with a stable velocity.

  17. Genetic Background Modulates Impaired Excitability of Inhibitory Neurons in a Mouse Model of Dravet Syndrome

    PubMed Central

    Rubinstein, Moran; Westenbroek, Ruth E.; Yu, Frank H.; Jones, Christina J.; Scheuer, Todd; Catterall, William A.

    2014-01-01

    Dominant loss-of-function mutations in voltage-gated sodium channel NaV1.1 cause Dravet Syndrome, an intractable childhood-onset epilepsy. NaV1.1+/− Dravet Syndrome mice in C57BL/6 genetic background exhibit severe seizures, cognitive and social impairments, and premature death. Here we show that Dravet Syndrome mice in pure 129/SvJ genetic background have many fewer seizures and much less premature death than in pure C57BL/6 background. These mice also have a higher threshold for thermally induced seizures, fewer myoclonic seizures, and no cognitive impairment, similar to patients with Genetic Epilepsy with Febrile Seizures Plus. Consistent with this mild phenotype, mutation of NaV1.1 channels has much less physiological effect on neuronal excitability in 129/SvJ mice. In hippocampal slices, the excitability of CA1 Stratum Oriens interneurons is selectively impaired, while the excitability of CA1 pyramidal cells is unaffected. NaV1.1 haploinsufficiency results in increased rheobase and threshold for action potential firing and impaired ability to sustain high-frequency firing. Moreover, deletion of NaV1.1 markedly reduces the amplification and integration of synaptic events, further contributing to reduced excitability of interneurons. Excitability is less impaired in inhibitory neurons of Dravet Syndrome mice in 129/SvJ genetic background. Because specific deletion of NaV1.1 in forebrain GABAergic interneuons is sufficient to cause the symptoms of Dravet Syndrome in mice, our results support the conclusion that the milder phenotype in 129/SvJ mice is caused by lesser impairment of sodium channel function and electrical excitability in their forebrain interneurons. This mild impairment of excitability of interneurons leads to a milder disease phenotype in 129/SvJ mice, similar to Genetic Epilepsy with Febrile Seizures Plus in humans. PMID:25281316

  18. Stim and Orai proteins in neuronal Ca2+ signaling and excitability

    PubMed Central

    Moccia, Francesco; Zuccolo, Estella; Soda, Teresa; Tanzi, Franco; Guerra, Germano; Mapelli, Lisa; Lodola, Francesco; D’Angelo, Egidio

    2015-01-01

    Stim1 and Orai1 are ubiquitous proteins that have long been known to mediate Ca2+ release-activated Ca2+ (CRAC) current (ICRAC) and store-operated Ca2+ entry (SOCE) only in non-excitable cells. SOCE is activated following the depletion of the endogenous Ca2+ stores, which are mainly located within the endoplasmic reticulum (ER), to replete the intracellular Ca2+ reservoir and engage specific Ca2+-dependent processes, such as proliferation, migration, cytoskeletal remodeling, and gene expression. Their paralogs, Stim2, Orai2 and Orai3, support SOCE in heterologous expression systems, but their physiological role is still obscure. Ca2+ inflow in neurons has long been exclusively ascribed to voltage-operated and receptor-operated channels. Nevertheless, recent work has unveiled that Stim1–2 and Orai1-2, but not Orai3, proteins are also expressed and mediate SOCE in neurons. Herein, we survey current knowledge about the neuronal distribution of Stim and Orai proteins in rodent and human brains; we further discuss that Orai2 is the main pore-forming subunit of CRAC channels in central neurons, in which it may be activated by either Stim1 or Stim2 depending on species, brain region and physiological stimuli. We examine the functions regulated by SOCE in neurons, where this pathway is activated under resting conditions to refill the ER, control spinogenesis and regulate gene transcription. Besides, we highlighted the possibility that SOCE also controls neuronal excitation and regulate synaptic plasticity. Finally, we evaluate the involvement of Stim and Orai proteins in severe neurodegenerative and neurological disorders, such as Alzheimer’s disease and epilepsy. PMID:25964739

  19. Phasic, suprathreshold excitation and sustained inhibition underlie neuronal selectivity for short-duration sounds.

    PubMed

    Alluri, Rishi K; Rose, Gary J; Hanson, Jessica L; Leary, Christopher J; Vasquez-Opazo, Gustavo A; Graham, Jalina A; Wilkerson, Jeremy

    2016-03-29

    Sound duration is important in acoustic communication, including speech recognition in humans. Although duration-selective auditory neurons have been found, the underlying mechanisms are unclear. To investigate these mechanisms we combined in vivo whole-cell patch recordings from midbrain neurons, extraction of excitatory and inhibitory conductances, and focal pharmacological manipulations. We show that selectivity for short-duration stimuli results from integration of short-latency, sustained inhibition with delayed, phasic excitation; active membrane properties appeared to amplify responses to effective stimuli. Blocking GABAAreceptors attenuated stimulus-related inhibition, revealed suprathreshold excitation at all stimulus durations, and decreased short-pass selectivity without changing resting potentials. Blocking AMPA and NMDA receptors to attenuate excitation confirmed that inhibition tracks stimulus duration and revealed no evidence of postinhibitory rebound depolarization inherent to coincidence models of duration selectivity. These results strongly support an anticoincidence mechanism of short-pass selectivity, wherein inhibition and suprathreshold excitation show greatest temporal overlap for long duration stimuli. PMID:26976602

  20. Markers of pathological excitability derived from principal dynamic modes of hippocampal neurons

    NASA Astrophysics Data System (ADS)

    Kang, Eunji E.; Zalay, Osbert C.; Serletis, Demitre; Carlen, Peter L.; Bardakjian, Berj L.

    2012-10-01

    Transformation of principal dynamic modes (PDMs) under epileptogenic conditions was investigated by computing the Volterra kernels in a rodent epilepsy model derived from a mouse whole hippocampal preparation, where epileptogenesis was induced by altering the concentrations of Mg2 + and K+ of the perfusate for different levels of excitability. Both integrating and differentiating PDMs were present in the neuronal dynamics, and both of them increased in absolute magnitude for increased excitability levels. However, the integrating PDMs dominated at all levels of excitability in terms of their relative contributions to the overall response, whereas the dominant frequency responses of the differentiating PDMs were shifted to higher ranges under epileptogenic conditions, from ripple activities (75-200 Hz) to fast ripple activities (200-500 Hz).

  1. Markers of pathological excitability derived from principal dynamic modes of hippocampal neurons.

    PubMed

    Kang, Eunji E; Zalay, Osbert C; Serletis, Demitre; Carlen, Peter L; Bardakjian, Berj L

    2012-10-01

    Transformation of principal dynamic modes (PDMs) under epileptogenic conditions was investigated by computing the Volterra kernels in a rodent epilepsy model derived from a mouse whole hippocampal preparation, where epileptogenesis was induced by altering the concentrations of Mg(2 +) and K(+) of the perfusate for different levels of excitability. Both integrating and differentiating PDMs were present in the neuronal dynamics, and both of them increased in absolute magnitude for increased excitability levels. However, the integrating PDMs dominated at all levels of excitability in terms of their relative contributions to the overall response, whereas the dominant frequency responses of the differentiating PDMs were shifted to higher ranges under epileptogenic conditions, from ripple activities (75-200 Hz) to fast ripple activities (200-500 Hz). PMID:22871606

  2. Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons.

    PubMed

    Robarge, Jason D; Duarte, Djane B; Shariati, Behzad; Wang, Ruizhong; Flockhart, David A; Vasko, Michael R

    2016-07-01

    Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000nmol of adenosine 5'-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats. PMID:27072527

  3. Long-term potentiation of neuronal excitation by neuron-glia interactions in the rat spinal dorsal horn.

    PubMed

    Ikeda, Hiroshi; Tsuda, Makoto; Inoue, Kazuhide; Murase, Kazuyuki

    2007-03-01

    By imaging neuronal excitation in rat spinal cord slices with a voltage-sensitive dye, we examined the role of glial cells in the P2X receptor agonist alphabeta-methylene ATP (alphabetameATP)-triggered long-term potentiation (LTP) in the dorsal horn. Bath application of alphabetameATP potentiated neuronal excitation in the superficial dorsal horn. The potentiation was inhibited in the presence of the P2X receptor antagonists TNP-ATP, PPADS and A-317491, and was not induced in slices taken from rats neonatally treated with capsaicin. These results suggest that alphabetameATP acts on P2X receptors, possibly P2X(3) and/or P2X(2/3), in capsaicin-sensitive primary afferent terminals. Furthermore, the potentiation was inhibited by treatment with the glial metabolism inhibitor monofluoroacetic acid. Results obtained with the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580, tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, and antibodies to TNF-alpha and IL-6, as well as by double immunolabelling of activated p38 MAPK with markers of astrocytes and microglia, demonstrated that alphabetameATP activated p38 MAPK in astrocytes, and that the presence of proinflammatory cytokines and p38 MAPK activation were necessary for the induction of alphabetameATP-triggered LTP. These findings indicate that glial cells contribute to the alphabetameATP-induced LTP, which might be part of a cellular mechanism for the induction of persistent pain. PMID:17425556

  4. Disruption of Slc4a10 augments neuronal excitability and modulates synaptic short-term plasticity

    PubMed Central

    Sinning, Anne; Liebmann, Lutz; Hübner, Christian A.

    2015-01-01

    Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. Slc4a10 knockout (KO) mice have collapsed brain ventricles and display an increased seizure threshold, while heterozygous deletions in man have been associated with idiopathic epilepsy and other neurological symptoms. To further characterize the role of Slc4a10 for network excitability, we compared input-output relations as well as short and long term changes of evoked field potentials in Slc4a10 KO and wildtype (WT) mice. While responses of CA1 pyramidal neurons to stimulation of Schaffer collaterals were increased in Slc4a10 KO mice, evoked field potentials did not differ between genotypes in the stratum radiatum or the neocortical areas analyzed. Paired pulse facilitation was diminished in the hippocampus upon disruption of Slc4a10. In the neocortex paired pulse depression was increased. Though short term plasticity is modulated via Slc4a10, long term potentiation appears independent of Slc4a10. Our data support that Slc4a10 dampens neuronal excitability and thus sheds light on the pathophysiology of SLC4A10 associated pathologies. PMID:26136660

  5. A characterization of the effects on neuronal excitability due to prolonged microstimulation with chronically implanted microelectrodes.

    PubMed

    McCreery, D B; Yuen, T G; Agnew, W F; Bullara, L A

    1997-10-01

    Localized, long-lasting stimulation-induced depression of neuronal excitability (SIDNE) is a consequence of prolonged, high-frequency microstimulation in the central nervous system (CNS). It represents a persisting refractory state in the neurons and axons near the stimulating microelectrode, that occurs in the absence of histologically detectable tissue injury. It does not involve a change in synaptic efficacy and, in this respect, it differs from the more familiar phenomenon of long-term depression (LTD). Although SIDNE is ultimately reversible (after several days), it must be taken into account in the design of neural prostheses based on microstimulation in the central nervous system and in animal studies that require prolonged microstimulation in the CNS. In this study, we have characterized the phenomenon, using as the paradigm, iridium microelectrodes implanted chronically in the cat's posteroventral cochlear nucleus. Although the SIDNE may persist for several days after the end of the stimulation protocol, it does not become more severe from day to day when the stimulation protocol is repeated on successive days. The severity of the SIDNE is strongly dependent upon both the instantaneous frequency and the duty cycle of the electrical stimulation. The character of the SIDNE, including its localization to the immediate vicinity of the stimulating microelectrodes, suggests that the phenomenon is a direct consequence of the prolonged electrical excitation of the neurons close to the microelectrode. The problem of designing microstimulation systems that allow high-frequency stimulation of a neural substrate, while minimizing SIDNE are discussed. PMID:9311162

  6. Prenatal Stress Alters the Development of Socioemotional Behavior and Amygdala Neuron Excitability in Rats

    PubMed Central

    Ehrlich, David E; Rainnie, Donald G

    2015-01-01

    Prenatal stress (PS) is a risk factor for neurodevelopmental disorders with diverse ages of onset and socioemotional symptoms. Some PS-linked disorders involve characteristic social deficits, such as autism spectrum disorders and schizophrenia, but PS also promotes anxiety disorders. We propose the diversity of symptoms following PS arises from perturbations to early brain development. To this end, we characterized the effects of PS on the developmental trajectory of physiology of the amygdala, a late-developing center for socioemotional control. We found that PS dampened socioemotional behavior and reduced amygdala neuron excitability in offspring during infancy (at postnatal days (P)10, 14, 17 and 21), preadolescence (day 28), and adulthood (day 60). PS offspring in infancy produced fewer isolation-induced vocalizations and in adulthood exhibited less anxiety-like behavior and deficits in social interaction. PS neurons had a more hyperpolarized resting membrane potential from infancy to adulthood and produced fewer action potentials. Moreover, adult amygdala neurons from PS animals expressed larger action potential afterhyperpolarizations and H-current relative to controls, further limiting excitability. Our results suggest that PS can suppress socioemotional behavior throughout development and produce age-specific alterations to amygdala physiology. PMID:25716930

  7. Brain excitability and connectivity of neuronal assemblies in Alzheimer's disease: from animal models to human findings.

    PubMed

    D'Amelio, Marcello; Rossini, Paolo Maria

    2012-10-01

    The human brain contains about 100 billion neurons forming an intricate network of innumerable connections, which continuously adapt and rewire themselves following inputs from external and internal environments as well as the physiological synaptic, dendritic and axonal sculpture during brain maturation and throughout the life span. Growing evidence supports the idea that Alzheimer's disease (AD) targets selected and functionally connected neuronal networks and, specifically, their synaptic terminals, affecting brain connectivity well before producing neuronal loss and compartmental atrophy. The understanding of the molecular mechanisms underlying the dismantling of neuronal circuits and the implementation of 'clinically oriented' methods to map-out the dynamic interactions amongst neuronal assemblies will enhance early/pre-symptomatic diagnosis and monitoring of disease progression. More important, this will open the avenues to innovative treatments, bridging the gap between molecular mechanisms and the variety of symptoms forming disease phenotype. In the present review a set of evidence supports the idea that altered brain connectivity, exhausted neural plasticity and aberrant neuronal activity are facets of the same coin linked to age-related neurodegenerative dementia of Alzheimer type. Investigating their respective roles in AD pathophysiology will help in translating findings from basic research to clinical applications. PMID:22789698

  8. Pulsed infrared radiation excites cultured neonatal spiral and vestibular ganglion neurons by modulating mitochondrial calcium cycling

    PubMed Central

    Lumbreras, Vicente; Bas, Esperanza; Gupta, Chhavi

    2014-01-01

    Cochlear implants are currently the most effective solution for profound sensorineural hearing loss, and vestibular prostheses are under development to treat bilateral vestibulopathies. Electrical current spread in these neuroprostheses limits channel independence and, in some cases, may impair their performance. In comparison, optical stimuli that are spatially confined may result in a significant functional improvement. Pulsed infrared radiation (IR) has previously been shown to elicit responses in neurons. This study analyzes the response of neonatal rat spiral and vestibular ganglion neurons in vitro to IR (wavelength = 1,863 nm) using Ca2+ imaging. Both types of neurons responded consistently with robust intracellular Ca2+ ([Ca2+]i) transients that matched the low-frequency IR pulses applied (4 ms, 0.25–1 pps). Radiant exposures of ∼637 mJ/cm2 resulted in continual neuronal activation. Temperature or [Ca2+] variations in the media did not alter the IR-evoked transients, ruling out extracellular Ca2+ involvement or primary mediation by thermal effects on the plasma membrane. While blockage of Na+, K+, and Ca2+ plasma membrane channels did not alter the IR-evoked response, blocking of mitochondrial Ca2+ cycling with CGP-37157 or ruthenium red reversibly inhibited the IR-evoked [Ca2+]i transients. Additionally, the magnitude of the IR-evoked transients was dependent on ryanodine and cyclopiazonic acid-dependent Ca2+ release. These results suggest that IR modulation of intracellular calcium cycling contributes to stimulation of spiral and vestibular ganglion neurons. As a whole, the results suggest selective excitation of neurons in the IR beam path and the potential of IR stimulation in future auditory and vestibular prostheses. PMID:24920028

  9. Pulsed infrared radiation excites cultured neonatal spiral and vestibular ganglion neurons by modulating mitochondrial calcium cycling.

    PubMed

    Lumbreras, Vicente; Bas, Esperanza; Gupta, Chhavi; Rajguru, Suhrud M

    2014-09-15

    Cochlear implants are currently the most effective solution for profound sensorineural hearing loss, and vestibular prostheses are under development to treat bilateral vestibulopathies. Electrical current spread in these neuroprostheses limits channel independence and, in some cases, may impair their performance. In comparison, optical stimuli that are spatially confined may result in a significant functional improvement. Pulsed infrared radiation (IR) has previously been shown to elicit responses in neurons. This study analyzes the response of neonatal rat spiral and vestibular ganglion neurons in vitro to IR (wavelength = 1,863 nm) using Ca(2+) imaging. Both types of neurons responded consistently with robust intracellular Ca(2+) ([Ca(2+)]i) transients that matched the low-frequency IR pulses applied (4 ms, 0.25-1 pps). Radiant exposures of ∼637 mJ/cm(2) resulted in continual neuronal activation. Temperature or [Ca(2+)] variations in the media did not alter the IR-evoked transients, ruling out extracellular Ca(2+) involvement or primary mediation by thermal effects on the plasma membrane. While blockage of Na(+), K(+), and Ca(2+) plasma membrane channels did not alter the IR-evoked response, blocking of mitochondrial Ca(2+) cycling with CGP-37157 or ruthenium red reversibly inhibited the IR-evoked [Ca(2+)]i transients. Additionally, the magnitude of the IR-evoked transients was dependent on ryanodine and cyclopiazonic acid-dependent Ca(2+) release. These results suggest that IR modulation of intracellular calcium cycling contributes to stimulation of spiral and vestibular ganglion neurons. As a whole, the results suggest selective excitation of neurons in the IR beam path and the potential of IR stimulation in future auditory and vestibular prostheses. PMID:24920028

  10. Motivation and Affective Judgments Differentially Recruit Neurons in the Primate Dorsolateral Prefrontal and Anterior Cingulate Cortex

    PubMed Central

    Amemori, Ken-ichi; Amemori, Satoko

    2015-01-01

    The judgment of whether to accept or to reject an offer is determined by positive and negative affect related to the offer, but affect also induces motivational responses. Rewarding and aversive cues influence the firing rates of many neurons in primate prefrontal and cingulate neocortical regions, but it still is unclear whether neurons in these regions are related to affective judgment or to motivation. To address this issue, we recorded simultaneously the neuronal spike activities of single units in the dorsolateral prefrontal cortex (dlPFC) and the anterior cingulate cortex (ACC) of macaque monkeys as they performed approach–avoidance (Ap–Av) and approach–approach (Ap–Ap) decision-making tasks that can behaviorally dissociate affective judgment and motivation. Notably, neurons having activity correlated with motivational condition could be distinguished from neurons having activity related to affective judgment, especially in the Ap–Av task. Although many neurons in both regions exhibited similar, selective patterns of task-related activity, we found a larger proportion of neurons activated in low motivational conditions in the dlPFC than in the ACC, and the onset of this activity was significantly earlier in the dlPFC than in the ACC. Furthermore, the temporal onsets of affective judgment represented by neuronal activities were significantly slower in the low motivational conditions than in the other conditions. These findings suggest that motivation and affective judgment both recruit dlPFC and ACC neurons but with differential degrees of involvement and timing. PMID:25653353

  11. Motivation and affective judgments differentially recruit neurons in the primate dorsolateral prefrontal and anterior cingulate cortex.

    PubMed

    Amemori, Ken-ichi; Amemori, Satoko; Graybiel, Ann M

    2015-02-01

    The judgment of whether to accept or to reject an offer is determined by positive and negative affect related to the offer, but affect also induces motivational responses. Rewarding and aversive cues influence the firing rates of many neurons in primate prefrontal and cingulate neocortical regions, but it still is unclear whether neurons in these regions are related to affective judgment or to motivation. To address this issue, we recorded simultaneously the neuronal spike activities of single units in the dorsolateral prefrontal cortex (dlPFC) and the anterior cingulate cortex (ACC) of macaque monkeys as they performed approach-avoidance (Ap-Av) and approach-approach (Ap-Ap) decision-making tasks that can behaviorally dissociate affective judgment and motivation. Notably, neurons having activity correlated with motivational condition could be distinguished from neurons having activity related to affective judgment, especially in the Ap-Av task. Although many neurons in both regions exhibited similar, selective patterns of task-related activity, we found a larger proportion of neurons activated in low motivational conditions in the dlPFC than in the ACC, and the onset of this activity was significantly earlier in the dlPFC than in the ACC. Furthermore, the temporal onsets of affective judgment represented by neuronal activities were significantly slower in the low motivational conditions than in the other conditions. These findings suggest that motivation and affective judgment both recruit dlPFC and ACC neurons but with differential degrees of involvement and timing. PMID:25653353

  12. Alterations in CA1 pyramidal neuronal intrinsic excitability mediated by Ih channel currents in a rat model of amyloid beta pathology.

    PubMed

    Eslamizade, M J; Saffarzadeh, F; Mousavi, S M M; Meftahi, G H; Hosseinmardi, N; Mehdizadeh, M; Janahmadi, M

    2015-10-01

    Amyloid beta (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD) by changing the neuronal excitability. However, the cellular mechanisms by which accumulation of Aβ affects intrinsic neuronal properties are not well understood. The effect of bilateral intra-frontal cortex Aβ (1-42) peptide injection on the intrinsic excitability of hippocampal CA1 pyramidal neurons with particular focus on the contribution of hyperpolarization-activated (Ih) channel currents was examined using whole-cell patch-clamp recording. Passive avoidance memory impairment and morphological changes in rats receiving intra-frontal Aβ treatment were observed, which was associated with significant changes both in passive and active intrinsic electrical membrane properties of CA1 pyramidal neurons. Electrophysiological recording showed a significant decrease in neuronal excitability associated with an augmentation in the first spike after-hyperpolarization (AHP) amplitude. In addition, the depolarizing sag voltage was altered in neurons recorded from Aβ-treated group. In voltage-clamp condition, a hyperpolarizing activated inward current sensitive to ZD7288 and capsaicin was significantly increased in neurons from Aβ-treated rats. The Ih current density was increased and the activation curve was shifted toward less negative potential in the Aβ-treated group as compared to control group. The enhancing effect of Aβ treatment on Ih current was confirmed by showing upregulation of the mRNA of HCN1 channel in the CA1 pyramidal layer of hippocampi. These findings suggest the contribution of Ih and possibly TRPV1 channel currents to the changes induced by Aβ treatment in the intrinsic membrane properties, which, in turn, may provide therapeutic targets for treatment of AD. PMID:26254243

  13. Dual role of medial A10 dopamine neurons in affective encoding.

    PubMed

    Liu, Zhong-Hua; Shin, Rick; Ikemoto, Satoshi

    2008-11-01

    Increasing evidence suggests that the activation of medial A10 neurons mediates positive affective encoding. However, little is known about the functions of the inhibition of midbrain dopamine neurons. Here we show evidence suggesting that the inhibition of medial A10 neurons mediates a negative affective state, leading to negative affective encoding, whereas blunting the activation of medial A10 neurons disrupts positive affective encoding involving food reward. We used a microinjection procedure, in which the D(2) dopamine receptor agonist quinpirole was administered into the cell body region of the dopamine neurons, a procedure that reduces dopamine cell firing. Microinjections of quinpirole into the posteromedial ventral tegmental area, but not its more lateral counterparts, led to conditioned place aversion. Quinpirole administration to this site also decreased food intake and basal dopamine concentration in the ventromedial striatum, a major projection area of medial A10 neurons. In addition, moderate quinpirole doses that did not lead to conditioned place aversion or disrupt food intake abolished food-conditioned place preference, suggesting that blunting dopamine impulse activity in response to food reward disrupts positive affective encoding in associated external stimuli. Our data support the hypothesis that activation of medial A10 dopamine neurons mediates a positive affective state, leading to positive affective encoding, while their inhibition mediates a negative affective state, leading to negative affective encoding. Together with previous findings, we propose that medial A10 neurons are an important component of the mechanism via which animals learn to avoid negative incentive stimuli. PMID:18256592

  14. Intrinsic excitability varies by sex in prepubertal striatal medium spiny neurons

    PubMed Central

    Dorris, David M.; Cao, Jinyan; Willett, Jaime A.; Hauser, Caitlin A.

    2014-01-01

    Sex differences in neuron electrophysiological properties were traditionally associated with brain regions directly involved in reproduction in adult, postpubertal animals. There is growing acknowledgement that sex differences can exist in other developmental periods and brain regions as well. This includes the dorsal striatum (caudate/putamen), which shows robust sex differences in gene expression, neuromodulator action (including dopamine and 17β-estradiol), and relevant sensorimotor behaviors and pathologies such as the responsiveness to drugs of abuse. Here we examine whether these sex differences extend to striatal neuron electrophysiology. We test the hypothesis that passive and active medium spiny neuron (MSN) electrophysiological properties in prepubertal rat dorsal striatum differ by sex. We made whole cell recordings from male and females MSNs from acute brain slices. The slope of the evoked firing rate to current injection curve was increased in MSNs recorded from females compared with males. The initial action potential firing rate was increased in MSNs recorded from females compared with males. Action potential after-hyperpolarization peak was decreased, and threshold was hyperpolarized in MSNs recorded from females compared with males. No sex differences in passive electrophysiological properties or miniature excitatory synaptic currents were detected. These findings indicate that MSN excitability is increased in prepubertal females compared with males, providing a new mechanism that potentially contributes to generating sex differences in striatal-mediated processes. Broadly, these findings demonstrate that sex differences in neuron electrophysiological properties can exist prepuberty in brain regions not directly related to reproduction. PMID:25376786

  15. Molecular mechanism of modulation of nociceptive neuron membrane excitability by a tripeptide.

    PubMed

    Shelykh, T N; Rogachevsky, I V; Nozdrachev, A D; Veselkina, O S; Podzorova, S A; Krylov, B V; Plakhova, V B

    2016-01-01

    Using the whole-cell patch-clamp method, the ability of arginine-containing tripeptide Ac-RER-NH2, dipeptide Ac-RR-NH2, and free Arg molecule to modulate the membrane excitability of nociceptors was studied. Extracellular Ac-RER-NH2 upon interaction with the outer membrane of the nociceptive neuron decreases the Zeff value of the activation gating system of Nav1.8 channels. Thus, the tripeptide Ac-RER-NH2 can be considered as a new effective and safe analgesic. PMID:27025494

  16. Dopamine D4 Receptor Excitation of Lateral Habenula Neurons via Multiple Cellular Mechanisms

    PubMed Central

    Good, Cameron H.; Wang, Huikun; Chen, Yuan-Hao; Mejias-Aponte, Carlos A.; Hoffman, Alexander F.

    2013-01-01

    Glutamatergic lateral habenula (LHb) output communicates negative motivational valence to ventral tegmental area (VTA) dopamine (DA) neurons via activation of the rostromedial tegmental nucleus (RMTg). However, the LHb also receives a poorly understood DA input from the VTA, which we hypothesized constitutes an important feedback loop regulating DA responses to stimuli. Using whole-cell electrophysiology in rat brain slices, we find that DA initiates a depolarizing inward current (IDAi) and increases spontaneous firing in 32% of LHb neurons. IDAi was also observed upon application of amphetamine or the DA uptake blockers cocaine or GBR12935, indicating involvement of endogenous DA. IDAi was blocked by D4 receptor (D4R) antagonists (L745,870 or L741,742), and mimicked by a selective D4R agonist (A412997). IDAi was associated with increased whole-cell conductance and was blocked by Cs+ or a selective blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel, ZD7288. IDAi was also associated with a depolarizing shift in half-activation voltage for the hyperpolarization-activated cation current (Ih) mediated by HCN channels. Recordings from LHb neurons containing fluorescent retrograde tracers revealed that IDAi was observed only in cells projecting to the RMTg and not the VTA. In parallel with direct depolarization, DA also strongly increased synaptic glutamate release and reduced synaptic GABA release onto LHb cells. These results demonstrate that DA can excite glutamatergic LHb output to RMTg via multiple cellular mechanisms. Since the RMTg strongly inhibits midbrain DA neurons, activation of LHb output to RMTg by DA represents a negative feedback loop that may dampen DA neuron output following activation. PMID:24155292

  17. Label-free distinguishing between neurons and glial cells based on two-photon excited fluorescence signal of neuron perinuclear granules

    NASA Astrophysics Data System (ADS)

    Du, Huiping; Jiang, Liwei; Wang, Xingfu; Liu, Gaoqiang; Wang, Shu; Zheng, Liqin; Li, Lianhuang; Zhuo, Shuangmu; Zhu, Xiaoqin; Chen, Jianxin

    2016-08-01

    Neurons and glial cells are two critical cell types of brain tissue. Their accurate identification is important for the diagnosis of psychiatric disorders such as depression and schizophrenia. In this paper, distinguishing between neurons and glial cells by using the two-photon excited fluorescence (TPEF) signals of intracellular intrinsic sources was performed. TPEF microscopy combined with TUJ-1 and GFAP immunostaining and quantitative image analysis demonstrated that the perinuclear granules of neurons in the TPEF images of brain tissue and the primary cultured cortical cells were a unique characteristic of neurons compared to glial cells which can become a quantitative feature to distinguish neurons from glial cells. With the development of miniaturized TPEF microscope (‘two-photon fiberscopes’) imaging devices, TPEF microscopy can be developed into an effective diagnostic and monitoring tool for psychiatric disorders such as depression and schizophrenia.

  18. Motor imagery muscle contraction strength influences spinal motor neuron excitability and cardiac sympathetic nerve activity

    PubMed Central

    Bunno, Yoshibumi; Suzuki, Toshiaki; Iwatsuki, Hiroyasu

    2015-01-01

    [Purpose] The aim of this study was to investigate the changes in spinal motor neuron excitability and autonomic nervous system activity during motor imagery of isometric thenar muscle activity at 10% and 50% maximal voluntary contraction (MVC). [Methods] The F-waves and low frequency/high frequency (LF/HF) ratio were recorded at rest, during motor imagery, and post-trial. For motor imagery trials, subjects were instructed to imagine thenar muscle activity at 10% and 50% MVC while holding the sensor of a pinch meter for 5 min. [Results] The F-waves and LF/HF ratio during motor imagery at 50% MVC were significantly increased compared with those at rest, whereas those during motor imagery at 10% MVC were not significantly different from those at rest. The relative values of the F/M amplitude ratio during motor imagery at 50% MVC were significantly higher than those at 10% MVC. The relative values of persistence and the LF/HF ratio during motor imagery were similar during motor imagery at the two muscle contraction strengths. [Conclusion] Motor imagery can increase the spinal motor neuron excitability and cardiac sympathetic nerve activity. Motor imagery at 50% MVC may be more effective than motor imagery at 10% MVC. PMID:26834354

  19. Multiplicative and Additive Modulation of Neuronal Tuning with Population Activity Affects Encoded Information.

    PubMed

    Arandia-Romero, Iñigo; Tanabe, Seiji; Drugowitsch, Jan; Kohn, Adam; Moreno-Bote, Rubén

    2016-03-16

    Numerous studies have shown that neuronal responses are modulated by stimulus properties and also by the state of the local network. However, little is known about how activity fluctuations of neuronal populations modulate the sensory tuning of cells and affect their encoded information. We found that fluctuations in ongoing and stimulus-evoked population activity in primate visual cortex modulate the tuning of neurons in a multiplicative and additive manner. While distributed on a continuum, neurons with stronger multiplicative effects tended to have less additive modulation and vice versa. The information encoded by multiplicatively modulated neurons increased with greater population activity, while that of additively modulated neurons decreased. These effects offset each other so that population activity had little effect on total information. Our results thus suggest that intrinsic activity fluctuations may act as a "traffic light" that determines which subset of neurons is most informative. PMID:26924437

  20. Sperm Affects Head Sensory Neuron in Temperature Tolerance of Caenorhabditis elegans.

    PubMed

    Sonoda, Satoru; Ohta, Akane; Maruo, Ayana; Ujisawa, Tomoyo; Kuhara, Atsushi

    2016-06-28

    Tolerance to environmental temperature change is essential for the survival and proliferation of animals. The process is controlled by various body tissues, but the orchestration of activity within the tissue network has not been elucidated in detail. Here, we show that sperm affects the activity of temperature-sensing neurons (ASJ) that control cold tolerance in Caenorhabditis elegans. Genetic impairment of sperm caused abnormal cold tolerance, which was unexpectedly restored by impairment of temperature signaling in ASJ neurons. Calcium imaging revealed that ASJ neuronal activity in response to temperature was decreased in sperm mutant gsp-4 with impaired protein phosphatase 1 and rescued by expressing gsp-4 in sperm. Genetic analysis revealed a feedback network in which ASJ neuronal activity regulates the intestine through insulin and a steroid hormone, which then affects sperm and, in turn, controls ASJ neuronal activity. Thus, we propose that feedback between sperm and a sensory neuron mediating temperature tolerance. PMID:27320929

  1. Direct muscarinic and nicotinic receptor-mediated excitation of rat medial vestibular nucleus neurons in vitro

    NASA Technical Reports Server (NTRS)

    Phelan, K. D.; Gallagher, J. P.

    1992-01-01

    We have utilized intracellular recording techniques to investigate the cholinoceptivity of rat medial vestibular nucleus (MVN) neurons in a submerged brain slice preparation. Exogenous application of the mixed cholinergic agonists, acetylcholine (ACh) or carbachol (CCh), produced predominantly membrane depolarization, induction of action potential firing, and decreased input resistance. Application of the selective muscarinic receptor agonist muscarine (MUSC), or the selective nicotinic receptor agonists nicotine (NIC) or 1,1-dimethyl-4-phenylpiperazinium (DMPP) also produced membrane depolarizations. The MUSC-induced depolarization was accompanied by decreased conductance, while an increase in conductance appeared to underlie the NIC- and DMPP-induced depolarizations. The muscarinic and nicotinic receptor mediated depolarizations persisted in tetrodotoxin and/or low Ca2+/high Mg2+ containing media, suggesting direct postsynaptic receptor activation. The MUSC-induced depolarization could be reversibly blocked by the selective muscarinic-receptor antagonist, atropine, while the DMPP-induced depolarization could be reversibly suppressed by the selective ganglionic nicotinic-receptor antagonist, mecamylamine. Some neurons exhibited a transient membrane hyperpolarization during the depolarizing response to CCh or MUSC application. This transient inhibition could be reversibly blocked by the gamma-aminobutyric acid (GABA) antagonist, bicuculline, suggesting that the underlying hyperpolarization results indirectly from the endogenous release of GABA acting at GABA receptors. This study confirms the cholinoceptivity of MVN neurons and establishes that individual MVN cells possess muscarinic as well as nicotinic receptors. The data provide support for a prominent role of cholinergic mechanisms in the direct and indirect regulation of the excitability of MVN neurons.

  2. Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice

    PubMed Central

    Tamagnini, Francesco; Novelia, Janet; Kerrigan, Talitha L.; Brown, Jon T.; Tsaneva-Atanasova, Krasimira; Randall, Andrew D.

    2015-01-01

    Amyloidopathy involves the accumulation of insoluble amyloid β (Aβ) species in the brain’s parenchyma and is a key histopathological hallmark of Alzheimer’s disease (AD). Work on transgenic mice that overexpress Aβ suggests that elevated Aβ levels in the brain are associated with aberrant epileptiform activity and increased intrinsic excitability (IE) of CA1 hippocampal neurons. In this study we examined if similar changes could be observed in hippocampal CA1 pyramidal neurons from aged PDAPP mice (20–23 month old, Indiana mutation: V717F on APP gene) compared to their age-matched wild-type littermate controls. Whole-cell current clamp recordings revealed that sub-threshold intrinsic properties, such as input resistance, resting membrane potential and hyperpolarization activated “sag” were unaffected, but capacitance was significantly decreased in the transgenic animals. No differences between genotypes were observed in the overall number of action potentials (AP) elicited by 500 ms supra-threshold current stimuli. PDAPP neurons, however, exhibited higher instantaneous firing frequencies after accommodation in response to high intensity current injections. The AP waveform was narrower and shorter in amplitude in PDAPP mice: these changes, according to our in silico model of a CA1/3 pyramidal neuron, depended on the respective increase and reduction of K+ and Na+ voltage-gated channels maximal conductances. Finally, the after-hyperpolarization, seen after the first AP evoked by a +300 pA current injection and after 50 Hz AP bursts, was more pronounced in PDAPP mice. These data show that Aβ-overexpression in aged mice altered the capacitance, the neuronal firing and the AP waveform of CA1 pyramidal neurons. Some of these findings are consistent with previous work on younger PDAPP; they also show important differences that can be potentially ascribed to the interaction between amyloidopathy and ageing. Such a change of IE properties over time underlies

  3. Modeling the electrical behavior of anatomically complex neurons using a network analysis program: excitable membrane.

    PubMed

    Bunow, B; Segev, I; Fleshman, J W

    1985-01-01

    We present methods for using the general-purpose network analysis program, SPICE, to construct computer models of excitable membrane displaying Hodgkin-Huxley-like kinetics. The four non-linear partial differential equations of Hodgkin and Huxley (H-H; 1952) are implemented using electrical circuit elements. The H-H rate constants, alpha and beta, are approximated by polynomial functions rather than exponential functions, since the former are handled more efficiently by SPICE. The process of developing code to implement the H-H sodium conductance is described in detail. The Appendix contains a complete listing of the code required to simulate an H-H action potential. The behavior of models so constructed is validated by comparison with the space-clamped and propagating action potentials of Hodgkin and Huxley. SPICE models of multiply branched axons were tested and found to behave as predicted by previous numerical solutions for propagation in inhomogeneous axons. New results are presented for two cases. First, a detailed, anatomically based model is constructed of group Ia input to an alpha-motoneuron with an excitable soma, a myelinated axon and passive dendrites. Second, we simulate interactions among clusters of mixed excitable and passive dendritic spines on an idealized neuron. The methods presented in this paper and its companion (Segev et al. 1985) should permit neurobiologists to construct and explore models which simulate much more closely the real morphological and physiological characteristics of nerve cells. PMID:3841014

  4. Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity

    PubMed Central

    D'Amico, Jessica M.; Condliffe, Elizabeth G.; Martins, Karen J. B.; Bennett, David J.; Gorassini, Monica A.

    2014-01-01

    The state of areflexia and muscle weakness that immediately follows a spinal cord injury (SCI) is gradually replaced by the recovery of neuronal and network excitability, leading to both improvements in residual motor function and the development of spasticity. In this review we summarize recent animal and human studies that describe how motoneurons and their activation by sensory pathways become hyperexcitable to compensate for the reduction of functional activation of the spinal cord and the eventual impact on the muscle. Specifically, decreases in the inhibitory control of sensory transmission and increases in intrinsic motoneuron excitability are described. We present the idea that replacing lost patterned activation of the spinal cord by activating synaptic inputs via assisted movements, pharmacology or electrical stimulation may help to recover lost spinal inhibition. This may lead to a reduction of uncontrolled activation of the spinal cord and thus, improve its controlled activation by synaptic inputs to ultimately normalize circuit function. Increasing the excitation of the spinal cord with spared descending and/or peripheral inputs by facilitating movement, instead of suppressing it pharmacologically, may provide the best avenue to improve residual motor function and manage spasticity after SCI. PMID:24860447

  5. Phasic excitation of ventral tegmental dopamine neurons potentiates the initiation of conditioned approach behavior: parametric and reinforcement-schedule analyses

    PubMed Central

    Ilango, Anton; Kesner, Andrew J.; Broker, Carl J.; Wang, Dong V.; Ikemoto, Satoshi

    2014-01-01

    Midbrain dopamine neurons are implicated in motivation and learning. However, it is unclear how phasic excitation of dopamine neurons, which is implicated in learning, is involved in motivation. Here we used a self-stimulation procedure to examine how mice seek for optogenetically-induced phasic excitation of dopamine neurons, with an emphasis on the temporal dimension. TH-Cre transgenic mice received adeno-associated viral vectors encoding channelrhodopsin-2 into the ventral tegmental area, resulting in selective expression of the opsin in dopamine neurons. These mice were trained to press on a lever for photo-pulse trains that phasically excited dopamine neurons. They learned to self-stimulate in a fast, constant manner, and rapidly reduced pressing during extinction. We first determined effective parameters of photo-pulse trains in self-stimulation. Lever-press rates changed as a function of the manipulation of pulse number, duration, intensity, and frequency. We then examined effects of interval and ratio schedules of reinforcement on photo-pulse train reinforcement, which was contrasted with food reinforcement. Reinforcement with food inhibited lever pressing for a few seconds, after which pressing was robustly regulated in a goal-directed manner. In contrast, phasic excitation of dopamine neurons robustly potentiated the initiation of lever pressing; however, this effect did not last more than 1 s and quickly diminished. Indeed, response rates markedly decreased when lever pressing was reinforced with inter-reinforcement interval schedules of 3 or 10 s or ratio schedules requiring multiple responses per reinforcement. Thus, phasic excitation of dopamine neurons briefly potentiates the initiation of approach behavior with apparent lack of long-term motivational regulation. PMID:24834037

  6. A Novel Subtype of Astrocytes Expressing TRPV4 (Transient Receptor Potential Vanilloid 4) Regulates Neuronal Excitability via Release of Gliotransmitters*

    PubMed Central

    Shibasaki, Koji; Ikenaka, Kazuhiro; Tamalu, Fuminobu; Tominaga, Makoto; Ishizaki, Yasuki

    2014-01-01

    Astrocytes play active roles in the regulation of synaptic transmission. Neuronal excitation can evoke Ca2+ transients in astrocytes, and these Ca2+ transients can modulate neuronal excitability. Although only a subset of astrocytes appears to communicate with neurons, the types of astrocytes that can regulate neuronal excitability are poorly characterized. We found that ∼30% of astrocytes in the brain express transient receptor potential vanilloid 4 (TRPV4), indicating that astrocytic subtypes can be classified on the basis of their expression patterns. When TRPV4+ astrocytes are activated by ligands such as arachidonic acid, the activation propagates to neighboring astrocytes through gap junctions and by ATP release from the TRPV4+ astrocytes. After activation, both TRPV4+ and TRPV4− astrocytes release glutamate, which acts as an excitatory gliotransmitter to increase synaptic transmission through type 1 metabotropic glutamate receptor (mGluR). Our results indicate that TRPV4+ astrocytes constitute a novel subtype of the population and are solely responsible for initiating excitatory gliotransmitter release to enhance synaptic transmission. We propose that TRPV4+ astrocytes form a core of excitatory glial assembly in the brain and function to efficiently increase neuronal excitation in response to endogenous TRPV4 ligands. PMID:24737318

  7. Sulforhodamine 101 induces long-tem potentiation of intrinsic excitability and synaptic efficacy in hippocampal CA1 pyramidal neurons

    PubMed Central

    Kang, Jian; Kang, Ning; Yu, Yufei; Zhang, Jinsong; Petersen, Nicolas; Tian, Guo-Feng; Nedergaard, Maiken

    2010-01-01

    Sulforhodamine 101 (SR101) has been extensively used for investigation as a specific marker for astroglia in vivo and activity-dependent dye for monitoring regulated exocytosis. Here, we report that SR101 has bioactive effects on neuronal activity. Perfusion of slices with SR101 (1 μM) for 10 min induced long-term potentiation of intrinsic neuronal excitability (LTP-IE) and a long-lasting increase in evoked EPSCs (eEPSCs) in CA1 pyramidal neurons in hippocampal slices. The increase in intrinsic neuronal excitability was a result of negative shifts in the action potential (AP) threshold. The N-methyl D-aspartate receptor (NMDAR) antagonist, AP-5 (50 μM), blocked SR101-induced LTP-IE, but glutamate receptor blockers, AP-5 (50 μM), MCPG (200 μM), and MSOP (100 μM), only partially blocked SR101-induced potentiation of eEPSCs. SR101 induced an enhancement of evoked synaptic NMDAR currents, suggesting that SR101 enhances activation of synaptic NMDARs. SR101-induced LTP-IE and potentiation of synaptic transmission triggered spontaneous neuronal firing in slices and in vivo epileptic seizures. Our results suggest that SR101 is an epileptogenic agent that long-lastingly lowers the AP threshold to increase intrinsic neuronal excitability and enhances the synaptic efficacy to increase synaptic inputs. As such, SR101 can be used as an experimental tool to induce epileptic seizures. PMID:20600669

  8. Neuronal migration and its disorders affecting the CA3 region

    PubMed Central

    Belvindrah, Richard; Nosten-Bertrand, Marika; Francis, Fiona

    2014-01-01

    In this review, we focus on CA3 neuronal migration disorders in the rodent. We begin by introducing the main steps of hippocampal development, and we summarize characteristic hippocampal malformations in human. We then describe various mouse mutants showing structural hippocampal defects. Notably, genes identified in human cortical neuronal migration disorders consistently give rise to a CA3 phenotype when mutated in the mouse. We successively describe their molecular, physiological and behavioral phenotypes that together contribute to a better understanding of CA3-dependent functions. We finally discuss potential factors underlying the CA3 vulnerability revealed by these mouse mutants and that may also contribute to other human neurological and psychiatric disorders. PMID:24624057

  9. Dynamic response of ensemble neurons to pulsed optical and electrical excitation in vivo and in vitro

    NASA Astrophysics Data System (ADS)

    Akchurin, Garif G.; Seleverstov, George A.; Kamenskih, Tatyana G.; Akchurin, George G.; Bondarenko, Olga A.

    2002-07-01

    The nonlinear response of the Hodgkin-Huxley model neuron with external electrical pulsed was investigated. Dynamic response of somatic frog nerve on electrical pulsed duration was study in vitro. Transcutaneous millisecond of excitation of the ganglion cell of the human retina by electric uses is used for diagnosis, determination of the extent of optic nerve damage, and also partial restoration of visual function in patients with glaucoma, myopia and different types of optic nerve atrophy. Correlation between the threshold of phosphen formation and duration of the stimulating electric pulses was determined experimentally in normal eyes and in eyes with various pathologies. Comparison of optical and electrical scintillating frequency gives information about the dynamic processes in the normal and pathological retina.

  10. Ionic Mechanisms of Neuronal Excitation by Inhibitory GABA_A Receptors

    NASA Astrophysics Data System (ADS)

    Staley, Kevin J.; Soldo, Brandi L.; Proctor, William R.

    1995-08-01

    Gamma-aminobutyric acid A (GABA_A) receptors are the principal mediators of synaptic inhibition, and yet when intensely activated, dendritic GABA_A receptors excite rather than inhibit neurons. The membrane depolarization mediated by GABA_A receptors is a result of the differential, activity-dependent collapse of the opposing concentration gradients of chloride and bicarbonate, the anions that permeate the GABA_A ionophore. Because this depolarization diminishes the voltage-dependent block of the N-methyl-D-aspartate (NMDA) receptor by magnesium, the activity-dependent depolarization mediated by GABA is sufficient to account for frequency modulation of synaptic NMDA receptor activation. Anionic gradient shifts may represent a mechanism whereby the rate and coherence of synaptic activity determine whether dendritic GABA_A receptor activation is excitatory or inhibitory.

  11. Effects of acute and chronic administration of neurosteroid dehydroepiandrosterone sulfate on neuronal excitability in mice

    PubMed Central

    Svob Strac, Dubravka; Vlainic, Josipa; Samardzic, Janko; Erhardt, Julija; Krsnik, Zeljka

    2016-01-01

    Background Neurosteroid dehydroepiandrosterone sulfate (DHEAS) has been associated with important brain functions, including neuronal survival, memory, and behavior, showing therapeutic potential in various neuropsychiatric and cognitive disorders. However, the antagonistic effects of DHEAS on γ-amino-butyric acidA receptors and its facilitatory action on glutamatergic neurotransmission might lead to enhanced brain excitability and seizures and thus limit DHEAS therapeutic applications. The aim of this study was to investigate possible age and sex differences in the neuronal excitability of the mice following acute and chronic DHEAS administration. Methods DHEAS was administered intraperitoneally in male and female adult and old mice either acutely or repeatedly once daily for 4 weeks in a 10 mg/kg dose. To investigate the potential proconvulsant properties of DHEAS, we studied the effects of acute and chronic DHEAS treatment on picrotoxin-, pentylentetrazole-, and N-methyl-D-aspartate-induced seizures in mice. The effects of acute and chronic DHEAS administration on the locomotor activity, motor coordination, and body weight of the mice were also studied. We also investigated the effects of DHEAS treatment on [3H]flunitrazepam binding to the mouse brain membranes. Results DHEAS did not modify the locomotor activity, motor coordination, body weight, and brain [3H]flunitrazepam binding of male and female mice. The results failed to demonstrate significant effects of single- and long-term DHEAS treatment on the convulsive susceptibility in both adult and aged mice of both sexes. However, small but significant changes regarding sex differences in the susceptibility to seizures were observed following DHEAS administration to mice. Conclusion Although our findings suggest that DHEAS treatment might be safe for various potential therapeutic applications in adult as well as in old age, they also support subtle interaction of DHEAS with male and female hormonal status

  12. Peroxide alters neuronal excitability in the CA1 region of guinea-pig hippocampus in vitro

    SciTech Connect

    Pellmar, T.C.

    1987-01-01

    Effects of peroxidative damage on neuronal excitability were investigated with electrophysiological techniques in CAl pyramidal cells of the hippocampal slice preparation. Hydrogen peroxide alone or combined with ferrous ions (peroxide/iron) is likely to produce hydroxyl free radicals through the Fenton reaction. Intracellularly recorded excitatory postsynaptic potentials and inhibitory postsynaptic potentials were significantly reduced by exposure to peroxide, while responses to iontophoretically applied gamma aminobutyric acid and glutamate were unaffected. These results suggest that peroxide has presynaptic actions. Peroxide and peroxide/iron also increased frequency adaptation; after exposure, neurons fired fewer action potentials at a lower frequency in response to the same depolarizing current step. A voltage clamp analysis revealed that the potassium currents were unaffected by peroxide/iron. Calcium current was not obviously altered by exposure to peroxide. Sodium spike thresholds was also unaffected. Calcium spike threshold was significantly increased by peroxide. This action of peroxide may underlie its presynaptic actions. It is concluded that peroxide produces both presynaptic and postsynaptic damage. This damage is likely to result from the production of free radicals which have been postulated to underlie a number of pathological states.

  13. Corticotropin releasing factor excites neurons of posterior hypothalamic nucleus to produce tachycardia in rats

    PubMed Central

    Gao, He-Ren; Zhuang, Qian-Xing; Li, Bin; Li, Hong-Zhao; Chen, Zhang-Peng; Wang, Jian-Jun; Zhu, Jing-Ning

    2016-01-01

    Corticotropin releasing factor (CRF), a peptide hormone involved in the stress response, holds a key position in cardiovascular regulation. Here, we report that the central effect of CRF on cardiovascular activities is mediated by the posterior hypothalamic nucleus (PH), an important structure responsible for stress-induced cardiovascular changes. Our present results demonstrate that CRF directly excites PH neurons via two CRF receptors, CRFR1 and CRFR2, and consequently increases heart rate (HR) rather than the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). Bilateral vagotomy does not influence the tachycardia response to microinjection of CRF into the PH, while β adrenergic receptor antagonist propranolol almost totally abolishes the tachycardia. Furthermore, microinjecting CRF into the PH primarily increases neuronal activity of the rostral ventrolateral medulla (RVLM) and rostral ventromedial medulla (RVMM), but does not influence that of the dorsal motor nucleus of the vagus nerve (DMNV). These findings suggest that the PH is a critical target for central CRF system in regulation of cardiac activity and the PH-RVLM/RVMM-cardiac sympathetic nerve pathways, rather than PH-DMNV-vagus pathway, may contribute to the CRF-induced tachycardia. PMID:26831220

  14. Dexmedetomidine alleviates postoperative cognitive dysfunction by inhibiting neuron excitation in aged rats

    PubMed Central

    Xiong, Bo; Shi, Qiqing; Fang, Hao

    2016-01-01

    The perioperative stress response is one of the factors leading to postoperative cognitive dysfunction (POCD). Dexmedetomidine (Dex) can reduce the stress response and hippocampus neuroapoptosis, but its mechanism of action on POCD remains unknown. This study investigated the protective effect and possible mechanism of Dex on POCD in aged rats. Ninety-six aged male rats were randomly divided into four groups (n = 24 rats per group): a non-surgical control group, a surgical (model) group, a surgical group receiving a high dose of Dex (12 μg/kg), and a surgical group receiving a low dose of Dex (3 μg/kg). Cognitive function and neuronal apoptosis were evaluated after splenectomy. Compared with the control group, the model group had significantly longer escape latencies and fewer platform crossings in the Morris water-maze test. Immunohistochemistry showed that relaxin-3 and c-fos positive neurons in the hippocampus increased on postoperative days 1 and 3. Greater downregulation of the Bcl-2 protein and upregulation of Fas, caspase-8, and caspase-9 significantly increased neuroapoptosis in the model group. Compared with the model group, rats given Dex had (1) shorter escape latencies, (2) more platform crossings, (3) fewer relaxin-3 and c-fos positive neurons in the hippocampal CA1 area, (4) upregulation of Bcl-2, (5) downregulation of Fas, caspase-8, and caspase-9 proteins, and (6) decreased neuroapoptosis in the hippocampus. Thus, our data suggest that Dex may improve cognitive functioning in aged rats by inhibiting neural over-excitability. The mechanism may operate by restraining relaxin-3 and c-fos expression. PMID:27069541

  15. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate.

    PubMed Central

    Anis, N. A.; Berry, S. C.; Burton, N. R.; Lodge, D.

    1983-01-01

    The interaction of two dissociative anaesthetics, ketamine and phencyclidine, with the responses of spinal neurones to the electrophoretic administration of amino acids and acetylcholine was studied in decerebrate or pentobarbitone-anaesthetized cats and rats. Both ketamine and phencyclidine selectively blocked excitation by N-methyl-aspartate (NMA) with little effect on excitation by quisqualate and kainate. Ketamine reduced responses to L-aspartate somewhat more than those of L-glutamate; the sensitivity of responses to these two putative transmitters was between that to NMA on one hand and that to quisqualate or kainate on the other. On Renshaw cells, ketamine and phencyclidine reduced responses to acetylcholine less than those to NMA but more than those to quisqualate or kainate. Dorsal root-evoked synaptic excitation of Renshaw cells was reduced to a greater extent than that following ventral root excitation. Intravenous ketamine, 2.5-20 mg/kg, and phencyclidine, 0.2-0.5 mg/kg, also selectively blocked excitation of neurones by NMA. Ketamine showed no consistent or selective effect on inhibition of spinal neurones by electrophoretically administered glycine or gamma-aminobutyricacid (GABA). The results suggest that reduction of synaptic excitation mediated via NMA receptors contributes to the anaesthetic/analgesic properties of these two dissociative anaesthetics. PMID:6317114

  16. Phospholipase A2 – nexus of aging, oxidative stress, neuronal excitability, and functional decline of the aging nervous system? Insights from a snail model system of neuronal aging and age-associated memory impairment

    PubMed Central

    Hermann, Petra M.; Watson, Shawn N.; Wildering, Willem C.

    2014-01-01

    The aging brain undergoes a range of changes varying from subtle structural and physiological changes causing only minor functional decline under healthy normal aging conditions, to severe cognitive or neurological impairment associated with extensive loss of neurons and circuits due to age-associated neurodegenerative disease conditions. Understanding how biological aging processes affect the brain and how they contribute to the onset and progress of age-associated neurodegenerative diseases is a core research goal in contemporary neuroscience. This review focuses on the idea that changes in intrinsic neuronal electrical excitability associated with (per)oxidation of membrane lipids and activation of phospholipase A2 (PLA2) enzymes are an important mechanism of learning and memory failure under normal aging conditions. Specifically, in the context of this special issue on the biology of cognitive aging we portray the opportunities offered by the identifiable neurons and behaviorally characterized neural circuits of the freshwater snail Lymnaea stagnalis in neuronal aging research and recapitulate recent insights indicating a key role of lipid peroxidation-induced PLA2 as instruments of aging, oxidative stress and inflammation in age-associated neuronal and memory impairment in this model system. The findings are discussed in view of accumulating evidence suggesting involvement of analogous mechanisms in the etiology of age-associated dysfunction and disease of the human and mammalian brain. PMID:25538730

  17. From neurons to epidemics: How trophic coherence affects spreading processes.

    PubMed

    Klaise, Janis; Johnson, Samuel

    2016-06-01

    Trophic coherence, a measure of the extent to which the nodes of a directed network are organised in levels, has recently been shown to be closely related to many structural and dynamical aspects of complex systems, including graph eigenspectra, the prevalence or absence of feedback cycles, and linear stability. Furthermore, non-trivial trophic structures have been observed in networks of neurons, species, genes, metabolites, cellular signalling, concatenated words, P2P users, and world trade. Here, we consider two simple yet apparently quite different dynamical models-one a susceptible-infected-susceptible epidemic model adapted to include complex contagion and the other an Amari-Hopfield neural network-and show that in both cases the related spreading processes are modulated in similar ways by the trophic coherence of the underlying networks. To do this, we propose a network assembly model which can generate structures with tunable trophic coherence, limiting in either perfectly stratified networks or random graphs. We find that trophic coherence can exert a qualitative change in spreading behaviour, determining whether a pulse of activity will percolate through the entire network or remain confined to a subset of nodes, and whether such activity will quickly die out or endure indefinitely. These results could be important for our understanding of phenomena such as epidemics, rumours, shocks to ecosystems, neuronal avalanches, and many other spreading processes. PMID:27368799

  18. From neurons to epidemics: How trophic coherence affects spreading processes

    NASA Astrophysics Data System (ADS)

    Klaise, Janis; Johnson, Samuel

    2016-06-01

    Trophic coherence, a measure of the extent to which the nodes of a directed network are organised in levels, has recently been shown to be closely related to many structural and dynamical aspects of complex systems, including graph eigenspectra, the prevalence or absence of feedback cycles, and linear stability. Furthermore, non-trivial trophic structures have been observed in networks of neurons, species, genes, metabolites, cellular signalling, concatenated words, P2P users, and world trade. Here, we consider two simple yet apparently quite different dynamical models—one a susceptible-infected-susceptible epidemic model adapted to include complex contagion and the other an Amari-Hopfield neural network—and show that in both cases the related spreading processes are modulated in similar ways by the trophic coherence of the underlying networks. To do this, we propose a network assembly model which can generate structures with tunable trophic coherence, limiting in either perfectly stratified networks or random graphs. We find that trophic coherence can exert a qualitative change in spreading behaviour, determining whether a pulse of activity will percolate through the entire network or remain confined to a subset of nodes, and whether such activity will quickly die out or endure indefinitely. These results could be important for our understanding of phenomena such as epidemics, rumours, shocks to ecosystems, neuronal avalanches, and many other spreading processes.

  19. Optogenetic excitation of neurons with channelrhodopsins: light instrumentation, expression systems, and channelrhodopsin variants.

    PubMed

    Lin, John Y

    2012-01-01

    Classically, temporally precise excitation of membrane potential in neurons within intact tissue can be achieved by direct electrical stimulation or indirect electrical stimulation induced by changing magnetic fields. Both of these approaches have a predetermined selectivity based on the biophysical properties of the nervous tissue and membrane in the region of the stimulation. A recent advance in selective excitation of neurons is the "optogenetic" approach utilizing channelrhodopsins (ChRs). By expressing the light-responsive ChR in neurons using cell-type selective promoters or other methods, specific neurons can be depolarized by light in a temporally precise manner with millisecond resolution even if their membrane biophysical properties are less favorable for electrical stimulation. In addition, ChRs can be used to depolarize nonneuronal cells in the nervous tissue, and to sustain depolarization over a prolonged period of time, both of which cannot be achieved with electrical or magnetic stimulations. To conduct an experiment with ChR, experimenters need to make the correct choices on the three main components to such an experiment: the expression system, the illumination source, and the ChR variant used. This chapter aims to provide some discussions on the current developments of these aspects of the experiments. To express ChR in neurons, the common expression systems include viral vectors, in utero electroporation, and transgenic animals, each with their advantages and limitations regarding the cost, expression pattern, and the required effort. In terms of the instrumentation, an illumination source that is capable of providing the desired wavelength with high intensity is crucial for the success of the experiment. The important factors regarding the light source used include the cost, light density output, efficiency for fiber coupling for in vivo rodent experiments, and the available methods to control light intensity and onset/termination. The third

  20. Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.

    PubMed

    Frazzini, V; Guarnieri, S; Bomba, M; Navarra, R; Morabito, C; Mariggiò, M A; Sensi, S L

    2016-01-01

    Altered neuronal excitability is emerging as an important feature in Alzheimer's disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimer's disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca(2+)]i spikes. Compared with wild-type (Non-Tg (non-transgenic mouse model)) cultures, 3xTg-AD neurons showed enhanced spike frequency and decreased intensity. Compared with Non-Tg cultures, 3xTg-AD hippocampal neurons revealed reduced Kv2.1-dependent Ik current densities as well as normalized conductances. 3xTg-AD cultures also exhibited an overall decrease in the number of functional Kv2.1 channels. Immunofluorescence assay revealed an increase in Kv2.1 channel oligomerization, a condition associated with blockade of channel function. In Non-Tg neurons, pharmacological blockade of Kv2.1 channels reproduced the altered pattern found in the 3xTg-AD cultures. Moreover, compared with untreated sister cultures, pharmacological inhibition of Kv2.1 in 3xTg-AD neurons did not produce any significant modification in Ik current densities. Reactive oxygen species (ROS) promote Kv2.1 oligomerization, thereby acting as negative modulator of the channel activity. Glutamate receptor activation produced higher ROS levels in hippocampal 3xTg-AD cultures compared with Non-Tg neurons. Antioxidant treatment with N-Acetyl-Cysteine was found to rescue Kv2.1-dependent currents and decreased spontaneous hyperexcitability in 3xTg-AD neurons. Analogous results regarding spontaneous synaptic activity were observed in neuronal cultures treated with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Our study indicates that AD-related mutations may promote enhanced ROS generation, oxidative

  1. 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

  2. Brivaracetam Differentially Affects Voltage-Gated Sodium Currents Without Impairing Sustained Repetitive Firing in Neurons

    PubMed Central

    Niespodziany, Isabelle; André, Véronique Marie; Leclère, Nathalie; Hanon, Etienne; Ghisdal, Philippe; Wolff, Christian

    2015-01-01

    Aims Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF). Methods Brivaracetam investigations on the voltage-gated sodium current (INa) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100–300 μM) experiments were performed in comparison with 100 μM carbamazepine (CBZ). Results Brivaracetam and CBZ reduced INa in N1E-115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect INa in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75–93%. Conclusions The lack of effect of BRV on SRF in neurons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties. PMID:25444522

  3. Diet composition, not calorie intake, rapidly alters intrinsic excitability of hypothalamic AgRP/NPY neurons in mice

    PubMed Central

    Wei, Wei; Pham, Kevin; Gammons, Jesse W.; Sutherland, Daniel; Liu, Yanyun; Smith, Alana; Kaczorowski, Catherine C.; O’Connell, Kristen M.S.

    2015-01-01

    Obesity is a chronic condition resulting from a long-term pattern of poor diet and lifestyle. Long-term consumption of high-fat diet (HFD) leads to persistent activation and leptin resistance in AgRP neurons in the arcuate nucleus of the hypothalamus (ARH). Here, for the first time, we demonstrate acute effects of HFD on AgRP neuronal excitability and highlight a critical role for diet composition. In parallel with our earlier finding in obese, long-term HFD mice, we found that even brief HFD feeding results in persistent activation of ARH AgRP neurons. However, unlike long-term HFD-fed mice, AgRP neurons from short-term HFD-fed mice were still leptin-sensitive, indicating that the development of leptin-insensitivity is not a prerequisite for the increased firing rate of AgRP neurons. To distinguish between diet composition, caloric intake, and body weight, we compared acute and long-term effects of HFD and CD in pair-fed mice on AgRP neuronal spiking. HFD consumption in pair-fed mice resulted in a significant increase in AgRP neuronal spiking despite controls for weight gain and caloric intake. Taken together, our results suggest that diet composition may be more important than either calorie intake or body weight for electrically remodeling arcuate AgRP/NPY neurons. PMID:26592769

  4. Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus.

    PubMed

    Baver, Scott B; Hope, Kevin; Guyot, Shannon; Bjørbaek, Christian; Kaczorowski, Catherine; O'Connell, Kristen M S

    2014-04-16

    The hypothalamic arcuate nucleus (ARH) is a brain region critical for regulation of food intake and a primary area for the action of leptin in the CNS. In lean mice, the adipokine leptin inhibits neuropeptide Y (NPY) and agouti-related peptide (AgRP) neuronal activity, resulting in decreased food intake. Here we show that diet-induced obesity in mice is associated with persistent activation of NPY neurons and a failure of leptin to reduce the firing rate or hyperpolarize the resting membrane potential. However, the molecular mechanism whereby diet uncouples leptin's effect on neuronal excitability remains to be fully elucidated. In NPY neurons from lean mice, the Kv channel blocker 4-aminopyridine inhibited leptin-induced changes in input resistance and spike rate. Consistent with this, we found that ARH NPY neurons have a large, leptin-sensitive delayed rectifier K(+) current and that leptin sensitivity of this current is blunted in neurons from diet-induced obese mice. This current is primarily carried by Kv2-containing channels, as the Kv2 channel inhibitor stromatoxin-1 significantly increased the spontaneous firing rate in NPY neurons from lean mice. In HEK cells, leptin induced a significant hyperpolarizing shift in the voltage dependence of Kv2.1 but had no effect on the function of the closely related channel Kv2.2 when these channels were coexpressed with the long isoform of the leptin receptor LepRb. Our results suggest that dynamic modulation of somatic Kv2.1 channels regulates the intrinsic excitability of NPY neurons to modulate the spontaneous activity and the integration of synaptic input onto these neurons in the ARH. PMID:24741039

  5. Pretreatment with nonselective cationic channel inhibitors blunts the PACAP-induced increase in guinea pig cardiac neuron excitability.

    PubMed

    Merriam, Laura A; Roman, Carolyn W; Baran, Caitlin N; Girard, Beatrice M; May, Victor; Parsons, Rodney L

    2012-11-01

    Calcium influx is required for the pituitary adenylyl cyclase activating polypeptide (PACAP)-induced increase in guinea pig cardiac neuron excitability, noted as a change from a phasic to multiple action potential firing pattern. Intracellular recordings indicated that pretreatment with the nonselective cationic channel inhibitors, 2-aminoethoxydiphenylborate (2-APB), 1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SKF 96365), and flufenamic acid (FFA) reduced the 20-nM PACAP-induced excitability increase. Additional experiments tested whether 2-APB, FFA, and SKF 96365 could suppress the increase in excitability by PACAP once it had developed. The increased action potential firing remained following application of 2-APB but was diminished by FFA. SKF 96365 transiently depressed the PACAP-induced excitability increase. A decrease and recovery of action potential amplitude paralleled the excitability shift. Since semiquantitative PCR indicated that cardiac neurons express TRPC subunit transcripts, we hypothesize that PACAP activates calcium-permeable, nonselective cationic channels, which possibly are members of the TRPC family. Our results are consistent with calcium influx being required for the initiation of the PACAP-induced increase in excitability, but suggest that it may not be required to sustain the peptide effect. The present results also demonstrate that nonselective cationic channel inhibitors could have other actions, which might contribute to the inhibition of the PACAP-induced excitability increase. PMID:22528456

  6. Mutations affecting the chemosensory neurons of Caenorhabditis elegans.

    PubMed

    Starich, T A; Herman, R K; Kari, C K; Yeh, W H; Schackwitz, W S; Schuyler, M W; Collet, J; Thomas, J H; Riddle, D L

    1995-01-01

    We have identified and characterized 95 mutations that reduce or abolish dye filling of amphid and phasmid neurons and that have little effect on viability, fertility or movement. Twenty-seven mutations occurred spontaneously in strains with a high frequency of transposon insertion. Sixty-eight were isolated after treatment with EMS. All of the mutations result in defects in one or more chemosensory responses, such as chemotaxis to ammonium chloride or formation of dauer larvae under conditions of starvation and overcrowding. Seventy-five of the mutations are alleles of 12 previously defined genes, mutations which were previously shown to lead to defects in amphid ultrastructure. We have assigned 20 mutations to 13 new genes, called dyf-1 through dyf-13. We expect that the genes represented by dye-filing defective mutants are important for the differentiation of amphid and phasmid chemosensilla. PMID:7705621

  7. Mutations affecting the chemosensory neurons of Caenorhabditis elegans

    SciTech Connect

    Starich, T.A.; Herman, R.K.; Kari, C.K.

    1995-01-01

    We have identified and characterized 95 mutations that reduce or abolish dye filling of amphid and phasmid neurons and that have little effect on viability, fertility or movement. Twenty-seven mutations occurred spontaneously in strains with a high frequency of transposon insertion. Sixty-eight were isolated after treatment with EMS. All of the mutations result in defects in one or more chemosensory responses, such as chemotaxis to ammonium chloride or formation of dauer larvae under conditions of starvation and overcrowding. Seventy-five of the mutations are alleles of 12 previously defined genes, mutations which were previously shown to lead to defects in amphid ultrastructure. We have assigned 20 mutations to 13 new genes, called dyf-1 through dyf-13. We expect that the genes represented by dye-filling defective mutants are important for the differentiation of amphid and phasmid chemosensilla. 58 refs., 3 figs., 6 tabs.

  8. Intrinsic excitability changes induced by acute treatment of hippocampal CA1 pyramidal neurons with exogenous amyloid β peptide.

    PubMed

    Tamagnini, Francesco; Scullion, Sarah; Brown, Jon T; Randall, Andrew D

    2015-07-01

    Accumulation of beta-amyloid (Aβ) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Aβ-overexpressing transgenic mice indicates that increased brain Aβ levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2-5 h treatment with an oligomeric preparation of synthetic human Aβ 1-42 peptide. Whole cell current clamp recordings were compared between Aβ-(500 nM) and vehicle-(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Aβ treatment did not produce alterations in sub-threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated "sag". Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra-threshold stimuli. However, Aβ 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Aβ at 500 nM depressed the after-hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Aβ oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients. PMID:25515596

  9. Intrinsic excitability changes induced by acute treatment of hippocampal CA1 pyramidal neurons with exogenous amyloid β peptide

    PubMed Central

    Scullion, Sarah; Brown, Jon T.; Randall, Andrew D.

    2015-01-01

    ABSTRACT Accumulation of beta‐amyloid (Aβ) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Aβ‐overexpressing transgenic mice indicates that increased brain Aβ levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2–5 h treatment with an oligomeric preparation of synthetic human Aβ 1–42 peptide. Whole cell current clamp recordings were compared between Aβ‐(500 nM) and vehicle‐(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Aβ treatment did not produce alterations in sub‐threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated “sag”. Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra‐threshold stimuli. However, Aβ 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Aβ at 500 nM depressed the after‐hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Aβ oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID:25515596

  10. Enhanced Excitability of Primary Sensory Neurons and Altered Gene Expression of Neuronal Ion Channels in Dorsal Root Ganglion in Paclitaxel-Induced Peripheral Neuropathy

    PubMed Central

    Zhang, Haijun; Dougherty, Patrick M.

    2014-01-01

    Background The mechanism of chemotherapy-induced peripheral neuropathy after paclitaxel treatment is not well understood. Given the poor penetration of paclitaxel into central nervous system, peripheral nervous system is most at risk. Methods Intrinsic membrane properties of dorsal root ganglion (DRG) neurons were studied by intracellular recordings. Multiple-gene real-time Polymerase Chain Reaction array was used to investigate gene expression of DRG neuronal ion channels. Results Paclitaxel increased the incidence of spontaneous activity from 4.8% to 27.1% in large and from 0% to 33.3% in medium-sized neurons. Paclitaxel decreased the rheobase (nA) from 1.6 ± 0.1 to 0.8 ± 0.1 in large, from 1.5 ± 0.2 to 0.6 ± 0.1 in medium-sized, and from 1.6 ± 0.2 to 1.0 ± 0.1 in small neurons. After paclitaxel, other characteristics of membrane properties in each group remained the same except that Aδ neurons showed shorter action potential fall time (ms) (1.0 ± 0.2, n = 10 vs. 1.8 ± 0.3, n = 9, paclitaxel vs. vehicle). Meanwhile, real-time polymerase chain reaction array revealed an alteration in expression of some neuronal ion channel genes including upregulation of HCN1 (fold change 1.76 ± 0.06) and Nav1.7 (1.26 ± 0.02) and downregulation of Kir channels (Kir1.1, 0.73 ± 0.05, Kir3.4, 0.66 ± 0.06) in paclitaxel-treated animals. Conclusions The increased neuronal excitability and the changes in gene expression of some neuronal ion channels in DRG may provide insight into the molecular and cellular basis of paclitaxel neuropathy, which may lead to novel therapeutic strategies. PMID:24534904

  11. Monoclonal antibody identification of subpopulations of cerebral cortical neurons affected in Alzheimer disease.

    PubMed Central

    Miller, C A; Rudnicka, M; Hinton, D R; Blanks, J C; Kozlowski, M

    1987-01-01

    Neuronal degeneration is one of the hallmarks of Alzheimer disease (AD). Given the paucity of molecular markers available for the identification of neuronal subtypes, the specificity of neuronal loss within the cerebral cortex has been difficult to evaluate. With a panel of four monoclonal antibodies (mAbs) applied to central nervous system tissues from AD patients, we have immunocytochemically identified a population of vulnerable cortical neurons; a subpopulation of pyramidal neurons is recognized by mABs 3F12 and 44.1 in the hippocampus and neocortex, and clusters of multipolar neurons in the entorhinal cortex reactive with mAb 44.1 show selective degeneration. Closely adjacent stellate-like neurons in these regions, identified by mAB 6A2, show striking preservation in AD. The neurons recognized by mAbs 3F12 and 44.1, to the best of our knowledge, do not comprise a single known neurotransmitter system. mAb 3A4 identifies a phosphorylated antigen that is undetectable in normal brain but accumulates early in the course of AD in somas of vulnerable neurons. Antigen 3A4 is distinct from material reactive with thioflavin S or antibody generated against paired helical filaments. Initially, antigen 3A4 is localized to neurons in the entorhinal cortex and subiculum, later in the association neocortex, and, ultimately in cases of long duration, in primary sensory cortical regions. mAb 3F12 recognizes multiple bands on immunoblots of homogenates of normal and AD cortical tissues, whereas mAb 3A4 does not bind to immunoblots containing neurofilament proteins or brain homogenates from AD patients. Ultrastructurally, antigen 3A4 is localized to paired helical filaments. Using these mAbs, further molecular characterization of the affected cortical neurons is now possible. Images PMID:3120196

  12. Local administration of resveratrol inhibits excitability of nociceptive wide-dynamic range neurons in rat trigeminal spinal nucleus caudalis.

    PubMed

    Shimazu, Yoshihito; Shibuya, Eri; Takehana, Shiori; Sekiguchi, Kenta; Oshima, Katsuo; Kamata, Hiroaki; Karibe, Hiroyuki; Takeda, Mamoru

    2016-06-01

    Although we recently reported that intravenous administration of resveratrol suppresses trigeminal nociception, the precise peripheral effect of resveratrol on nociceptive and non-nociceptive mechanical stimulation-induced trigeminal neuron activity in vivo remains to be determined. The aim of the present study was to investigate whether local subcutaneous administration of resveratrol attenuates mechanical stimulation-induced excitability of trigeminal spinal nucleus caudalis (SpVc) neuron activity in rats, in vivo. Extracellular single-unit recordings were made of SpVc wide-dynamic range (WDR) neuron activity in response to orofacial mechanical stimulation in pentobarbital-anesthetized rats. Neurons responded to non-noxious and noxious mechanical stimulation applied to the orofacial skin. Local subcutaneous administration of resveratrol (1-10mM) into the orofacial skin dose dependently and significantly reduced the mean number of SpVc WDR neurons firing in response to both non-noxious and noxious mechanical stimuli, with the maximal inhibition of discharge frequency in response to both stimuli being seen within 5min. These inhibitory effects were no longer evident after approximately 20min. The mean magnitude of inhibition by resveratrol (10mM) of SpVc neuron discharge frequency was almost equal to that of the local anesthetic 1% lidocaine (37mM). These results suggest that local injection of resveratrol into the peripheral receptive field suppresses the excitability of SpVc neurons, possibly via inhibition of Na(+) channels in the nociceptive nerve terminals of trigeminal ganglion neurons. Therefore, local subcutaneous administration of resveratrol may provide relief of trigeminal nociceptive pain, without side effects, thus contributing to the suite of complementary and alternative medicines used as local anesthetic agents. PMID:27288246

  13. Affective Neuronal Selection: The Nature of the Primordial Emotion Systems

    PubMed Central

    Toronchuk, Judith A.; Ellis, George F. R.

    2013-01-01

    Based on studies in affective neuroscience and evolutionary psychiatry, a tentative new proposal is made here as to the nature and identification of primordial emotional systems. Our model stresses phylogenetic origins of emotional systems, which we believe is necessary for a full understanding of the functions of emotions and additionally suggests that emotional organizing systems play a role in sculpting the brain during ontogeny. Nascent emotional systems thus affect cognitive development. A second proposal concerns two additions to the affective systems identified by Panksepp. We suggest there is substantial evidence for a primary emotional organizing program dealing with power, rank, dominance, and subordination which instantiates competitive and territorial behavior and is an evolutionary contributor to self-esteem in humans. A program underlying disgust reactions which originally functioned in ancient vertebrates to protect against infection and toxins is also suggested. PMID:23316177

  14. L-Phosphinothricin modulation of inwardly rectifying K(+) channels increased excitability in striatal medium-sized spiny neurons.

    PubMed

    Domingos, Laetitia; Desrus, Agnès; Même, Sandra; Même, William

    2016-07-01

    Phosphinotricin (L-PPT) is the active compound of a broad-spectrum herbicide. Acute poisoning with L-PPT has various clinical manifestations, including seizures and convulsions. However, the exact mechanism of L-PPT toxicity remains unclear. The present study addressed the role of L-PPT, in the excitability of striatal medium-sized spiny neurons (MSNs). In whole-cell current-clamp experiments, L-PPT increased the input resistance (Ri), decreased the rheobase and increased the firing frequency of action potentials. In voltage-clamp experiments, L-PPT inhibited the inward-rectifying potassium (Kir) currents. Finally, the effects of L-PPT mimicked the inhibition of Kir channels with Ba(2+) on neuronal excitability. Altogether, these results suggest that the herbicide L-PPT is a modulator of Kir channels in MSNs. Thereby, Kir channels are potent regulators of the excitability of MSNs and reduced open probability of these channels would generate a powerful upregulation of neuronal output. This effect may represent a possible mechanism for L-PPT dependent neuronal toxicity. PMID:27136897

  15. Maternal immune activation produces neonatal excitability defects in offspring hippocampal neurons from pregnant rats treated with poly I:C

    PubMed Central

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-01

    Maternal immune activation (MIA) resulting from prenatal exposure to infectious pathogens or inflammatory stimuli is increasingly recognized to play an important etiological role in neuropsychiatric disorders with neurodevelopmental features. MIA in pregnant rodents induced by injection of the synthetic double-stranded RNA, Poly I:C, a mimic of viral infection, leads to a wide spectrum of behavioral abnormalities as well as structural and functional defects in the brain. Previous MIA studies using poly I:C prenatal treatment suggested that neurophysiological alterations occur in the hippocampus. However, these investigations used only juvenile or adult animals. We postulated that MIA-induced alterations could occur earlier at neonatal/early postnatal stages. Here we examined the neurophysiological properties of cultured pyramidal-like hippocampal neurons prepared from neonatal (P0-P2) offspring of pregnant rats injected with poly I:C. Offspring neurons from poly I:C-treated mothers exhibited significantly lower intrinsic excitability and stronger spike frequency adaptation, compared to saline. A similar lower intrinsic excitability was observed in CA1 pyramidal neurons from hippocampal slices of two weeks-old poly I:C offspring. Cultured hippocampal neurons also displayed lower frequency of spontaneous firing, higher charge transfer of IPSCs and larger amplitude of miniature IPSCs. Thus, maternal immune activation leads to strikingly early neurophysiological abnormalities in hippocampal neurons. PMID:26742695

  16. Modulation of network excitability by persistent activity: how working memory affects the response to incoming stimuli.

    PubMed

    Tartaglia, Elisa M; Brunel, Nicolas; Mongillo, Gianluigi

    2015-02-01

    Persistent activity and match effects are widely regarded as neuronal correlates of short-term storage and manipulation of information, with the first serving active maintenance and the latter supporting the comparison between memory contents and incoming sensory information. The mechanistic and functional relationship between these two basic neurophysiological signatures of working memory remains elusive. We propose that match signals are generated as a result of transient changes in local network excitability brought about by persistent activity. Neurons more active will be more excitable, and thus more responsive to external inputs. Accordingly, network responses are jointly determined by the incoming stimulus and the ongoing pattern of persistent activity. Using a spiking model network, we show that this mechanism is able to reproduce most of the experimental phenomenology of match effects as exposed by single-cell recordings during delayed-response tasks. The model provides a unified, parsimonious mechanistic account of the main neuronal correlates of working memory, makes several experimentally testable predictions, and demonstrates a new functional role for persistent activity. PMID:25695777

  17. The 'too muchness' of excitement: sexuality in light of excess, attachment and affect regulation.

    PubMed

    Benjamin, Jessica; Atlas, Galit

    2015-02-01

    This paper brings together contemporary thinking about early attachment and affect regulation with our clinical and theoretical understanding of the problems of adult sexuality. In addition to recent theories of affect regulation and attachment, we incorporate Laplanche's idea of 'excess', which was an important transitional concept integrating real experience with fantasy in sexuality. We elaborate the idea of excess-- 'too-muchness' --to illuminate the early overwhelming of the psyche that affects the formation of sexuality. Linked to recent theoretical developments, this idea helps to grasp the relationship between sexual excitement and early affect regulation, showing how excitement becomes dangerous, thus impeding or distorting desire. The 'too-muchness' of excitement recalls the experience of being a stimulated, overwhelmed, unsoothed child and influences later inability to tolerate sexual arousal and the excitement affect. A clinical case illustrates this connection between attachment trauma, anxiety about sexuality, as well as shameful experiences of gender identity as an area of trauma. We emphasize the importance of working through the terrors and desires of the mother-baby relationship as they emerge in the transference-countertransference in order to develop the ability to hold excitement and stimulation without experiencing the too-much as the intolerable. This includes the working-through of ruptures related to overstimulation as well as the delicate balance of attention to fantasy and intersubjective work in the transference. PMID:25704459

  18. Nicotine enhances inhibition of mouse vagal motor neurons by modulating excitability of premotor GABAergic neurons in the nucleus tractus solitarii.

    PubMed

    Xu, Hong; Boychuk, Jeffery A; Boychuk, Carie R; Uteshev, Victor V; Smith, Bret N

    2015-02-15

    The caudal nucleus of the solitary tract (NTS) serves as the site of the first synapse for visceral sensory inputs to the central nervous system. The NTS sends functional projections to multiple brain nuclei, with gastric-related projections primarily targeting the dorsal motor nucleus of the vagus (DMV). Previous studies have demonstrated that the majority of caudal NTS neurons that project to the DMV respond robustly to nicotine and express nicotinic acetylcholine receptors (nAChRs). However, the cytochemical identity and relationship with specific viscera of DMV-projecting, nicotine-responsive caudal NTS neurons have not been determined. The present study used transgenic mice that express enhanced green fluorescent protein (EGFP) under a GAD67 promoter in a subset of GABAergic neurons, in vivo retrograde pseudorabies viral labeling to identify gastric-related vagal complex neurons, and patch-clamp electrophysiology in acute brain stem slices to test the hypothesis that gastric-related and GABAergic inhibitory synaptic input to the DMV from the caudal NTS is under a robust modulatory control by nAChRs. Our results suggest that activation of nAChRs in the caudal NTS, but not DMV, potentiates GABAergic, but not glutamatergic, input to the DMV. Gastric-related caudal NTS and DMV neurons are directly involved in this nicotine-sensitive circuitry. Understanding the central patterns of nicotinic modulation of visceral sensory-motor circuitry may help develop therapeutic interventions to restore autonomic homeostasis in patients with autonomic impairments. PMID:25429117

  19. DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

    PubMed Central

    Caron, Alexandre; Labbé, Sébastien M.; Mouchiroud, Mathilde; Huard, Renaud; Richard, Denis

    2016-01-01

    We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEPTOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brain-liver connection. PMID:27097662

  20. DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance.

    PubMed

    Caron, Alexandre; Labbé, Sébastien M; Mouchiroud, Mathilde; Huard, Renaud; Richard, Denis; Laplante, Mathieu

    2016-06-01

    We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEPTOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brain-liver connection. PMID:27097662

  1. Distinct forms of synaptic inhibition and neuromodulation regulate calretinin-positive neuron excitability in the spinal cord dorsal horn.

    PubMed

    Smith, K M; Boyle, K A; Mustapa, M; Jobling, P; Callister, R J; Hughes, D I; Graham, B A

    2016-06-21

    The dorsal horn (DH) of the spinal cord contains a heterogenous population of neurons that process incoming sensory signals before information ascends to the brain. We have recently characterized calretinin-expressing (CR+) neurons in the DH and shown that they can be divided into excitatory and inhibitory subpopulations. The excitatory population receives high-frequency excitatory synaptic input and expresses delayed firing action potential discharge, whereas the inhibitory population receives weak excitatory drive and exhibits tonic or initial bursting discharge. Here, we characterize inhibitory synaptic input and neuromodulation in the two CR+ populations, in order to determine how each is regulated. We show that excitatory CR+ neurons receive mixed inhibition from GABAergic and glycinergic sources, whereas inhibitory CR+ neurons receive inhibition, which is dominated by glycine. Noradrenaline and serotonin produced robust outward currents in excitatory CR+ neurons, predicting an inhibitory action on these neurons, but neither neuromodulator produced a response in CR+ inhibitory neurons. In contrast, enkephalin (along with selective mu and delta opioid receptor agonists) produced outward currents in inhibitory CR+ neurons, consistent with an inhibitory action but did not affect the excitatory CR+ population. Our findings show that the pharmacology of inhibitory inputs and neuromodulator actions on CR+ cells, along with their excitatory inputs can define these two subpopulations further, and this could be exploited to modulate discrete aspects of sensory processing selectively in the DH. PMID:27045594

  2. ATP excites mouse vomeronasal sensory neurons through activation of P2X receptors.

    PubMed

    Vick, J S; Delay, R J

    2012-09-18

    Purinergic signaling through activation of P2X and P2Y receptors is critically important in the chemical senses. In the mouse main olfactory epithelium (MOE), adenosine 5'-triphosphate (ATP) elicits an increase in intracellular calcium ([Ca(2+)](I)) and reduces the responsiveness of olfactory sensory neurons to odorants through activation of P2X and P2Y receptors. We investigated the role of purinergic signaling in vomeronasal sensory neuron (VSN)s from the mouse vomeronasal organ (VNO), an olfactory organ distinct from the MOE that responds to many conspecific chemical cues. Using a combination of calcium imaging and patch-clamp electrophysiology with isolated VSNs, we demonstrated that ATP elicits an increase in [Ca(2+)](I) and an inward current with similar EC(50)s. Neither adenosine nor the P2Y receptor ligands adenosine 5'-diphosphate, uridine 5'-triphosphate, and uridine-5'-disphosphate could mimic either effect of ATP. Moreover, the increase in [Ca(2+)](I) required the presence of extracellular calcium and the inward current elicited by ATP was partially blocked by the P2X receptor antagonists pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate and 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate. Consistent with the activation of P2X receptors, we detected gene expression of the P2X1 and 3 receptors in the VNO by Reverse transcription polymerase chain reaction (RT-PCR). When co-delivered with dilute urine, a natural stimulus, ATP significantly increased the inward current above that elicited by dilute urine or ATP alone. Mechanical stimulation of the VNO induced the release of ATP, detected by luciferin-luciferase luminometry, and this release of ATP was completely abolished in the presence of the connexin/pannexin hemichannel blocker, carbenoxolone. We conclude that the release of ATP could occur during the activity of the vasomotor pump that facilitates the movement of chemicals into the VNO for detection by VSNs. This mechanism could lead to a

  3. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability.

    PubMed

    Hsu, Wei-Chun J; Scala, Federico; Nenov, Miroslav N; Wildburger, Norelle C; Elferink, Hannah; Singh, Aditya K; Chesson, Charles B; Buzhdygan, Tetyana; Sohail, Maveen; Shavkunov, Alexander S; Panova, Neli I; Nilsson, Carol L; Rudra, Jai S; Lichti, Cheryl F; Laezza, Fernanda

    2016-06-01

    Recent data shows that fibroblast growth factor 14 (FGF14) binds to and controls the function of the voltage-gated sodium (Nav) channel with phenotypic outcomes on neuronal excitability. Mutations in the FGF14 gene in humans have been associated with brain disorders that are partially recapitulated in Fgf14(-/-) mice. Thus, signaling pathways that modulate the FGF14:Nav channel interaction may be important therapeutic targets. Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. In 1 d in vitro hippocampal neurons, TBB induced a reduction in FGF14 expression, a decrease in transient Na(+) current amplitude, and a hyperpolarizing shift in the voltage dependence of Nav channel steady-state inactivation. In mature neurons, TBB reduces the axodendritic polarity of FGF14. In cornu ammonis area 1 hippocampal slices from wild-type mice, TBB impairs neuronal excitability by increasing action potential threshold and lowering firing frequency. Importantly, these changes in excitability are recapitulated in Fgf14(-/-) mice, and deletion of Fgf14 occludes TBB-dependent phenotypes observed in wild-type mice. These results suggest that a CK2-FGF14 axis may regulate Nav channels and neuronal excitability.-Hsu, W.-C. J., Scala, F., Nenov, M. N., Wildburger, N. C., Elferink, H., Singh, A. K., Chesson, C. B., Buzhdygan, T., Sohail, M., Shavkunov, A. S., Panova, N. I., Nilsson, C. L., Rudra, J. S., Lichti, C. F., Laezza, F. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal

  4. Light exposure induces short- and long-term changes in the excitability of retinorecipient neurons in suprachiasmatic nucleus

    PubMed Central

    LeSauter, Joseph; Cloues, Robin; Witkovsky, Paul

    2011-01-01

    The suprachiasmatic nucleus (SCN) is the locus of a hypothalamic circadian clock that synchronizes physiological and behavioral responses to the daily light-dark cycle. The nucleus is composed of functionally and peptidergically diverse populations of cells for which distinct electrochemical properties are largely unstudied. SCN neurons containing gastrin-releasing peptide (GRP) receive direct retinal input via the retinohypothalamic tract. We targeted GRP neurons with a green fluorescent protein (GFP) marker for whole cell patch-clamping. In these neurons, we studied short (0.5–1.5 h)- and long-term (2–6 h) effects of a 1-h light pulse (LP) given 2 h after lights off [Zeitgeber time (ZT) 14:00–15:00] on membrane potential and spike firing. In brain slices taken from light-exposed animals, cells were depolarized, and spike firing rate increased between ZT 15:30 and 16:30. During a subsequent 4-h period beginning around ZT 17:00, GRP neurons from light-exposed animals were hyperpolarized by ∼15 mV. None of these effects was observed in GRP neurons from animals not exposed to light or in immediately adjacent non-GRP neurons whether or not exposed to light. Depolarization of GRP neurons was associated with a reduction in GABAA-dependent synaptic noise, whereas hyperpolarization was accompanied both by a loss of GABAA drive and suppression of a TTX-resistant leakage current carried primarily by Na. This suggests that, in the SCN, exposure to light may induce a short-term increase in GRP neuron excitability mediated by retinal neurotransmitters and neuropeptides, followed by long-term membrane hyperpolarization resulting from suppression of a leakage current, possibly resulting from genomic signals. PMID:21593396

  5. Pulse exposure of cultured rat neurons to aluminum-maltol affected the axonal transport system.

    PubMed

    Kashiwagi, Y; Nakamura, Y; Miyamae, Y; Hashimoto, R; Takeda, M

    1998-08-01

    Although chronic aluminum neurotoxicity has been well established, the mechanism of the toxicity has not been elucidated yet. In order to simplify the study of the aluminum neurotoxicity, we employed the pulse exposure of cultured rat cortical neurons to 250 microM aluminum-maltol for 1 h at the early stage (6 h after plating), which resulted in abnormal distribution of neurofilament L (NFL) and fast axonal transported proteins, whereas the axonal transport of tubulin, actin, and clathrin were not impaired. Otherwise, the pulse exposure of neurons at the late stage (4 days after plating) to the same concentration of aluminum-maltol did not affect the cell morphology and the distribution of NFL. The pulse exposure of cultured neurons to aluminum-maltol at the early stage might affect the axonal transport system of NFL and fast axonal transported proteins. PMID:9756345

  6. Genetic Inhibition of CaMKII in Dorsal Striatal Medium Spiny Neurons Reduces Functional Excitatory Synapses and Enhances Intrinsic Excitability

    PubMed Central

    Klug, Jason R.; Mathur, Brian N.; Kash, Thomas L.; Wang, Hui-Dong; Matthews, Robert T.; Robison, A. J.; Anderson, Mark E.; Deutch, Ariel Y.; Lovinger, David M.; Colbran, Roger J.; Winder, Danny G.

    2012-01-01

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) is abundant in striatal medium spiny neurons (MSNs). CaMKII is dynamically regulated by changes in dopamine signaling, as occurs in Parkinson's disease as well as addiction. Although CaMKII has been extensively studied in the hippocampus where it regulates excitatory synaptic transmission, relatively little is known about how it modulates neuronal function in the striatum. Therefore, we examined the impact of selectively overexpressing an EGFP-fused CaMKII inhibitory peptide (EAC3I) in striatal medium spiny neurons (MSNs) using a novel transgenic mouse model. EAC3I-expressing cells exhibited markedly decreased excitatory transmission, indicated by a decrease in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs). This decrease was not accompanied by changes in the probability of release, levels of glutamate at the synapse, or changes in dendritic spine density. CaMKII regulation of the AMPA receptor subunit GluA1 is a major means by which the kinase regulates neuronal function in the hippocampus. We found that the decrease in striatal excitatory transmission seen in the EAC3I mice is mimicked by deletion of GluA1. Further, while CaMKII inhibition decreased excitatory transmission onto MSNs, it increased their intrinsic excitability. These data suggest that CaMKII plays a critical role in setting the excitability rheostat of striatal MSNs by coordinating excitatory synaptic drive and the resulting depolarization response. PMID:23028932

  7. Neurosteroid interactions with synaptic and extrasynaptic GABAa receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

    PubMed Central

    Chase Matthew, Carver; Doodipala Samba, Reddy

    2013-01-01

    Rationale Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal GABAa receptors are one of the prime molecular targets of neurosteroids. Objective This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABAa receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABAa receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABAa receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABAa receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior. Conclusion The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABAa receptors provide many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions. PMID:24071826

  8. Excitability of spinal motor neurons during motor imagery of thenar muscle activity under maximal voluntary contractions of 50% and 100%

    PubMed Central

    Bunno, Yoshibumi; Onigata, Chieko; Suzuki, Toshiaki

    2015-01-01

    [Purpose] We often perform physical therapy using motor imagery of muscle contraction to improve motor function for healthy subjects and central nerve disorders. This study aimed to determine the differences in the excitability of spinal motor neurons during motor imagery of a muscle contraction at different contraction strengths. [Subjects] We recorded the F-wave in 15 healthy subjects. [Methods] In resting trial, the muscle was relaxed during F-wave recording. For motor imagery trial, subjects were instructed to imagine maximal voluntary contractions of 50% and 100% while holding the sensor of a pinch meter, and F-waves were recorded for each contraction. The F-wave was recorded immediately after motor imagery. [Results] Persistence and F/M amplitude ratio during motor imagery under maximal voluntary contractions of 50% and 100% were significantly higher than that at rest. In addition, the relative values of persistence, F/M amplitude ratio, and latency were similar during motor imagery under the two muscle contraction strengths. [Conclusion] Motor imagery under maximal voluntary contractions of 50% and 100% can increase the excitability of spinal motor neurons. Differences in the imagined muscle contraction strengths are not involved in changes in the excitability of spinal motor neurons. PMID:26504291

  9. Suppression of ATP-induced excitability in rat small-diameter trigeminal ganglion neurons by activation of GABAB receptor.

    PubMed

    Takeda, Mamoru; Ikeda, Mizuho; Takahashi, Masayuki; Kanazawa, Takuya; Nasu, Masanori; Matsumoto, Shigeji

    2013-09-01

    The aim of the present study was to investigate whether a GABAB receptor agonist could modulate ATP-activated neuronal excitability of nociceptive TRG neurons using perforated whole-cell patch-clamp and immunohistochemical techniques. Immunohistochemical analysis revealed that 86% of P2X3 receptor-immunoreactive, small-diameter TRG neurons co-expressed GABAB receptor. Under voltage-clamp conditions (Vh=-60mV), application of ATP activated the inward current in acutely isolated rat TRG neurons in a dose-dependent manner (10-50 μM) and this current could be blocked by pyridoxal-phosphate-6-azophenyl-27,47-disulfonic acid (PPADS) (10 μM), a selective P2 purinoreceptor antagonist. The peak amplitude of ATP-activated currents was significantly inhibited after application of GABAB receptor agonist, baclofen (10-50 μM), in a concentration-dependent and reversible manner. The baclofen-induced inhibition of ATP-activated current was abolished by co-application of 3-amino-2 (4-chlorophenyl)-2hydroxypropysufonic acid) saclofen, a GABAB receptor antagonist (50 μM). Under current-clamp conditions, application of 20 μM ATP significantly depolarized the membrane potential resulting in increased mean action potential frequencies, and these ATP-induced effects were significantly inhibited by baclofen and these effects were antagonized by co-application of saclofen. Together, the results suggested that GABAB receptor activation could inhibit the ATP-induced excitability of small-diameter TRG neurons activated through the P2X3 receptor. Thus, the interaction between P2X3 and GABAB receptors of small-diameter TRG neuronal cell bodies is a potential therapeutic target for the treatment of trigeminal nociception. PMID:24004472

  10. Stress-Hyperresponsive WKY Rats Demonstrate Depressed Dorsal Raphe Neuronal Excitability and Dysregulated CRF-Mediated Responses

    PubMed Central

    Lemos, Julia C; Zhang, Guojun; Walsh, Teresa; Kirby, Lynn G; Akanwa, Adaure; Brooks-Kayal, Amy; Beck, Sheryl G

    2011-01-01

    Major depression is a debilitating psychiatric disease that may be precipitated by a dysregulation of stress neurocircuitry caused by chronic or severe stress exposure. Moreover, hyperresponsivity to stressors correlates with depressed mood and may contribute to the etiology of major depression. The serotonergic dorsal raphe nucleus (DRN) is an important site in the neurocircuitry underlying behavioral responses to stressors, and is tightly regulated, in part, by a combination of intrinsic cell properties, autoinhibition, and GABAergic synaptic transmission. The stress-related neurotransmitter corticotropin-releasing factor (CRF) modulates DRN neuronal excitability and subsequent 5-HT release in the forebrain. Wistar Kyoto (WKY) rats exhibit exaggerated behavioral responses to stressors, that is, stress hyperresponsivity, and are considered an animal model of depression. To better understand the neurobiological basis of the stress hyperresponsivity, we used a combination of mRNA analysis and whole-cell electrophysiological techniques to measure differences in intrinsic activity and receptor response, in 5-HT- and non-5-HT-containing neurons of the DRN in WKY rats compared with Sprague-Dawley controls. In the WKY rat, there was a decrease in the neuronal excitability of 5-HT neurons coupled with decreased TPH2 production. Additionally, we found that CRF did not increase GABAergic activity in 5-HT neurons as is normally seen in 5-HT neurons of Sprague-Dawley controls. The CRF modulation of 5-HT DRN neurotransmission at the single-cell level is selectively disrupted in the WKY animal model of depression and may be one of the cellular correlates underlying depression. PMID:21160465

  11. Mild systemic inflammation and moderate hypoxia transiently alter neuronal excitability in mouse somatosensory cortex.

    PubMed

    Mordel, Jérôme; Sheikh, Aminah; Tsohataridis, Simeon; Kanold, Patrick O; Zehendner, Christoph M; Luhmann, Heiko J

    2016-04-01

    During the perinatal period, the brain is highly vulnerable to hypoxia and inflammation, which often cause white matter injury and long-term neuronal dysfunction such as motor and cognitive deficits or epileptic seizures. We studied the effects of moderate hypoxia (HYPO), mild systemic inflammation (INFL), or the combination of both (HYPO+INFL) in mouse somatosensory cortex induced during the first postnatal week on network activity and compared it to activity in SHAM control animals. By performing in vitro electrophysiological recordings with multi-electrode arrays from slices prepared directly after injury (P8-10), one week after injury (P13-16), or in young adults (P28-30), we investigated how the neocortical network developed following these insults. No significant difference was observed between the four groups in an extracellular solution close to physiological conditions. In extracellular 8mM potassium solution, slices from the HYPO, INFL, and HYPO+INFL group were more excitable than SHAM at P8-10 and P13-16. In these two age groups, the number and frequency of spontaneous epileptiform events were significantly increased compared to SHAM. The frequency of epileptiform events was significantly reduced by the NMDA antagonist D-APV in HYPO, INFL, and HYPO+INFL, but not in SHAM, indicating a contribution of NMDA receptors to this pathophysiological activity. In addition, the AMPA/kainate receptor antagonist CNQX suppressed the remaining epileptiform activity. Electrical stimulation evoked prominent epileptiform activity in slices from HYPO, INFL and HYPO+INFL animals. Stimulation threshold to elicit epileptiform events was lower in these groups than in SHAM. Evoked events spread over larger areas and lasted longer in treated animals than in SHAM. In addition, the evoked epileptiform activity was reduced in the older (P28-30) group indicating that cortical dysfunction induced by hypoxia and inflammation was transient and compensated during early development. PMID

  12. Involvement of the mirror neuron system in blunted affect in schizophrenia.

    PubMed

    Lee, Jung Suk; Chun, Ji Won; Yoon, Sang Young; Park, Hae-Jeong; Kim, Jae-Jin

    2014-01-01

    Blunted affect is a relatively enduring schizophrenic symptom and its presence brings about poor functioning and outcomes. Functional impairment in the mirror neuron system which is involved in both motor execution and imitation may be a neural basis of blunted affect, but it is not proved yet. Fifteen patients with schizophrenia and 16 healthy controls performed the facial expression task during functional magnetic resonance imaging. The task was to reproduce facial expressions in response to the face or word stimuli for happiness, sadness, and meaningless expression. Brain activities during facial expressions in patients compared with controls and their relationship with affective flattening were analyzed. Compared to controls, patients exhibited decreased activity in the widespread dorsal frontal regions and increased activity in the ventral frontal and subcortical regions. Patients also demonstrated significant negative correlation of the severity of affective flattening with activities in the mirror neuron system, such as the premotor cortex, motor cortex, and inferior parietal lobule. Emotional expression in patients with schizophrenia may be related to hypoactivity of the dorsal system and hyperactivity of the ventral system. An imbalance of these two systems may contribute to blunted affect. Directly addressing blunted affect using emotional expression provides a new perspective that functional disturbance of the mirror neuron system may play an important role in manifestation of blunted affect in schizophrenia. PMID:24268934

  13. Sleep deprivation does not affect neuronal susceptibility to mild traumatic brain injury in the rat.

    PubMed

    Caron, Aimee M; Stephenson, Richard

    2015-01-01

    Mild and moderate traumatic brain injuries (TBIs) (and concussion) occur frequently as a result of falls, automobile accidents, and sporting activities, and are a major cause of acute and chronic disability. Fatigue and excessive sleepiness are associated with increased risk of accidents, but it is unknown whether prior sleep debt also affects the pathophysiological outcome of concussive injury. Using the "dark neuron" (DN) as a marker of reversible neuronal damage, we tested the hypothesis that acute (48 hours) total sleep deprivation (TSD) and chronic sleep restriction (CSR; 10 days, 6-hour sleep/day) affect DN formation following mild TBI in the rat. TSD and CSR were administered using a walking wheel apparatus. Mild TBI was administered under anesthesia using a weight-drop impact model, and the acute neuronal response was observed without recovery. DNs were detected using standard bright-field microscopy with toluidine blue stain following appropriate tissue fixation. DN density was low under home cage and sleep deprivation control conditions (respective median DN densities, 0.14% and 0.22% of neurons), and this was unaffected by TSD alone (0.1%). Mild TBI caused significantly higher DN densities (0.76%), and this was unchanged by preexisting acute or chronic sleep debt (TSD, 0.23%; CSR, 0.7%). Thus, although sleep debt may be predicted to increase the incidence of concussive injury, the present data suggest that sleep debt does not exacerbate the resulting neuronal damage. PMID:26124685

  14. Chronic alcohol exposure affects the cell components involved in membrane traffic in neuronal dendrites.

    PubMed

    Romero, Ana M; Renau-Piqueras, Jaime; Marín, M Pilar; Esteban-Pretel, Guillermo

    2015-01-01

    The specific traffic of the membrane components in neurons is a major requirement to establish and maintain neuronal domains-the axonal and the somatodendritic domains-and their polarized morphology. Unlike axons, dendrites contain membranous organelles, which are involved in the secretory pathway, including the endoplasmic reticulum, the Golgi apparatus and post-Golgi apparatus carriers, the cytoskeleton, and plasma membrane. A variety of molecules and factors are also involved in this process. Previous studies have shown that chronic alcohol exposure negatively affects several of these cell components, such as the Golgi apparatus or cytoskeleton in neurons. Yet very little information is available on the possible effects of this exposure on the remaining cell elements involved in intracellular trafficking in neurons, particularly in dendrites. By qualitative and quantitative electron microscopy, immunofluorescence and immunoblotting, we herein show that chronic exposure to moderate levels (30 mM) of ethanol in cultured neurons reduces the volume and surface density of the rough endoplasmic reticulum, and increases the levels of GRP78, a chaperone involved in endoplasmic reticulum stress. Ethanol also significantly diminishes the proportion of neurons that show an extension of Golgi into dendrites and dendritic Golgi outposts, a structure present exclusively in longer, thicker apical dendrites. Both Golgi apparatus types were also fragmented into a large number of cells. We also investigated the effect of alcohol on the levels of microtubule-based motor proteins KIF5, KIF17, KIFC2, dynein, and myosin IIb, responsible for transporting different cargoes in dendrites. Of these, alcohol differently affects several of them by lowering dynein and raising KIF5, KIFC2, and myosin IIb. These results, together with other previously published ones, suggest that practically all the protein trafficking steps in dendrites are altered to a greater or lesser extent by chronic

  15. Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation

    PubMed Central

    Kantor, Gal; Cheishvili, David; Even, Aviel; Birger, Anastasya; Turetsky, Tikva; Gil, Yaniv; Even-Ram, Sharona; Aizenman, Einat; Bashir, Nibal; Maayan, Channa; Razin, Aharon; Reubinoff, Benjamim E.; Weil, Miguel

    2015-01-01

    A splicing mutation in the IKBKAP gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we found new molecular insights for the IKAP role and the impact of the FD mutation in the human PNS lineage by using a novel and unique human embryonic stem cell (hESC) line homozygous to the FD mutation originated by pre implantation genetic diagnosis (PGD) analysis. We found that IKBKAP downregulation during PNS differentiation affects normal migration in FD-hESC derived neural crest cells (NCC) while at later stages the PNS neurons show reduced intracellular colocalization between vesicular proteins and IKAP. Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons. Moreover we show that kinetin (a drug that corrects IKBKAP alternative splicing) promotes the recovery of IKAP expression and these IKAP functional associated genes identified in the study. Altogether, these results support the view that IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons. This function seems to be mostly affected in FD-hESC derived PNS neurons probably reflecting some PNS neuronal dysfunction observed in FD. PMID:26437462

  16. Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels.

    PubMed

    Valente, Pierluigi; Lignani, Gabriele; Medrihan, Lucian; Bosco, Federica; Contestabile, Andrea; Lippiello, Pellegrino; Ferrea, Enrico; Schachner, Melitta; Benfenati, Fabio; Giovedì, Silvia; Baldelli, Pietro

    2016-05-01

    L1 (also known as L1CAM) is a trans-membrane glycoprotein mediating neuron-neuron adhesion through homophilic and heterophilic interactions. Although experimental evidence has implicated L1 in axonal outgrowth, fasciculation and pathfinding, its contribution to voltage-gated Na(+) channel function and membrane excitability has remained unknown. Here, we show that firing rate, single cell spiking frequency and Na(+) current density are all reduced in hippocampal excitatory neurons from L1-deficient mice both in culture and in slices owing to an overall reduced membrane expression of Na(+) channels. Remarkably, normal firing activity was restored when L1 was reintroduced into L1-deficient excitatory neurons, indicating that abnormal firing patterns are not related to developmental abnormalities, but are a direct consequence of L1 deletion. Moreover, L1 deficiency leads to impairment of action potential initiation, most likely due to the loss of the interaction of L1 with ankyrin G that produces the delocalization of Na(+) channels at the axonal initial segment. We conclude that L1 contributes to functional expression and localization of Na(+) channels to the neuronal plasma membrane, ensuring correct initiation of action potential and normal firing activity. PMID:26985064

  17. miR-128 regulates neuronal migration, outgrowth and intrinsic excitability via the intellectual disability gene Phf6

    PubMed Central

    Franzoni, Eleonora; Booker, Sam A; Parthasarathy, Srinivas; Rehfeld, Frederick; Grosser, Sabine; Srivatsa, Swathi; Fuchs, Heiko R; Tarabykin, Victor; Vida, Imre; Wulczyn, F Gregory

    2015-01-01

    miR-128, a brain-enriched microRNA, has been implicated in the control of neurogenesis and synaptogenesis but its potential roles in intervening processes have not been addressed. We show that post-transcriptional mechanisms restrict miR-128 accumulation to post-mitotic neurons during mouse corticogenesis and in adult stem cell niches. Whereas premature miR-128 expression in progenitors for upper layer neurons leads to impaired neuronal migration and inappropriate branching, sponge-mediated inhibition results in overmigration. Within the upper layers, premature miR-128 expression reduces the complexity of dendritic arborization, associated with altered electrophysiological properties. We show that Phf6, a gene mutated in the cognitive disorder Börjeson-Forssman-Lehmann syndrome, is an important regulatory target for miR-128. Restoring PHF6 expression counteracts the deleterious effect of miR-128 on neuronal migration, outgrowth and intrinsic physiological properties. Our results place miR-128 upstream of PHF6 in a pathway vital for cortical lamination as well as for the development of neuronal morphology and intrinsic excitability. DOI: http://dx.doi.org/10.7554/eLife.04263.001 PMID:25556700

  18. Dissecting mechanisms of brain aging by studying the intrinsic excitability of neurons

    PubMed Central

    Rizzo, Valerio; Richman, Jeffrey; Puthanveettil, Sathyanarayanan V.

    2015-01-01

    Several studies using vertebrate and invertebrate animal models have shown aging associated changes in brain function. Importantly, changes in soma size, loss or regression of dendrites and dendritic spines and alterations in the expression of neurotransmitter receptors in specific neurons were described. Despite this understanding, how aging impacts intrinsic properties of individual neurons or circuits that govern a defined behavior is yet to be determined. Here we discuss current understanding of specific electrophysiological changes in individual neurons and circuits during aging. PMID:25610394

  19. Distinct ensembles of medial prefrontal cortex neurons are activated by threatening stimuli that elicit excitation vs. inhibition of movement.

    PubMed

    Halladay, Lindsay R; Blair, Hugh T

    2015-08-01

    Neural circuits controlling defensive behavior were investigated by recording single units in medial prefrontal cortex (mPFC) and dorsolateral periaqueductal gray (dlPAG) while rats expressed conditioned fear responses to an auditory conditioned stimulus (CS; 20-s train of white noise pips) previously paired with an aversive unconditioned stimulus (US; 2-s train of periorbital shocks). The CS elicited conditioned movement inhibition (CMI; characterized by decreased movement speed and freezing) when rats had not recently encountered the US, whereas the CS elicited conditioned movement excitation (CME; characterized by increased movement speed and flight behavior) after recent US encounters. Many mPFC neurons were "strategy-selective" cells that changed their firing rates only when the CS elicited CME (15/71) or CMI (13/71) responses, whereas few mPFC cells (4/71) responded nonselectively to the CS during either response. By contrast, many dlPAG neurons (20/74) responded nonselectively to the CS, but most (40/74) were excited by the CS selectively during CME trials (and none during CMI trials). CME-selective neurons in dlPAG responded phasically after CS pips that elicited CME responses, whereas CME-selective neurons in mPFC showed tonically elevated activity before and after pips that evoked CME responses. These findings suggest that, at the time when the CS occurs, tonic firing rates of CME- and CMI-selective mPFC neurons may bias the rat's choice of whether to express CME vs. CMI responses, perhaps via projections to downstream structures (such as amygdala and PAG) that influence how sensory stimuli are mapped onto motor circuits that drive the expression of competing behaviors. PMID:25972588

  20. Prostaglandin D2 Modulates Neuronal Excitation of the Trigeminal Ganglion to Augment Allergic Rhinitis in Guinea Pigs.

    PubMed

    Nagira, Yoji; Goto, Kumiko; Tanaka, Hiroyuki; Aoki, Miwa; Furue, Shingo; Inagaki, Naoki; Tomita, Yasuhiko; Shichijo, Michitaka

    2016-05-01

    Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis. PMID:26945085

  1. Distinct ensembles of medial prefrontal cortex neurons are activated by threatening stimuli that elicit excitation vs. inhibition of movement

    PubMed Central

    Blair, Hugh T.

    2015-01-01

    Neural circuits controlling defensive behavior were investigated by recording single units in medial prefrontal cortex (mPFC) and dorsolateral periaqueductal gray (dlPAG) while rats expressed conditioned fear responses to an auditory conditioned stimulus (CS; 20-s train of white noise pips) previously paired with an aversive unconditioned stimulus (US; 2-s train of periorbital shocks). The CS elicited conditioned movement inhibition (CMI; characterized by decreased movement speed and freezing) when rats had not recently encountered the US, whereas the CS elicited conditioned movement excitation (CME; characterized by increased movement speed and flight behavior) after recent US encounters. Many mPFC neurons were “strategy-selective” cells that changed their firing rates only when the CS elicited CME (15/71) or CMI (13/71) responses, whereas few mPFC cells (4/71) responded nonselectively to the CS during either response. By contrast, many dlPAG neurons (20/74) responded nonselectively to the CS, but most (40/74) were excited by the CS selectively during CME trials (and none during CMI trials). CME-selective neurons in dlPAG responded phasically after CS pips that elicited CME responses, whereas CME-selective neurons in mPFC showed tonically elevated activity before and after pips that evoked CME responses. These findings suggest that, at the time when the CS occurs, tonic firing rates of CME- and CMI-selective mPFC neurons may bias the rat's choice of whether to express CME vs. CMI responses, perhaps via projections to downstream structures (such as amygdala and PAG) that influence how sensory stimuli are mapped onto motor circuits that drive the expression of competing behaviors. PMID:25972588

  2. Excitation and inhibition onto central courtship neurons biases Drosophila mate choice

    PubMed Central

    Kallman, Benjamin R; Kim, Heesoo; Scott, Kristin

    2015-01-01

    The ability to distinguish males from females is essential for productive mate selection and species propagation. Recent studies in Drosophila have identified different classes of contact chemosensory neurons that detect female or male pheromones and influence courtship decisions. Here, we examine central neural pathways in the male brain that process female and male pheromones using anatomical, calcium imaging, optogenetic, and behavioral studies. We find that sensory neurons that detect female pheromones, but not male pheromones, activate a novel class of neurons in the ventral nerve cord to cause activation of P1 neurons, male-specific command neurons that trigger courtship. In addition, sensory neurons that detect male pheromones, as well as those that detect female pheromones, activate central mAL neurons to inhibit P1. These studies demonstrate that the balance of excitatory and inhibitory drives onto central courtship-promoting neurons controls mating decisions. DOI: http://dx.doi.org/10.7554/eLife.11188.001 PMID:26568316

  3. AMPA receptor mediated synaptic excitation drives state-dependent bursting in Purkinje neurons of zebrafish larvae

    PubMed Central

    Sengupta, Mohini; Thirumalai, Vatsala

    2015-01-01

    Purkinje neurons are central to cerebellar function and show membrane bistability when recorded in vitro or in vivo under anesthesia. The existence of bistability in vivo in awake animals is disputed. Here, by recording intracellularly from Purkinje neurons in unanesthetized larval zebrafish (Danio rerio), we unequivocally demonstrate bistability in these neurons. Tonic firing was seen in depolarized regimes and bursting at hyperpolarized membrane potentials. In addition, Purkinje neurons could switch from one state to another spontaneously or with current injection. While GABAAR or NMDAR were not required for bursting, activation of AMPARs by climbing fibers (CFs) was sufficient to trigger bursts. Further, by recording Purkinje neuron membrane potential intracellularly, and motor neuron spikes extracellularly, we show that initiation of motor neuron spiking is correlated with increased incidence of CF EPSPs and membrane depolarization. Developmentally, bistability was observed soon after Purkinje neuron specification and persists at least until late larval stages. DOI: http://dx.doi.org/10.7554/eLife.09158.001 PMID:26416140

  4. Differentiation of voltage-gated potassium current and modulation of excitability in cultured amphibian spinal neurones.

    PubMed Central

    Barish, M E

    1986-01-01

    Gigaohm-seal whole-cell voltage-clamp techniques were used to study the development of ionic currents in the membrane of embryonic amphibian (Ambystoma) spinal neurones during in vitro differentiation. Dissociated neural plate cells, some of which are neuronal precursor cells, were placed into culture. Cells became excitable at the time of neurite outgrowth, 2-3 days later, and over the next 2-10 days the duration of the action potential shortened from about 100 ms to about 1 ms. Voltage-clamp recordings demonstrated that at the time of appearance of neurites, activatable Na, Ca and voltage-gated K channels were present in the membrane (Ca-dependent K channels were not studied). Over succeeding days in culture, records of total membrane current indicated that the amplitudes of peak inward and steady-state outward currents both increased. As a result of these increases, the pattern of total membrane current came to be increasingly dominated by outward currents. With inward Na and Ca currents blocked, a voltage-gated K current (IK(V] could be studied in isolation. The reversal potential of this current varied in good agreement with the equilibrium potential for K ions predicted by the Nernst relation. The wave form of IK(V) activation was sigmoidal. Activation was more rapid at more positive voltages (relative to the usual holding potential of -70 mV), and deactivation was more rapid at more negative voltages. The amplitude of IK(V) increased during neural development, while cell size remained approximately constant. Increases in rates of activation and deactivation were observed in parallel with the increase in current density. When measured at 0 mV, cells studied on day 4 of culture or earlier showed steady-state chord conductances (gK(V] of less than 20 nS, and one-half activation times (t1/2) of 2 X 5-10 ms. Older cells showed gK(V)s of 10-80 nS, and t1/2s of 0 X 8-2 X 5 ms. As Na, and to a lesser extent Ca, current amplitudes were also increasing during

  5. A STRIPAK component Strip regulates neuronal morphogenesis by affecting microtubule stability

    PubMed Central

    Sakuma, Chisako; Okumura, Misako; Umehara, Tomoki; Miura, Masayuki; Chihara, Takahiro

    2015-01-01

    During neural development, regulation of microtubule stability is essential for proper morphogenesis of neurons. Recently, the striatin-interacting phosphatase and kinase (STRIPAK) complex was revealed to be involved in diverse cellular processes. However, there is little evidence that STRIPAK components regulate microtubule dynamics, especially in vivo. Here, we show that one of the core STRIPAK components, Strip, is required for microtubule organization during neuronal morphogenesis. Knockdown of Strip causes a decrease in the level of acetylated α-tubulin in Drosophila S2 cells, suggesting that Strip influences the stability of microtubules. We also found that Strip physically and genetically interacts with tubulin folding cofactor D (TBCD), an essential regulator of α- and β-tubulin heterodimers. Furthermore, we demonstrate the genetic interaction between strip and Down syndrome cell adhesion molecule (Dscam), a cell surface molecule that is known to work with TBCD. Thus, we propose that Strip regulates neuronal morphogenesis by affecting microtubule stability. PMID:26644129

  6. System characterization of neuronal excitability in the hippocampus and its relevance to observed dynamics of spontaneous seizure-like transitions

    NASA Astrophysics Data System (ADS)

    Zalay, Osbert C.; Serletis, Demitre; Carlen, Peter L.; Bardakjian, Berj L.

    2010-06-01

    Most forms of epilepsy are marked by seizure episodes that arise spontaneously. The low-magnesium/high-potassium (low-Mg2+/high-K+) experimental model of epilepsy is an acute model that produces spontaneous, recurring seizure-like events (SLEs). To elucidate the nature of spontaneous seizure transitions and their relationship to neuronal excitability, whole-cell recordings from the intact hippocampus were undertaken in vitro, and the response of hippocampal CA3 neurons to Gaussian white noise injection was obtained before and after treatment with various concentrations of low-Mg2+/high-K+ solution. A second-order Volterra kernel model was estimated for each of the input-output response pairs. The spectral energy of the responses was also computed, providing a quantitative measure of neuronal excitability. Changes in duration and amplitude of the first-order kernel correlated positively with the spectral energy increase following treatment with low-Mg2+/high-K+ solution, suggesting that variations in neuronal excitability are coded by the system kernels, in part by differences to the profile of the first-order kernel. In particular, kernel duration was more sensitive than amplitude to changes in spectral energy, and correlated more strongly with kernel area. An oscillator network model of the hippocampal CA3 was constructed to investigate the relationship of kernel duration to network excitability, and the model was able to generate spontaneous, recurrent SLEs by increasing the duration of a mode function analogous to the first-order kernel. Results from the model indicated that disruption to the dynamic balance of feedback was responsible for seizure-like transitions and the observed intermittency of SLEs. A physiological candidate for feedback imbalance consistent with the network model is the destabilizing interaction of extracellular potassium and paroxysmal neuronal activation. Altogether, these results (1) validate a mathematical model for epileptiform

  7. System characterization of neuronal excitability in the hippocampus and its relevance to observed dynamics of spontaneous seizure-like transitions.

    PubMed

    Zalay, Osbert C; Serletis, Demitre; Carlen, Peter L; Bardakjian, Berj L

    2010-06-01

    Most forms of epilepsy are marked by seizure episodes that arise spontaneously. The low-magnesium/high-potassium (low-Mg(2+)/high-K(+)) experimental model of epilepsy is an acute model that produces spontaneous, recurring seizure-like events (SLEs). To elucidate the nature of spontaneous seizure transitions and their relationship to neuronal excitability, whole-cell recordings from the intact hippocampus were undertaken in vitro, and the response of hippocampal CA3 neurons to Gaussian white noise injection was obtained before and after treatment with various concentrations of low-Mg(2+)/high-K(+) solution. A second-order Volterra kernel model was estimated for each of the input-output response pairs. The spectral energy of the responses was also computed, providing a quantitative measure of neuronal excitability. Changes in duration and amplitude of the first-order kernel correlated positively with the spectral energy increase following treatment with low-Mg(2+)/high-K(+) solution, suggesting that variations in neuronal excitability are coded by the system kernels, in part by differences to the profile of the first-order kernel. In particular, kernel duration was more sensitive than amplitude to changes in spectral energy, and correlated more strongly with kernel area. An oscillator network model of the hippocampal CA3 was constructed to investigate the relationship of kernel duration to network excitability, and the model was able to generate spontaneous, recurrent SLEs by increasing the duration of a mode function analogous to the first-order kernel. Results from the model indicated that disruption to the dynamic balance of feedback was responsible for seizure-like transitions and the observed intermittency of SLEs. A physiological candidate for feedback imbalance consistent with the network model is the destabilizing interaction of extracellular potassium and paroxysmal neuronal activation. Altogether, these results (1) validate a mathematical model for

  8. Motor-Neuron Pool Excitability of the Lower Leg Muscles After Acute Lateral Ankle Sprain

    PubMed Central

    Klykken, Lindsey W.; Pietrosimone, Brian G.; Kim, Kyung-Min; Ingersoll, Christopher D.; Hertel, Jay

    2011-01-01

    Context: Neuromuscular deficits in leg muscles that are associated with arthrogenic muscle inhibition have been reported in people with chronic ankle instability, yet whether these neuromuscular alterations are present in individuals with acute sprains is unknown. Objective: To compare the effect of acute lateral ankle sprain on the motor-neuron pool excitability (MNPE) of injured leg muscles with that of uninjured contralateral leg muscles and the leg muscles of healthy controls. Design: Case-control study. Setting: Laboratory. Patients or Other Participants: Ten individuals with acute ankle sprains (6 females, 4 males; age = 19.2 ± 3.8 years, height = 169.4 ± 8.5 cm, mass = 66.3 ±11.6 kg) and 10 healthy individuals (6 females, 4 males; age = 20.6 ± 4.0 years, height = 169.9 ± 10.6 cm, mass = 66.3 ± 10.2 kg) participated. Intervention(s): The independent variables were group (acute ankle sprain, healthy) and limb (injured, uninjured). Separate dependent t tests were used to determine differences in MNPE between legs. Main Outcome Measure(s): The MNPE of the soleus, fibularis longus, and tibialis anterior was measured by the maximal Hoffmann reflex (Hmax) and maximal muscle response (Mmax) and was then normalized using the Hmax:Mmax ratio. Results: The soleus MNPE in the ankle-sprain group was higher in the injured limb (Hmax:Mmax = 0.63; 95% confidence interval [CI], 0.46, 0.80) than in the uninjured limb (Hmax:Mmax = 0.47; 95% CI, 0.08, 0.93) (t6 = 3.62, P = .01). In the acute ankle-sprain group, tibialis anterior MNPE tended to be lower in the injured ankle (Hmax:Mmax = 0.06; 95% CI, 0.01, 0.10) than in the uninjured ankle (Hmax:Mmax = 0.22; 95% CI, 0.09, 0.35), but this finding was not different (t9 = −2.01, P = .07). No differences were detected between injured (0.22; 95% CI, 0.14, 0.29) and uninjured (0.25; 95% CI, 0.12, 0.38) ankles for the fibularis longus in the ankle-sprain group (t9 = −0.739, P = .48). We found no side-to-side differences in

  9. Sleep deprivation does not affect neuronal susceptibility to mild traumatic brain injury in the rat

    PubMed Central

    Caron, Aimee M; Stephenson, Richard

    2015-01-01

    Mild and moderate traumatic brain injuries (TBIs) (and concussion) occur frequently as a result of falls, automobile accidents, and sporting activities, and are a major cause of acute and chronic disability. Fatigue and excessive sleepiness are associated with increased risk of accidents, but it is unknown whether prior sleep debt also affects the pathophysiological outcome of concussive injury. Using the “dark neuron” (DN) as a marker of reversible neuronal damage, we tested the hypothesis that acute (48 hours) total sleep deprivation (TSD) and chronic sleep restriction (CSR; 10 days, 6-hour sleep/day) affect DN formation following mild TBI in the rat. TSD and CSR were administered using a walking wheel apparatus. Mild TBI was administered under anesthesia using a weight-drop impact model, and the acute neuronal response was observed without recovery. DNs were detected using standard bright-field microscopy with toluidine blue stain following appropriate tissue fixation. DN density was low under home cage and sleep deprivation control conditions (respective median DN densities, 0.14% and 0.22% of neurons), and this was unaffected by TSD alone (0.1%). Mild TBI caused significantly higher DN densities (0.76%), and this was unchanged by preexisting acute or chronic sleep debt (TSD, 0.23%; CSR, 0.7%). Thus, although sleep debt may be predicted to increase the incidence of concussive injury, the present data suggest that sleep debt does not exacerbate the resulting neuronal damage. PMID:26124685

  10. Vasoactive Intestinal Peptide Excites GnRH Neurons in Male and Female Mice.

    PubMed

    Piet, Richard; Dunckley, Henry; Lee, Kiho; Herbison, Allan E

    2016-09-01

    A variety of external and internal factors modulate the activity of GnRH neurons to control fertility in mammals. A direct, vasoactive intestinal peptide (VIP)-mediated input to GnRH neurons originating from the suprachiasmatic nucleus is thought to relay circadian information within this network. In the present study, we examined the effects of VIP on GnRH neuron activity in male and female mice at different stages of the estrous cycle. We carried out cell-attached recordings in slices from GnRH-green fluorescent protein mice and calcium imaging in slices from a mouse line expressing the genetically encoded calcium indicator GCaMP3 selectively in GnRH neurons. We show that 50%-80% of GnRH neurons increase their firing rate in response to bath-applied VIP (1nM-1000nM) in both male and female mice and that this is accompanied by a robust increase in intracellular calcium concentrations. This effect is mediated directly at the GnRH neuron likely through activation of high-affinity VIP receptors. Because suprachiasmatic nucleus-derived timing cues trigger the preovulatory surge only on the afternoon of proestrus in female mice, we examined the effects of VIP during the estrous cycle at different times of day. VIP responsiveness in GnRH neurons did not vary significantly in diestrous and proestrous mice before or around the time of the expected preovulatory surge. These results indicate that the majority of GnRH neurons in male and female mice express functional VIP receptors and that the effects of VIP on GnRH neurons do not alter across the estrous cycle. PMID:27501185

  11. Spatiotemporal Computations of an Excitable and Plastic Brain: Neuronal Plasticity Leads to Noise-Robust and Noise-Constructive Computations

    PubMed Central

    Toutounji, Hazem; Pipa, Gordon

    2014-01-01

    It is a long-established fact that neuronal plasticity occupies the central role in generating neural function and computation. Nevertheless, no unifying account exists of how neurons in a recurrent cortical network learn to compute on temporally and spatially extended stimuli. However, these stimuli constitute the norm, rather than the exception, of the brain's input. Here, we introduce a geometric theory of learning spatiotemporal computations through neuronal plasticity. To that end, we rigorously formulate the problem of neural representations as a relation in space between stimulus-induced neural activity and the asymptotic dynamics of excitable cortical networks. Backed up by computer simulations and numerical analysis, we show that two canonical and widely spread forms of neuronal plasticity, that is, spike-timing-dependent synaptic plasticity and intrinsic plasticity, are both necessary for creating neural representations, such that these computations become realizable. Interestingly, the effects of these forms of plasticity on the emerging neural code relate to properties necessary for both combating and utilizing noise. The neural dynamics also exhibits features of the most likely stimulus in the network's spontaneous activity. These properties of the spatiotemporal neural code resulting from plasticity, having their grounding in nature, further consolidate the biological relevance of our findings. PMID:24651447

  12. A working memory model for serial order that stores information in the intrinsic excitability properties of neurons.

    PubMed

    Conde-Sousa, Eduardo; Aguiar, Paulo

    2013-10-01

    Models for temporary information storage in neuronal populations are dominated by mechanisms directly dependent on synaptic plasticity. There are nevertheless other mechanisms available that are well suited for creating short-term memories. Here we present a model for working memory which relies on the modulation of the intrinsic excitability properties of neurons, instead of synaptic plasticity, to retain novel information for periods of seconds to minutes. We show that it is possible to effectively use this mechanism to store the serial order in a sequence of patterns of activity. For this we introduce a functional class of neurons, named gate interneurons, which can store information in their membrane dynamics and can literally act as gates routing the flow of activations in the principal neurons population. The presented model exhibits properties which are in close agreement with experimental results in working memory. Namely, the recall process plays an important role in stabilizing and prolonging the memory trace. This means that the stored information is correctly maintained as long as it is being used. Moreover, the working memory model is adequate for storing completely new information, in time windows compatible with the notion of "one-shot" learning (hundreds of milliseconds). PMID:23539088

  13. Inverted optical intrinsic response accompanied by decreased cerebral blood flow are related to both neuronal inhibition and excitation

    PubMed Central

    Ma, Zengguang; Cao, Pengjia; Sun, Pengcheng; Zhao, Linna; Li, Liming; Tong, Shanbao; Lu, Yiliang; Yan, Yan; Chen, Yao; Chai, Xinyu

    2016-01-01

    Negative hemodynamic response has been widely reported in blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging studies, however its origin is still controversial. Optical intrinsic signal (OIS) imaging can be used to study brain activity by simultaneously recording hemodynamic signals at different wavelengths with high spatial resolution. In this study, we found transcorneal electrical stimulation (TcES) could elicit both positive OIS response (POR) and negative OIS response (NOR) in cats’ visual cortex. We then investigated the property of this negative response to TcES and its relationship with cerebral blood flow (CBF) and neuronal activity. Results from laser speckle contrast imaging showed decreased CBF in the NOR region while increased CBF in the POR region. Both planar and laminar electrophysiological recordings in the middle (500–700 μm) cortical layers demonstrated that decreased and increased neuronal activities were coexisted in the NOR region. Furthermore, decreased neuronal activity was also detected in the deep cortical layers in the NOR region. This work provides evidence that the negative OIS together with the decreased CBF should be explained by mechanisms of both neuronal inhibition and excitation within middle cortical layers. Our results would be important for interpreting neurophysiological mechanisms underlying the negative BOLD signals. PMID:26860040

  14. Neuromedin B and gastrin releasing peptide excite arcuate nucleus neuropeptide Y neurons in a novel transgenic mouse expressing strong renilla GFP in NPY neurons

    PubMed Central

    van den Pol, Anthony N.; Yao, Yang; Fu, Li-Ying; Foo, Kylie; Huang, Hao; Coppari, Roberto; Lowell, Brad; Broberger, Christian

    2009-01-01

    Neuropeptide Y (NPY) is one of the most widespread neuropeptides in the brain. Transgenic mice were generated that expressed bright renilla GFP in most or all of the known NPY cells in the brain, which otherwise were not identifiable. GFP expression in NPY cells was confirmed with immunocytochemistry and single cell RT-PCR. NPY neurons in the hypothalamic arcuate nucleus play an important role in energy homeostasis and endocrine control. Whole cell patch clamp recording was used to study identified arcuate NPY cells. Primary agents that regulate energy balance include melanocortin receptor agonists, AgRP, and cannabinoids; none of these substances substantially influenced electrical properties of NPY neurons. In striking contrast, neuropeptides of the bombesin family, including gastrin releasing peptide and neuromedin B which are found in axons in the arcuate nucleus and may also be released from the gut to signal the brain, showed strong direct excitatory actions at nanomolar levels on the NPY neurons, stronger than the actions of ghrelin and hypocretin/orexin. Bombesin-related peptides reduced input resistance and depolarized the membrane potential. The depolarization was attenuated by several factors: substitution of choline for sodium, extracellular Ni2+, inclusion of BAPTA in the pipette, KB-R7943 and SKF96365. Reduced extracellular calcium enhanced the current, which reversed around − 20 mV. Together, these data suggest two mechanisms, activation of non-selective cation channels and the sodium/calcium exchanger. Since both NPY and POMC neurons, which we also studied, are similarly directly excited by bombesin-like peptides, the peptides may function to initiate broad activation, rather than the cell-type selective activation or inhibition reported for many other compounds that modulate energy homeostasis. PMID:19357287

  15. Trace Fear Conditioning Differentially Modulates Intrinsic Excitability of Medial Prefrontal Cortex–Basolateral Complex of Amygdala Projection Neurons in Infralimbic and Prelimbic Cortices

    PubMed Central

    Song, Chenghui; Ehlers, Vanessa L.

    2015-01-01

    Neuronal activity in medial prefrontal cortex (mPFC) is critical for the formation of trace fear memory, yet the cellular mechanisms underlying these memories remain unclear. One possibility involves the modulation of intrinsic excitability within mPFC neurons that project to the basolateral complex of amygdala (BLA). The current study used a combination of retrograde labeling and in vitro whole-cell patch-clamp recordings to examine the effect of trace fear conditioning on the intrinsic excitability of layer 5 mPFC–BLA projection neurons in adult rats. Trace fear conditioning significantly enhanced the intrinsic excitability of regular spiking infralimbic (IL) projection neurons, as evidenced by an increase in the number of action potentials after current injection. These changes were also associated with a reduction in spike threshold and an increase in h current. In contrast, trace fear conditioning reduced the excitability of regular spiking prelimbic (PL) projection neurons, through a learning-related decrease of input resistance. Interestingly, the amount of conditioned freezing was (1) positively correlated with excitability of IL-BLA projection neurons after conditioning and (2) negatively correlated with excitability of PL-BLA projection neurons after extinction. Trace fear conditioning also significantly enhanced the excitability of burst spiking PL-BLA projection neurons. In both regions, conditioning-induced plasticity was learning specific (observed in conditioned but not in pseudoconditioned rats), flexible (reversed by extinction), and transient (lasted <10 d). Together, these data suggest that intrinsic plasticity within mPFC–BLA projection neurons occurs in a subregion- and cell-type-specific manner during acquisition, consolidation, and extinction of trace fear conditioning. SIGNIFICANCE STATEMENT Frontal lobe-related function is vital for a variety of important behaviors, some of which decline during aging. This study involves a novel

  16. Micro-electrode array recordings reveal reductions in both excitation and inhibition in cultured cortical neuron networks lacking Shank3.

    PubMed

    Lu, C; Chen, Q; Zhou, T; Bozic, D; Fu, Z; Pan, J Q; Feng, G

    2016-02-01

    Numerous risk genes have recently been implicated in susceptibility to autism and schizophrenia. Translating such genetic findings into disease-relevant neurobiological mechanisms is challenging due to the lack of throughput assays that can be used to assess their functions on an appropriate scale. To address this issue, we explored the feasibility of using a micro-electrode array (MEA) as a potentially scalable assay to identify the electrical network phenotypes associated with risk genes. We first characterized local and global network firing in cortical neurons with MEAs, and then developed methods to analyze the alternation between the network active period (NAP) and the network inactive period (NIP), each of which lasts tens of seconds. We then evaluated the electric phenotypes of neurons derived from Shank3 knockout (KO) mice. Cortical neurons cultured on MEAs displayed a rich repertoire of spontaneous firing, and Shank3 deletion led to reduced firing activity. Enhancing excitation with CX546 rescued the deficit in the spike rate in the Shank3 KO network. In addition, the Shank3 KO network produced a shorter NIP, and this altered network firing pattern was normalized by clonazepam, a positive modulator of the GABAA receptor. MEA recordings revealed electric phenotypes that displayed altered excitation and inhibition in the network lacking Shank3. Thus, our study highlights MEAs as an experimental framework for measuring multiple robust neurobiological end points in dynamic networks and as an assay system that could be used to identify electric phenotypes in cultured neuronal networks and to analyze additional risk genes identified in psychiatric genetics. PMID:26598066

  17. Raising cytosolic Cl− in cerebellar granule cells affects their excitability and vestibulo-ocular learning

    PubMed Central

    Seja, Patricia; Schonewille, Martijn; Spitzmaul, Guillermo; Badura, Aleksandra; Klein, Ilse; Rudhard, York; Wisden, William; Hübner, Christian A; De Zeeuw, Chris I; Jentsch, Thomas J

    2012-01-01

    Cerebellar cortical throughput involved in motor control comprises granule cells (GCs) and Purkinje cells (PCs), both of which receive inhibitory GABAergic input from interneurons. The GABAergic input to PCs is essential for learning and consolidation of the vestibulo-ocular reflex, but the role of GC excitability remains unclear. We now disrupted the Kcc2 K-Cl cotransporter specifically in either cell type to manipulate their excitability and inhibition by GABAA-receptor Cl− channels. Although Kcc2 may have a morphogenic role in synapse development, Kcc2 disruption neither changed synapse density nor spine morphology. In both GCs and PCs, disruption of Kcc2, but not Kcc3, increased [Cl−]i roughly two-fold. The reduced Cl− gradient nearly abolished GABA-induced hyperpolarization in PCs, but in GCs it merely affected excitability by membrane depolarization. Ablation of Kcc2 from GCs impaired consolidation of long-term phase learning of the vestibulo-ocular reflex, whereas baseline performance, short-term gain-decrease learning and gain consolidation remained intact. These functions, however, were affected by disruption of Kcc2 in PCs. GC excitability plays a previously unknown, but specific role in consolidation of phase learning. PMID:22252133

  18. Suppressive Effects of Resveratrol Treatment on The Intrinsic Evoked Excitability of CA1 Pyramidal Neurons

    PubMed Central

    Meftahi, Gholamhossein; Ghotbedin, Zohreh; Eslamizade, Mohammad Javad; Hosseinmardi, Narges; Janahmadi, Mahyar

    2015-01-01

    Objective Resveratrol, a phytoalexin, has a wide range of desirable biological actions. Despite a growing body of evidence indicating that resveratrol induces changes in neu- ronal function, little effort, if any, has been made to investigate the cellular effect of res- veratrol treatment on intrinsic neuronal properties. Materials and Methods This experimental study was performed to examine the acute effects of resveratrol (100 µM) on the intrinsic evoked responses of rat Cornu Ammonis (CA1) pyramidal neurons in brain slices, using whole cell patch clamp re- cording under current clamp conditions. Results Findings showed that resveratrol treatment caused dramatic changes in evoked responses of pyramidal neurons. Its treatment induced a significant (P<0.05) increase in the after hyperpolarization amplitude of the first evoked action potential. Resveratrol-treated cells displayed a significantly broader action potential (AP) when compared with either control or vehicle-treated groups. In addition, the mean instantaneous firing frequency between the first two action potentials was significantly lower in resveratrol-treated neurons. It also caused a significant reduction in the time to maximum decay of AP. The rheobase current and the utilization time were both significantly greater following resveratrol treatment. Neurons exhibited a significantly depolarized voltage threshold when exposed to resveratrol. Conclusion Results provide direct electrophysiological evidence for the inhibitory effects of resveratrol on pyramidal neurons, at least in part, by reducing the evoked neural activity. PMID:26464825

  19. Space flight affects magnocellular supraoptic neurons of young prepuberal rats: transient and permanent effects

    NASA Technical Reports Server (NTRS)

    Garcia-Ovejero, D.; Trejo, J. L.; Ciriza, I.; Walton, K. D.; Garcia-Segura, L. M.

    2001-01-01

    Effects of microgravity on postural control and volume of extracellular fluids as well as stress associated with space flight may affect the function of hypothalamic neurosecretory neurons. Since environmental modifications in young animals may result in permanent alterations in neuroendocrine function, the present study was designed to determine the effect of a space flight on oxytocinergic and vasopressinergic magnocellular hypothalamic neurons of prepuberal rats. Fifteen-day-old Sprague-Dawley female rats were flown aboard the Space Shuttle Columbia (STS-90, Neurolab mission, experiment 150) for 16 days. Age-matched litters remained on the ground in cages similar to those of the flight animals. Six animals from each group were killed on the day of landing and eight animals from each group were maintained under standard vivarium conditions and killed 18 weeks after landing. Several signs of enhanced transcriptional and biosynthetic activity were observed in magnocellular supraoptic neurons of flight animals on the day of landing compared to control animals. These include increased c-Fos expression, larger nucleoli and cytoplasm, and higher volume occupied in the neuronal perikaryon by mitochondriae, endoplasmic reticulum, Golgi apparatus, lysosomes and cytoplasmic inclusions known as nematosomes. In contrast, the volume occupied by neurosecretory vesicles in the supraoptic neuronal perikarya was significantly decreased in flight rats. This decrease was associated with a significant decrease in oxytocin and vasopressin immunoreactive levels, suggestive of an increased hormonal release. Vasopressin levels, cytoplasmic volume and c-Fos expression returned to control levels by 18 weeks after landing. These reversible effects were probably associated to osmotic stimuli resulting from modifications in the volume and distribution of extracellular fluids and plasma during flight and landing. However, oxytocin levels were still reduced at 18 weeks after landing in flight

  20. Extracellular Ca2+ fluctuations in vivo affect afterhyperpolarization potential and modify firing patterns of neocortical neurons.

    PubMed

    Boucetta, Sofiane; Crochet, Sylvain; Chauvette, Sylvain; Seigneur, Josée; Timofeev, Igor

    2013-07-01

    Neocortical neurons can be classified in four major electrophysiological types according to their pattern of discharge: regular-spiking (RS), intrinsically-bursting (IB), fast-rhythmic-bursting (FRB), and fast-spiking (FS). Previously, we have shown that these firing patterns are not fixed and can change as a function of membrane potential and states of vigilance. Other studies have reported that extracellular calcium concentration ([Ca(2+)]o) fluctuates as a function of the phase of the cortical slow oscillation. In the present study we investigated how spontaneous and induced changes in [Ca(2+)]o affect the properties of action potentials (APs) and firing patterns in cortical neurons in vivo. Intracellular recordings were performed in cats anesthetized with ketamine-xylazine during spontaneous [Ca(2+)]o fluctuation and while changing [Ca(2+)]o with reverse microdialysis. When [Ca(2+)]o fluctuated spontaneously according to the phase of the slow oscillation, we found an increase of the firing threshold and a decrease of the afterhyperpolarization (AHP) amplitude during the depolarizing (active, up) phase of the slow oscillation and some neurons also changed their firing pattern as compared with the hyperpolarizing (silent, down) phase. Induced changes in [Ca(2+)]o significantly affected the AP properties in all neurons. The AHP amplitude was increased in high calcium conditions and decreased in low calcium conditions, in particular the earliest components. Modulation of spike AHP resulted in notable modulation of intrinsic firing pattern and some RS neurons revealed burst firing when [Ca(2+)]o was decreased. We also found an increase in AHP amplitude in high [Ca(2+)]o with in vitro preparation. We suggest that during spontaneous network oscillations in vivo, the dynamic changes of firing patterns depend partially on fluctuations of the [Ca(2+)]o. PMID:23262121

  1. Effects of aversive stimuli beyond defensive neural circuits: reduced excitability in an identified neuron critical for feeding in Aplysia.

    PubMed

    Shields-Johnson, Maria E; Hernandez, John S; Torno, Cody; Adams, Katherine M; Wainwright, Marcy L; Mozzachiodi, Riccardo

    2013-01-01

    In Aplysia, repeated trials of aversive stimuli produce long-term sensitization (LTS) of defensive reflexes and suppression of feeding. Whereas the cellular underpinnings of LTS have been characterized, the mechanisms of feeding suppression remained unknown. Here, we report that LTS training induced a long-term decrease in the excitability of B51 (a decision-making neuron in the feeding circuit) that recovered at a time point in which LTS is no longer observed (72 h post-treatment). These findings indicate B51 as a locus of plasticity underlying feeding suppression. Finally, treatment with serotonin to induce LTS failed to alter feeding and B51 excitability, suggesting that serotonin does not mediate the effects of LTS training on the feeding circuit. PMID:23242417

  2. Changes in Neuronal Excitability by Activated Microglia: Differential Na+ Current Upregulation in Pyramid-Shaped and Bipolar Neurons by TNF-α and IL-18

    PubMed Central

    Klapal, Lars; Igelhorst, Birte A.; Dietzel-Meyer, Irmgard D.

    2016-01-01

    Microglia are activated during pathological events in the brain and are capable of releasing various types of inflammatory cytokines. Here, we demonstrate that the addition of 5% microglia activated by 1 μg/ml lipopolysaccharides (LPS) to hippocampal cultures upregulates Na+ current densities (INavD) of bipolar as well as pyramid-shaped neurons, thereby increasing their excitability. Deactivation of microglia by the addition of 10 ng/ml transforming growth factor-β (TGF-β) decreases INavD below control levels suggesting that the residual activated microglial cells influence neuronal excitability in control cultures. Preincubation of hippocampal cultures with 10 ng/ml tumor necrosis factor-α (TNF-α), a major cytokine released by activated microglia, upregulated INavD significantly by ~30% in bipolar cells, whereas in pyramid-shaped cells, the upregulation only reached an increase of ~14%. Incubation of the cultures with antibodies against either TNF-receptor 1 or 2 blocked the upregulation of INavD in bipolar cells, whereas in pyramid-shaped cells, increases in INavD were exclusively blocked by antibodies against TNF-receptor 2, suggesting that both cell types respond differently to TNF-α exposure. Since additional cytokines, such as interleukin-18 (IL-18), are released from activated microglia, we tested potential effects of IL-18 on INavD in both cell types. Exposure to 5–10 ng/ml IL-18 for 4 days increased INavD in both pyramid-shaped as well as bipolar neurons, albeit the dose–response curves were shifted to lower concentrations in bipolar cells. Our results suggest that by secretion of cytokines, microglial cells upregulate Na+ current densities in bipolar and pyramid-shaped neurons to some extent differentially. Depending on the exact cytokine composition and concentration released, this could change the balance between the activity of inhibitory bipolar and excitatory pyramid-shaped cells. Since bipolar cells show a larger upregulation of

  3. Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

    PubMed Central

    Pitcher, Jonathan; Abt, Anna; Myers, Jaclyn; Han, Rachel; Snyder, Melissa; Graziano, Alessandro; Festa, Lindsay; Kutzler, Michele; Garcia, Fernando; Gao, Wen-Jun; Fischer-Smith, Tracy; Rappaport, Jay; Meucci, Olimpia

    2014-01-01

    Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS. PMID:24401274

  4. [Regulation of neurogenesis: factors affecting of new neurons formation in adult mammals brain].

    PubMed

    Respondek, Michalina; Buszman, Ewa

    2015-01-01

    Neurogenesis is a complex and multi-step process of generating completely functional neurons. This process in adult brain is based on pluripotentional neuronal stem cells (NSC), which are able to proliferation and differentiation into mature neurons or glial cells. NSC are located in subgranular zone inside hippocampus and in subventricular zone. The new neurons formation depends on many endo- and exogenous factors which modulate each step of neurogenesis. This article describes the most important regulators of adult neurogenesis, mainly: neurotrophins, growth factors, hormones, neurotransmitters and microenvironment of NSC. Some drugs, especially antipsychotics, antidepressants and normothymics may affect the neurogenic properties of adult brain. Moreover pathological processes such as neuroinflammation, stroke or epilepsy are able to induce proliferation of NSC. The proneurogenic effects of psychotropic drugs and pathological processes are associated with their ability to increase some hormones and neurotrophins level, as well as with rising the expression of antiapoptotic Bcl-2 protein and metalloproteinase MMP-2. Additionaly, some drugs, for example haloperidol, are able to block prolactin and dopaminergic neuroblasts receptors. Down-regulation of adult neurogenesis is associated with alcohol abuse and high stress level. Negative effect of many drugs, such as cytostatics, COX-2 inhibitors and opioides was also observed. The proneurogenic effect of described factors suggest their broad therapeutic potential and gives a new perspective on an effective and modern treatment of many neuropsychiatric disorders. This effect can also help to clarify the pathogenesis of disorders associated with proliferation and degeneration of adult brain cells. PMID:27259217

  5. FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry.

    PubMed

    La Fata, Giorgio; Gärtner, Annette; Domínguez-Iturza, Nuria; Dresselaers, Tom; Dawitz, Julia; Poorthuis, Rogier B; Averna, Michele; Himmelreich, Uwe; Meredith, Rhiannon M; Achsel, Tilmann; Dotti, Carlos G; Bagni, Claudia

    2014-12-01

    Deficiencies in fragile X mental retardation protein (FMRP) are the most common cause of inherited intellectual disability, fragile X syndrome (FXS), with symptoms manifesting during infancy and early childhood. Using a mouse model for FXS, we found that Fmrp regulates the positioning of neurons in the cortical plate during embryonic development, affecting their multipolar-to-bipolar transition (MBT). We identified N-cadherin, which is crucial for MBT, as an Fmrp-regulated target in embryonic brain. Furthermore, spontaneous network activity and high-resolution brain imaging revealed defects in the establishment of neuronal networks at very early developmental stages, further confirmed by an unbalanced excitatory and inhibitory network. Finally, reintroduction of Fmrp or N-cadherin in the embryo normalized early postnatal neuron activity. Our findings highlight the critical role of Fmrp in the developing cerebral cortex and might explain some of the clinical features observed in patients with FXS, such as alterations in synaptic communication and neuronal network connectivity. PMID:25402856

  6. Decreased Zinc Availability Affects Glutathione Metabolism in Neuronal Cells and in the Developing Brain

    PubMed Central

    Omata, Yo; Salvador, Gabriela A.; Oteiza, Patricia I.

    2013-01-01

    A deficit in zinc (Zn) availability can increase cell oxidant production, affect the antioxidant defense system, and trigger oxidant-sensitive signals in neuronal cells. This work tested the hypothesis that a decreased Zn availability can affect glutathione (GSH) metabolism in the developing rat brain and in neuronal cells in culture, as well as the capacity of human neuroblastoma IMR-32 cells to upregulate GSH when challenged with dopamine (DA). GSH levels were low in the brain of gestation day 19 (GD19) fetuses from dams fed marginal Zn diets throughout gestation and in Zn-deficient IMR-32 cells. γ-Glutamylcysteine synthetase (GCL), the first enzyme in the GSH synthetic pathway, was altered by Zn deficiency (ZD). The protein and mRNA levels of the GCL modifier (GCLM) and catalytic (GCLC) subunits were lower in the Zn-deficient GD19 fetal brain and in IMR-32 cells compared with controls. The nuclear translocation of transcription factor nuclear factor (erythroid-derived 2)-like 2, which controls GCL transcription, was impaired by ZD. Posttranslationally, the caspase-3-dependent GCLC cleavage was high in Zn-deficient IMR-32 cells. Cells challenged with DA showed an increase in GCLM and GCLC protein and mRNA levels and a consequent increase in GSH concentration. Although Zn-deficient cells partially upregulated GCL subunits after exposure to DA, GSH content remained low. In summary, results show that a low Zn availability affects the GSH synthetic pathway in neuronal cells and fetal brain both at transcriptional and posttranslational levels. This can in part underlie the GSH depletion associated with ZD and the high sensitivity of Zn-deficient neurons to pro-oxidative stressors. PMID:23377617

  7. Excitation of locus coeruleus noradrenergic neurons by thyrotropin-releasing hormone.

    PubMed

    Ishibashi, Hitoshi; Nakahata, Yoshihisa; Eto, Kei; Nabekura, Junichi

    2009-12-01

    Locus coeruleus (LC) noradrenergic neurons are implicated in a variety of functions including the regulation of vigilance and the modulation of sensory processing. Thyrotropin-releasing hormone (TRH) is an endogenous neuropeptide that induces a variety of behavioural changes including arousal and antinociception. In the present study, we explored whether the activity of LC noradrenergic neurons is modulated by TRH. Using current-clamp recording from isolated rat LC neurons, we found that TRH increased the firing rate of spontaneous action potentials. The TRH action was mimicked by TRH analogues including taltirelin and TRH-gly. In voltage-clamp recording at a holding potential of 50 mV, TRH produced an inward current associated with a decrease in the membrane K+ conductance. This current was inhibited by the TRH receptor antagonist chlordiazepoxide. Following inhibition of the pH-sensitive K+ conductance by extracellular acidification, the TRH response was fully inhibited. The TRH-induced current was also inhibited by the phospholipase C (PLC) inhibitor U-73122, but not by the protein kinase C inhibitor chelerythrine nor by chelation of intracellular Ca2+ by BAPTA. The recovery from the facilitatory action of TRH on the spike frequency was markedly inhibited by a high concentration of wortmannin. These results suggest that TRH activates LC noradrenergic neurons by decreasing an acid-sensitive K+ conductance via PLC-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate. The present findings demonstrate that TRH activates LC neurons and characterize the underlying signalling mechanisms. The action of TRH on LC neurons may influence a variety of CNS functions related to the noradrenergic system which include arousal and analgesia. PMID:19840999

  8. Age-related changes to TNF receptors affect neuron survival in the presence of beta-amyloid

    PubMed Central

    Patel, Jigisha R.; Brewer, Gregory J.

    2007-01-01

    Inflammation including local accumulations of tumor necrosis factor alpha (TNFα) is a part of Alzheimer’s disease (AD) pathology and may exacerbate age-related neurodegeneration. Most studies on TNFα and TNF neuronal receptors are conducted using embryonic neurons. Few studies consider age-related deficits that may occur in neurons. Age-related changes in susceptibility to TNFα through TNF receptor 1 (TNFR1) and receptor 2 (TNFR2) expression could increase susceptibility to β-amyloid (1-42, Abeta42). Evidence is conflicting about which receptor mediates survival and/or apoptosis. We determined how aging affects receptor expression in cultured adult rat cortical neurons. Old neurons were more susceptible to Abeta42 toxicity than middle-age neurons and the addition of TNFα was neuroprotective in middle-age, but exacerbated the toxicity from Abeta42 in old neurons. These pathologic and protective responses in old and middle-age neurons respectively correlated with higher starting TNFR1 and TNFR2 mRNA levels in old versus middle-age neurons. Middle-age neurons treated with TNFα plus Abeta42 did not show an increase in either TNFR1 or TNFR2 mRNA but old neurons showed an upregulation in TNFR2 mRNA and not TNFR1 mRNA. Despite these mRNA changes, surface immunoreactivity of both TNFR1 and TNFR2 increased with dose of TNFα in middle-age neurons. However, middle-age neurons treated with TNFα plus Abeta42 showed an upregulation in both TNFR1 and TNFR2 surface expression, whereas old neurons failed to upregulate surface expression of either receptor. These findings support the hypothesis that age-related changes in TNFα surface receptor expression contribute to the neuronal loss associated with inflammation in AD. PMID:18418902

  9. Altered emotionality and neuronal excitability in mice lacking KCTD12, an auxiliary subunit of GABAB receptors associated with mood disorders

    PubMed Central

    Cathomas, F; Stegen, M; Sigrist, H; Schmid, L; Seifritz, E; Gassmann, M; Bettler, B; Pryce, C R

    2015-01-01

    Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, is fundamental to brain function and implicated in the pathophysiology of several neuropsychiatric disorders. GABA activates G-protein-coupled GABAB receptors comprising principal GABAB1 and GABAB2 subunits as well as auxiliary KCTD8, 12, 12b and 16 subunits. The KCTD12 gene has been associated with bipolar disorder, major depressive disorder and schizophrenia. Here we compare Kctd12 null mutant (Kctd12−/−) and heterozygous (Kctd12+/−) with wild-type (WT) littermate mice to determine whether lack of or reduced KCTD12 expression leads to phenotypes that, extrapolating to human, could constitute endophenotypes for neuropsychiatric disorders with which KCTD12 is associated. Kctd12−/− mice exhibited increased fear learning but not increased memory of a discrete auditory-conditioned stimulus. Kctd12+/− mice showed increased activity during the inactive (light) phase of the circadian cycle relative to WT and Kctd12−/− mice. Electrophysiological recordings from hippocampal slices, a region of high Kctd12 expression, revealed an increased intrinsic excitability of pyramidal neurons in Kctd12−/− and Kctd12+/− mice. This is the first direct evidence for involvement of KCTD12 in determining phenotypes of emotionality, behavioral activity and neuronal excitability. This study provides empirical support for the polymorphism and expression evidence that KCTD12 confers risk for and is associated with neuropsychiatric disorders. PMID:25689571

  10. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer's disease.

    PubMed

    Balez, Rachelle; Steiner, Nicole; Engel, Martin; Muñoz, Sonia Sanz; Lum, Jeremy Stephen; Wu, Yizhen; Wang, Dadong; Vallotton, Pascal; Sachdev, Perminder; O'Connor, Michael; Sidhu, Kuldip; Münch, Gerald; Ooi, Lezanne

    2016-01-01

    Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, yet current therapeutic treatments are inadequate due to a complex disease pathogenesis. The plant polyphenol apigenin has been shown to have anti-inflammatory and neuroprotective properties in a number of cell and animal models; however a comprehensive assessment has not been performed in a human model of AD. Here we have used a human induced pluripotent stem cell (iPSC) model of familial and sporadic AD, in addition to healthy controls, to assess the neuroprotective activity of apigenin. The iPSC-derived AD neurons demonstrated a hyper-excitable calcium signalling phenotype, elevated levels of nitrite, increased cytotoxicity and apoptosis, reduced neurite length and increased susceptibility to inflammatory stress challenge from activated murine microglia, in comparison to control neurons. We identified that apigenin has potent anti-inflammatory properties with the ability to protect neurites and cell viability by promoting a global down-regulation of cytokine and nitric oxide (NO) release in inflammatory cells. In addition, we show that apigenin is able to protect iPSC-derived AD neurons via multiple means by reducing the frequency of spontaneous Ca(2+) signals and significantly reducing caspase-3/7 mediated apoptosis. These data demonstrate the broad neuroprotective action of apigenin against AD pathogenesis in a human disease model. PMID:27514990

  11. Synthetic ciguatoxin CTX 3C induces a rapid imbalance in neuronal excitability.

    PubMed

    Martín, Victor; Vale, Carmen; Hirama, Masahiro; Yamashita, Shuji; Rubiolo, Juan Andrés; Vieytes, Mercedes R; Botana, Luis M

    2015-06-15

    Ciguatera is a human global disease caused by the consumption of contaminated fish that have accumulated ciguatoxins (CTXs), sodium channel activator toxins. Symptoms of ciguatera include neurological alterations such as paraesthesiae, dysaesthesiae, depression, and heightened nociperception, among others. An important issue to understand these long-term neurological alterations is to establish the role that changes in activity produced by CTX 3C represent to neurons. Here, the effects of synthetic ciguatoxin CTX 3C on membrane potential, spontaneous spiking, and properties of synaptic transmission in cultured cortical neurons of 11-18 days in vitro (DIV) were evaluated using electrophysiological approaches. CTX 3C induced a large depolarization that decreased neuronal firing and caused a rapid inward tonic current that was primarily GABAergic. Moreover, the toxin enhanced the amplitude of miniature postsynaptic inhibitory currents (mIPSCs), whereas it decreased the amplitude of miniature postsynaptic excitatory currents (mEPSCs). The frequency of mIPSCs increased, whereas the frequency of mEPSCs remained unaltered. We describe, for the first time, that a rapid membrane depolarization caused by CTX 3C in cortical neurons activates mechanisms that tend to suppress electrical activity by shifting the balance between excitatory and inhibitory synaptic transmission toward inhibition. Indeed, these results suggest that the acute effects of CTX on synaptic transmission could underlie some of the neurological symptoms caused by ciguatera in humans. PMID:25945403

  12. Electrical excitability of outgrowing neurites of embryonic neurones in cultures of dissociated neural plate of Xenopus laevis.

    PubMed Central

    Willard, A L

    1980-01-01

    1. I have studied the electrical excitability of outgrowing processes of individual neurones in cultures made from dissociated neural plates of embryos of Xenopus laevis prior to the time of neurite outgrowth in vivo. 2. The electrical excitability of neurites was tested by stimulating them extracellularly and recording responses with an intracellular electrode in their cell bodies; neurites were excitable at all times examined. 3. The ionic basis of the excitability of neurites was tested by recording from cells while changing the composition of the salines perfusing the cultures. 4. In cultures less than 10 hr old, all neurites tested made responses which depended on Ca2+. The action potentials of the cell bodies were also Ca2+-dependent at these times. 5. Between 10 and 12 hr in culture, a time at which the cell bodies still made Ca2+-dependent action potentials, neurites acquired the ability to make Na+-dependent responses. At these times, two-thirds of neurites tested retained the ability to produce divalent cation-dependent action potentials when perfused with solutions of isotonic Ba2+. 6. After 12 hr in culture, no neurites were observed to make Ca2+-or Ba2+-dependent responses; only Na+-dependent responses were observed. Cells continued to initiate and elongate new neurites until about 24 hr in culture. Thus neurites sent out at different times in culture differed in their development of excitability. 7. Cell bodies making exclusively Ca2+-dependent action potentials could be found until about 15 hr in culture, after which time a Na+-dependent component appeared. Cell bodies could then be observed to make action potentials which depended on both Ca2+ and Na+ until about 3 days in culture. After 3 days, most cell bodies made predominately Na+-dependent action potentials. Unlike the neurites, cell bodies retained the ability to make action potentials in isotonic Ba2+ for as long as the cultures were maintained (up to 5 days). 8. The possibility that changes

  13. Intrinsic Hippocampal Excitability Changes of Opposite Signs and Different Origins in CA1 and CA3 Pyramidal Neurons Underlie Aging-Related Cognitive Deficits

    PubMed Central

    Oh, M. Matthew; Simkin, Dina; Disterhoft, John F.

    2016-01-01

    Aging-related cognitive deficits have been attributed to dysfunction of neurons due to failures at synaptic or intrinsic loci, or both. Given the importance of the hippocampus for successful encoding of memory and that the main output of the hippocampus is via the CA1 pyramidal neurons, much of the research has been focused on identifying the aging-related changes of these CA1 pyramidal neurons. We and others have discovered that the postburst afterhyperpolarization (AHP) following a train of action potentials is greatly enlarged in CA1 pyramidal neurons of aged animals. This enlarged postburst AHP is a significant factor in reducing the intrinsic excitability of these neurons, and thus limiting their activity in the neural network during learning. Based on these data, it has largely been thought that aging-related cognitive deficits are attributable to reduced activity of pyramidal neurons. However, recent in vivo and ex vivo studies provide compelling evidence that aging-related deficits could also be due to a converse change in CA3 pyramidal neurons, which show increased activity with aging. In this review, we will incorporate these recent findings and posit that an interdependent dynamic dysfunctional change occurs within the hippocampal network, largely due to altered intrinsic excitability in CA1 and CA3 hippocampal pyramidal neurons, which ultimately leads to the aging-related cognitive deficits. PMID:27375440

  14. Chandelier cells control excessive cortical excitation: characteristics of whisker-evoked synaptic responses of layer 2/3 nonpyramidal and pyramidal neurons.

    PubMed

    Zhu, Yinghua; Stornetta, Ruth L; Zhu, J Julius

    2004-06-01

    Chandelier cells form inhibitory axo-axonic synapses on pyramidal neurons with their characteristic candlestick-like axonal terminals. The functional role of chandelier cells is still unclear, although the preferential loss of this cell type at epileptic loci suggests a role in epilepsy. Here we report an examination of whisker- and spontaneous activity-evoked responses in chandelier cells and other fast-spiking nonpyramidal neurons and regular-spiking pyramidal neurons in layer 2/3 of the barrel cortex. Fast-spiking nonpyramidal neurons, including chandelier cells, basket cells, neurogliaform cells, double bouquet cells, net basket cells, bitufted cells, and regular-spiking pyramidal neurons all respond to stimulation of multiple whiskers on the contralateral face. Whisker stimulation, however, evokes small, delayed EPSPs preceded by an earlier IPSP and no action potentials in chandelier cells, different from other nonpyramidal and pyramidal neurons. In addition, chandelier cells display a larger receptive field with lower acuity than other fast-spiking nonpyramidal neurons and pyramidal neurons. Notably, simultaneous dual whole-cell in vivo recordings show that chandelier cells, which rarely fire action potentials spontaneously, fire more robustly than other types of cortical neurons when the overall cortical excitation increases. Thus, chandelier cells may not process fast ascending sensory information but instead may be reserved to prevent excessive excitatory activity in neuronal networks. PMID:15175379

  15. Multisensory plasticity in adulthood: cross-modal experience enhances neuronal excitability and exposes silent inputs

    PubMed Central

    Yu, Liping; Rowland, Benjamin A.; Xu, Jinghong

    2013-01-01

    Multisensory superior colliculus neurons in cats were found to retain substantial plasticity to short-term, site-specific experience with cross-modal stimuli well into adulthood. Following cross-modal exposure trials, these neurons substantially increased their sensitivity to the cross-modal stimulus configuration as well as to its individual component stimuli. In many cases, the exposure experience also revealed a previously ineffective or “silent” input channel, rendering it overtly responsive. These experience-induced changes required relatively few exposure trials and could be retained for more than 1 h. However, their induction was generally restricted to experience with cross-modal stimuli. Only rarely were they induced by exposure to a modality-specific stimulus and were never induced by stimulating a previously ineffective input channel. This short-term plasticity likely provides substantial benefits to the organism in dealing with ongoing and sequential events that take place at a given location in space and may reflect the ability of multisensory superior colliculus neurons to rapidly alter their response properties to accommodate to changes in environmental challenges and event probabilities. PMID:23114212

  16. Depressing Antidepressant: Fluoxetine Affects Serotonin Neurons Causing Adverse Reproductive Responses in Daphnia magna.

    PubMed

    Campos, Bruno; Rivetti, Claudia; Kress, Timm; Barata, Carlos; Dircksen, Heinrich

    2016-06-01

    Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants. As endocrine disruptive contaminants in the environment, SSRIs affect reproduction in aquatic organisms. In the water flea Daphnia magna, SSRIs increase offspring production in a food ration-dependent manner. At limiting food conditions, females exposed to SSRIs produce more but smaller offspring, which is a maladaptive life-history strategy. We asked whether increased serotonin levels in newly identified serotonin-neurons in the Daphnia brain mediate these effects. We provide strong evidence that exogenous SSRI fluoxetine selectively increases serotonin-immunoreactivity in identified brain neurons under limiting food conditions thereby leading to maladaptive offspring production. Fluoxetine increases serotonin-immunoreactivity at low food conditions to similar maximal levels as observed under high food conditions and concomitantly enhances offspring production. Sublethal amounts of the neurotoxin 5,7-dihydroxytryptamine known to specifically ablate serotonin-neurons markedly decrease serotonin-immunoreactivity and offspring production, strongly supporting the effect to be serotonin-specific by reversing the reproductive phenotype attained under fluoxetine. Thus, SSRIs impair serotonin-regulation of reproductive investment in a planktonic key organism causing inappropriately increased reproduction with potentially severe ecological impact. PMID:27128505

  17. Synaptic excitation in the thoracic spinal cord from expiratory bulbospinal neurones in the cat.

    PubMed Central

    Kirkwood, P A

    1995-01-01

    1. Synaptic actions in the thoracic spinal cord of individual expiratory bulbospinal neurones were studied in anaesthetized cats by the use of two techniques: (i) the monosynaptic connections to motoneurones were assessed by cross-correlations between the discharges of the neurones and efferent discharges in the internal intercostal nerves of several segments bilaterally; and (ii) distributions of terminal and focal synaptic potentials were measured by extracellular spike-triggered averaging in the thoracic ventral horn. 2. Monosynaptic connections were identified by both the durations and timings of observed cross-correlation peaks, taking into account accurate conduction velocity measurements derived from collision tests and from spike-triggered averaging. Discrimination was made against peaks resulting from presynaptic synchronization. 3. Monosynaptic connections to motoneurones were identified for twenty-three out of twenty-seven neurones. The connections to nerves on the side ipsilateral to the cell somata were, on average, about 36% of the strength of those on the contralateral side. The overall strength of the connections was about twice as strong as previous estimates for similar connections from inspiratory bulbospinal neurones to phrenic motoneurones. The monosynaptic pathway was calculated to be able to provide most of the depolarization for the motoneurones concerned and therefore was likely to be the main determinant of their firing patterns under the conditions of these experiments. 4. However, taking into account previous measurements it is considered possible that these connections may only involve a minority of motoneurones, perhaps only 10% of the expiratory population. Thus, in general, the control of the whole pool of expiratory motoneurones, despite the strong monosynaptic connections measured here, is suggested to be mainly dependent on spinal interneurones, as has been concluded previously for inspiratory motoneurones. 5. Spike

  18. REST levels affect the functional expression of voltage dependent calcium channels and the migratory activity in immortalized GnRH neurons.

    PubMed

    Antoniotti, Susanna; Ruffinatti, Federico Alessandro; Torriano, Simona; Luganini, Anna; D'Alessandro, Rosalba; Lovisolo, Davide

    2016-08-26

    The repressor element-1 silencing transcription factor (REST) has emerged as a key controller of neuronal differentiation and has been shown to play a critical role in the expression of the neuronal phenotype; however, much has still to be learned about its role at specific developmental stages and about the functional targets affected. Among these targets, calcium signaling mechanisms are critically dependent on the developmental stage and their full expression is a hallmark of the mature, functional neuron. We have analyzed the role played by REST in GN11 cells, an immortalized cell line derived from gonadotropin hormone releasing hormone (GnRH) neurons at an early developmental stage, electrically non-excitable and with a strong migratory activity. We show for the first time that functional voltage-dependent calcium channels are expressed in wild type GN11 cells; down-regulation of REST by a silencing approach shifts these cells towards a more differentiated phenotype, increasing the functional expression of P/Q-type channels and reducing their migratory potential. PMID:27349310

  19. Neuronal Heterotopias Affect the Activities of Distant Brain Areas and Lead to Behavioral Deficits.

    PubMed

    Ishii, Kazuhiro; Kubo, Ken-ichiro; Endo, Toshihiro; Yoshida, Keitaro; Benner, Seico; Ito, Yukiko; Aizawa, Hidenori; Aramaki, Michihiko; Yamanaka, Akihiro; Tanaka, Kohichi; Takata, Norio; Tanaka, Kenji F; Mimura, Masaru; Tohyama, Chiharu; Kakeyama, Masaki; Nakajima, Kazunori

    2015-09-01

    Neuronal heterotopia refers to brain malformations resulting from deficits of neuronal migration. Individuals with heterotopias show a high incidence of neurological deficits, such as epilepsy. More recently, it has come to be recognized that focal heterotopias may also show a range of psychiatric problems, including cognitive and behavioral impairments. However, because focal heterotopias are not always located in the brain areas responsible for the symptoms, the causal relationship between the symptoms and heterotopias remains elusive. In this study, we showed that mice with focal heterotopias in the somatosensory cortex generated by in utero electroporation exhibited spatial working memory deficit and low competitive dominance behavior, which have been shown to be closely associated with the activity of the medial prefrontal cortex (mPFC) in rodents. Analysis of the mPFC activity revealed that the immediate-early gene expression was decreased and the local field potentials of the mPFC were altered in the mice with heterotopias compared with the control mice. Moreover, activation of these ectopic and overlying sister neurons using the DREADD (designer receptor exclusively activated by designer drug) system improved the working memory deficits. These findings suggest that cortical regions containing focal heterotopias can affect distant brain regions and give rise to behavioral abnormalities. Significance statement: Recent studies reported that patients with heterotopias have a variety of clinical symptoms, such as cognitive disturbance, psychiatric symptoms, and autistic behavior. However, the causal relationship between the symptoms and heterotopias remains elusive. Here we showed that mice with focal heterotopias in the somatosensory cortex generated by in utero electroporation exhibited behavioral deficits that have been shown to be associated with the mPFC activity in rodents. The existence of heterotopias indeed altered the neural activities of the mPFC, and

  20. FXYD1, a modulator of Na+,K+-ATPase activity, facilitates female sexual development by maintaining GnRH neuronal excitability

    PubMed Central

    Garcia-Rudaz, Cecilia; Deng, Vivianne; Matagne, Valerie; Ronnekleiv, Oline; Bosch, Martha; Han, Victor; Percy, Alan K.; Ojeda, Sergio R.

    2009-01-01

    The excitatory tone to GnRH neurones is a critical component underlying the pubertal increase in GnRH secretion. However, the homeostatic mechanisms modulating the response of GnRH neurones to excitatory inputs remain poorly understood. A basic mechanism of neuronal homeostasis is the Na+, K+-ATPase-dependent restoration of Na+ and K+ transmembrane gradients after neuronal excitation. This activity is reduced in a mouse model of Rett syndrome (RTT), a neurodevelopmental disorder in which expression of FXYD1, a modulator of Na+, K+-ATPase activity, is increased. We now report that the initiation, but not the completion of puberty, is advanced in girls with RTT, and that in rodents FXYD1 may contribute to the neuroendocrine regulation of female puberty by modulating GnRH neuronal excitability. Fxyd1 mRNA abundance reaches maximal levels in the female rat hypothalamus by the fourth postnatal week of life, i.e., around the time when the mode of GnRH secretion acquires an adult pattern of release. Although Fxyd1 mRNA expression is low in the hypothalamus, about 50% of GnRH neurones contain Fxyd1 transcripts. Whole-cell patch recording of GnRH-EGFP neurones revealed that the neurones of Fxyd1-null female mice respond to somatic current injections with a lower number of action potentials than wild-type cells. Both the age at vaginal opening and at first oestrous were delayed in Fxyd1-/- mice, but adult reproductive capacity was normal. These results suggest that FXYD1 contributes to facilitating the advent of puberty by maintaining GnRH neuronal excitability to incoming transsynaptic stimulatory inputs. PMID:19187398

  1. Aberrant dendritic excitability: a common pathophysiology in CNS disorders affecting memory?

    PubMed Central

    Nestor, Michael W.; Hoffman, Dax A.

    2012-01-01

    Discovering the etiology of pathophysiologies and aberrant behavior in many central nervous system (CNS) disorders has proven elusive because susceptibility to these diseases can be a product of multiple factors such as genetics, epigenetics, and environment. Advances in molecular biology and wide-scale genomics have shown that a large heterogeneity of genetic mutations are potentially responsible for the neuronal pathologies and dysfunctional behaviors seen in CNS disorders. (Need to distinguish between pure genetic forms which are rare, and what most people get which is probable combination of genetic susceptibility and environmental insults). Despite this seemingly complex array of genetic and physiological factors, many disorders of the CNS converge on common dysfunctions in memory. In this review, we propose that mechanisms underlying the development of many CNS diseases may share an underlying cause involving abnormal dendritic integration of synaptic signals. Through understanding the relationship between molecular genetics and dendritic computation, future research may uncover important links between neuronal physiology at the cellular level and higher-order circuit and network abnormalities observed in CNS diseases, and their subsequent affect on memory. PMID:22528602

  2. Hypothalamic Dopaminergic Neurons in an Animal Model of Seasonal Affective Disorder

    PubMed Central

    Deats, Sean P.; Adidharma, Widya; Yan, Lily

    2015-01-01

    Light has profound effects on mood regulation as exemplified in Seasonal Affective Disorder (SAD) and the therapeutic benefits of light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD. Following housing conditions of either 12:12hr Dim Light:Dark (DLD) or 8:16hr Short Photoperiod (SP), which mimic the lower light intensity or short day-length of winter, respectively, grass rats exhibit an increase in depression-like behavior compared to those housed in a 12:12hr Bright Light:Dark (BLD) condition. Furthermore, we revealed that the orexinergic system is involved in mediating the effects of light on mood and anxiety. To explore other potential neural substrates involved in the depressive phenotype, the present study examined hypothalamic dopaminergic (DA) and somatostatin (SST) neurons in the brains of grass rats housed in DLD, SP and BLD. Using immunostaining for tyrosine hydroxylase (TH) and SST, we found that the number of TH- and SST-ir cells in the hypothalamus was significantly lower in the DLD and SP groups compared to the BLD group. We also found that treating BLD animals with a selective orexin receptor 1 (OX1R) antagonist SB-334867 significantly reduced the number of hypothalamic TH-ir cells. The present study suggests that the hypothalamic DA neurons are sensitive to daytime light deficiency and are regulated by an orexinergic pathway. The results support the hypothesis that the orexinergic pathways mediate the effects of light on other neuronal systems that collectively contribute to light-dependent changes in the affective state. PMID:26116821

  3. Converging genetic and functional brain imaging evidence links neuronal excitability to working memory, psychiatric disease, and brain activity

    PubMed Central

    Heck, A.; Fastenrath, M.; Ackermann, S.; Auschra, B.; Bickel, H.; Coynel, D.; Gschwind, L.; Jessen, F.; Kaduszkiewicz, H.; Maier, W.; Milnik, A.; Pentzek, M.; Riedel-Heller, S.G.; Ripke, S.; Spalek, K.; Sullivan, P.; Vogler, C.; Wagner, M.; Weyerer, S.; Wolfsgruber, S.; de Quervain, D.; Papassotiropoulos, A.

    2014-01-01

    Summary Working memory, the capacity of actively maintaining task-relevant information during a cognitive task, is a heritable trait. Working memory deficits are characteristic for many psychiatric disorders. We performed genome-wide gene-set enrichment analyses in multiple independent data sets of young and aged cognitively healthy subjects (n = 2’824), and in a large schizophrenia case-control sample (n = 32’143). The voltage-gated cation channel activity gene-set, consisting of genes related to neuronal excitability, was robustly linked to performance in working memory-related tasks across ages, and to schizophrenia. Functional brain imaging in 707 healthy participants linked this gene-set also to working memory-related activity in the parietal cortex and the cerebellum. Gene-set analyses may help to dissect the molecular underpinnings of cognitive dimensions, brain activity and psychopathology. PMID:24529980

  4. Converging genetic and functional brain imaging evidence links neuronal excitability to working memory, psychiatric disease, and brain activity.

    PubMed

    Heck, Angela; Fastenrath, Matthias; Ackermann, Sandra; Auschra, Bianca; Bickel, Horst; Coynel, David; Gschwind, Leo; Jessen, Frank; Kaduszkiewicz, Hanna; Maier, Wolfgang; Milnik, Annette; Pentzek, Michael; Riedel-Heller, Steffi G; Ripke, Stephan; Spalek, Klara; Sullivan, Patrick; Vogler, Christian; Wagner, Michael; Weyerer, Siegfried; Wolfsgruber, Steffen; de Quervain, Dominique J-F; Papassotiropoulos, Andreas

    2014-03-01

    Working memory, the capacity of actively maintaining task-relevant information during a cognitive task, is a heritable trait. Working memory deficits are characteristic for many psychiatric disorders. We performed genome-wide gene set enrichment analyses in multiple independent data sets of young and aged cognitively healthy subjects (n = 2,824) and in a large schizophrenia case-control sample (n = 32,143). The voltage-gated cation channel activity gene set, consisting of genes related to neuronal excitability, was robustly linked to performance in working memory-related tasks across ages and to schizophrenia. Functional brain imaging in 707 healthy participants linked this gene set also to working memory-related activity in the parietal cortex and the cerebellum. Gene set analyses may help to dissect the molecular underpinnings of cognitive dimensions, brain activity, and psychopathology. PMID:24529980

  5. Evaluation of Motor Neuron Excitability by CMAP Scanning with Electric Modulated Current.

    PubMed

    Araújo, Tiago; Candeias, Rui; Nunes, Neuza; Gamboa, Hugo

    2015-01-01

    Introduction. Compound Muscle Action Potential (CMAP) scan is a noninvasive promissory technique for neurodegenerative pathologies diagnosis. In this work new CMAP scan protocols were implemented to study the influence of electrical pulse waveform on peripheral nerve excitability. Methods. A total of 13 healthy subjects were tested. Stimulation was performed with an increasing intensities range from 4 to 30 mA. The procedure was repeated 4 times per subject, using a different single pulse stimulation waveform: monophasic square and triangular and quadratic and biphasic square. Results. Different waveforms elicit different intensity-response amplitude curves. The square pulse needs less current to generate the same response amplitude regarding the other waves and this effect is gradually decreasing for the triangular, quadratic, and biphasic pulse, respectively. Conclusion. The stimulation waveform has a direct influence on the stimulus-response slope and consequently on the motoneurons excitability. This can be a new prognostic parameter for neurodegenerative disorders. PMID:26413499

  6. Inhibitory effects of endomorphin-2 on excitatory synaptic transmission and the neuronal excitability of sacral parasympathetic preganglionic neurons in young rats

    PubMed Central

    Chen, Ying-Biao; Huang, Fen-Sheng; Fen, Ban; Yin, Jun-Bin; Wang, Wei; Li, Yun-Qing

    2015-01-01

    The function of the urinary bladder is partly controlled by parasympathetic preganglionic neurons (PPNs) of the sacral parasympathetic nucleus (SPN). Our recent work demonstrated that endomorphin-2 (EM-2)-immunoreactive (IR) terminals form synapses with μ-opioid receptor (MOR)-expressing PPNs in the rat SPN. Here, we examined the effects of EM-2 on excitatory synaptic transmission and the neuronal excitability of the PPNs in young rats (24–30 days old) using a whole-cell patch-clamp approach. PPNs were identified by retrograde labeling with the fluorescent tracer tetramethylrhodamine-dextran (TMR). EM-2 (3 μM) markedly decreased both the amplitude and the frequency of the spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) of PPNs. EM-2 not only decreased the resting membrane potentials (RMPs) in 61.1% of the examined PPNs with half-maximal response at the concentration of 0.282 μM, but also increased the rheobase current and reduced the repetitive action potential firing of PPNs. Analysis of the current–voltage relationship revealed that the EM-2-induced current was reversed at −95 ± 2.5 mV and was suppressed by perfusion of the potassium channel blockers 4-aminopyridine (4-AP) or BaCl2 or by the addition of guanosine 5′-[β-thio]diphosphate trilithium salt (GDP-β-S) to the pipette solution, suggesting the involvement of the G-protein-coupled inwardly rectifying potassium (GIRK) channel. The above EM-2-invoked inhibitory effects were abolished by the MOR selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), indicating that the effects of EM-2 on PPNs were mediated by MOR via pre- and/or post-synaptic mechanisms. EM-2 activated pre- and post-synaptic MORs, inhibiting excitatory neurotransmitter release from the presynaptic terminals and decreasing the excitability of PPNs due to hyperpolarization of their membrane potentials, respectively. These inhibitory effects of EM-2 on PPNs at the spinal cord level may

  7. Inhibitory effects of endomorphin-2 on excitatory synaptic transmission and the neuronal excitability of sacral parasympathetic preganglionic neurons in young rats.

    PubMed

    Chen, Ying-Biao; Huang, Fen-Sheng; Fen, Ban; Yin, Jun-Bin; Wang, Wei; Li, Yun-Qing

    2015-01-01

    The function of the urinary bladder is partly controlled by parasympathetic preganglionic neurons (PPNs) of the sacral parasympathetic nucleus (SPN). Our recent work demonstrated that endomorphin-2 (EM-2)-immunoreactive (IR) terminals form synapses with μ-opioid receptor (MOR)-expressing PPNs in the rat SPN. Here, we examined the effects of EM-2 on excitatory synaptic transmission and the neuronal excitability of the PPNs in young rats (24-30 days old) using a whole-cell patch-clamp approach. PPNs were identified by retrograde labeling with the fluorescent tracer tetramethylrhodamine-dextran (TMR). EM-2 (3 μM) markedly decreased both the amplitude and the frequency of the spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) of PPNs. EM-2 not only decreased the resting membrane potentials (RMPs) in 61.1% of the examined PPNs with half-maximal response at the concentration of 0.282 μM, but also increased the rheobase current and reduced the repetitive action potential firing of PPNs. Analysis of the current-voltage relationship revealed that the EM-2-induced current was reversed at -95 ± 2.5 mV and was suppressed by perfusion of the potassium channel blockers 4-aminopyridine (4-AP) or BaCl2 or by the addition of guanosine 5'-[β-thio]diphosphate trilithium salt (GDP-β-S) to the pipette solution, suggesting the involvement of the G-protein-coupled inwardly rectifying potassium (GIRK) channel. The above EM-2-invoked inhibitory effects were abolished by the MOR selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), indicating that the effects of EM-2 on PPNs were mediated by MOR via pre- and/or post-synaptic mechanisms. EM-2 activated pre- and post-synaptic MORs, inhibiting excitatory neurotransmitter release from the presynaptic terminals and decreasing the excitability of PPNs due to hyperpolarization of their membrane potentials, respectively. These inhibitory effects of EM-2 on PPNs at the spinal cord level may explain

  8. Short-term increases in transient receptor potential vanilloid-1 mediate stress-induced enhancement of neuronal excitation.

    PubMed

    Weitlauf, Carl; Ward, Nicholas J; Lambert, Wendi S; Sidorova, Tatiana N; Ho, Karen W; Sappington, Rebecca M; Calkins, David J

    2014-11-12

    Progression of neurodegeneration in disease and injury is influenced by the response of individual neurons to stressful stimuli and whether this response includes mechanisms to counter declining function. Transient receptor potential (TRP) cation channels transduce a variety of disease-relevant stimuli and can mediate diverse stress-dependent changes in physiology, both presynaptic and postsynaptic. Recently, we demonstrated that knock-out or pharmacological inhibition of the TRP vanilloid-1 (TRPV1) capsaicin-sensitive subunit accelerates degeneration of retinal ganglion cell neurons and their axons with elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Here we probed the mechanism of the influence of TRPV1 on ganglion cell survival in mouse models of glaucoma. We found that induced elevations of ocular pressure increased TRPV1 in ganglion cells and its colocalization at excitatory synapses to their dendrites, whereas chronic elevation progressively increased ganglion cell Trpv1 mRNA. Enhanced TRPV1 expression in ganglion cells was transient and supported a reversal of the effect of TRPV1 on ganglion cells from hyperpolarizing to depolarizing, which was also transient. Short-term enhancement of TRPV1-mediated activity led to a delayed increase in axonal spontaneous excitation that was absent in ganglion cells from Trpv1(-/-) retina. In isolated ganglion cells, pharmacologically activated TRPV1 mobilized to discrete nodes along ganglion cell dendrites that corresponded to sites of elevated Ca(2+). These results suggest that TRPV1 may promote retinal ganglion cell survival through transient enhancement of local excitation and axonal activity in response to ocular stress. PMID:25392504

  9. Short-Term Increases in Transient Receptor Potential Vanilloid-1 Mediate Stress-Induced Enhancement of Neuronal Excitation

    PubMed Central

    Weitlauf, Carl; Ward, Nicholas J.; Lambert, Wendi S.; Sidorova, Tatiana N.; Ho, Karen W.; Sappington, Rebecca M.

    2014-01-01

    Progression of neurodegeneration in disease and injury is influenced by the response of individual neurons to stressful stimuli and whether this response includes mechanisms to counter declining function. Transient receptor potential (TRP) cation channels transduce a variety of disease-relevant stimuli and can mediate diverse stress-dependent changes in physiology, both presynaptic and postsynaptic. Recently, we demonstrated that knock-out or pharmacological inhibition of the TRP vanilloid-1 (TRPV1) capsaicin-sensitive subunit accelerates degeneration of retinal ganglion cell neurons and their axons with elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Here we probed the mechanism of the influence of TRPV1 on ganglion cell survival in mouse models of glaucoma. We found that induced elevations of ocular pressure increased TRPV1 in ganglion cells and its colocalization at excitatory synapses to their dendrites, whereas chronic elevation progressively increased ganglion cell Trpv1 mRNA. Enhanced TRPV1 expression in ganglion cells was transient and supported a reversal of the effect of TRPV1 on ganglion cells from hyperpolarizing to depolarizing, which was also transient. Short-term enhancement of TRPV1-mediated activity led to a delayed increase in axonal spontaneous excitation that was absent in ganglion cells from Trpv1−/− retina. In isolated ganglion cells, pharmacologically activated TRPV1 mobilized to discrete nodes along ganglion cell dendrites that corresponded to sites of elevated Ca2+. These results suggest that TRPV1 may promote retinal ganglion cell survival through transient enhancement of local excitation and axonal activity in response to ocular stress. PMID:25392504

  10. The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type

    PubMed Central

    Lee, Vallent; Maguire, Jamie

    2014-01-01

    The diversity of GABAA receptor (GABAAR) subunits and the numerous configurations during subunit assembly give rise to a variety of receptors with different functional properties. This heterogeneity results in variations in GABAergic conductances across numerous brain regions and cell types. Phasic inhibition is mediated by synaptically-localized receptors with a low affinity for GABA and results in a transient, rapidly desensitizing GABAergic conductance; whereas, tonic inhibition is mediated by extrasynaptic receptors with a high affinity for GABA and results in a persistent GABAergic conductance. The specific functions of tonic versus phasic GABAergic inhibition in different cell types and the impact on specific neural circuits are only beginning to be unraveled. Here we review the diversity in the magnitude of tonic GABAergic inhibition in various brain regions and cell types, and highlight the impact on neuronal excitability in different neuronal circuits. Further, we discuss the relevance of tonic inhibition in various physiological and pathological contexts as well as the potential of targeting these receptor subtypes for treatment of diseases, such as epilepsy. PMID:24550784

  11. Acid-Sensing Ion Channels Expression, Identity and Role in the Excitability of the Cochlear Afferent Neurons

    PubMed Central

    González-Garrido, Antonia; Vega, Rosario; Mercado, Francisco; López, Iván A.; Soto, Enrique

    2015-01-01

    Acid-sensing ion channels (ASICs) are activated by an increase in the extracellular proton concentration. There are four genes (ASIC1-4) that encode six subunits, and they are involved in diverse neuronal functions, such as mechanosensation, learning and memory, nociception, and modulation of retinal function. In this study, we characterize the ASIC currents of spiral ganglion neurons (SGNs). These ASIC currents are primarily carried by Na+, exhibit fast activation and desensitization, display a pH50 of 6.2 and are blocked by amiloride, indicating that these are ASIC currents. The ASIC currents were further characterized using several pharmacological tools. Gadolinium and acetylsalicylic acid reduced these currents, and FMRFamide, zinc (at high concentrations) and N,N,N’,N’–tetrakis-(2-piridilmetil)-ethylenediamine increased them, indicating that functional ASICs are composed of the subunits ASIC1, ASIC2, and ASIC3. Neomycin and streptomycin reduced the desensitization rate of the ASIC current in SGNs, indicating that ASICs may contribute to the ototoxic action of aminoglycosides. RT-PCR of the spiral ganglion revealed significant expression of all ASIC subunits. By immunohistochemistry the expression of the ASIC1a, ASIC2a, ASIC2b, and ASIC3 subunits was detected in SGNs. Although only a few SGNs exhibited action potential firing in response to an acidic stimulus, protons in the extracellular solution modulated SGN activity during sinusoidal stimulation. Our results show that protons modulate the excitability of SGNs via ASICs. PMID:26733809

  12. Suppression of neuronal excitability by the secretion of the lamprey (Lampetra japonica) provides a mechanism for its evolutionary stability.

    PubMed

    Chi, Shaopeng; Xiao, Rong; Li, Qingwei; Zhou, Liwei; He, Rongqiao; Qi, Zhi

    2009-07-01

    Lampreys are one of the most primitive vertebrates still living today. They attach themselves to the body surface of the host fish through their sucker-like mouths and suck blood of the host for days. Recent fossil evidence has indicated that morphology of lampreys in the late Devonian period, over 360 million years ago, already possessed the present day major characteristics, suggesting the evolutionary stability of a highly specialized parasitic feeding habit. Obviously, nociceptive responses and hemostasis of the host are two major barriers to long-term feeding of the parasitic lamprey. It has been found, to counteract hemostasis of the host, that paired buccal glands of lampreys secrete antihemostatic compounds to prevent blood of the host from coagulation. However, it is not known how lampreys make the host lose nociceptive responses. Here, we prepared components of the crude extract from the buccal glands of the lampreys (Lampetra japonica). Then, we show that crude extract and one of its purified components reduce the firing frequency of neuronal action potentials probably through inhibiting the voltage-dependent Na(+) channels. As the voltage-gated Na(+) channels are highly conserved throughout evolution, we argue that the secretion of the lampreys could exert the similar effect on the Na(+) channels of their host fish as well. Therefore, together with its antihemostatic effect, the secretion due to its inhibitory effect on neuronal excitability might provide a mechanism for the parasitic lampreys to keep their evolutionary stability. PMID:19198874

  13. Administration of copper reduced the hyper-excitability of neurons in CA1 hippocampal slices from epileptic rats.

    PubMed

    Leiva, Juan; Infante, Claudio

    2016-04-01

    Copper as a trace metal is involved in several neurodegenerative illnesses, such as Menkes, Wilson's, Alzheimer's, amyotrophic lateral sclerosis (ALS), and Creutzfeldt-Jakob. Electrophysiological evidence indicates that acute perfusion of copper can inhibit long-term synaptic potentiation in hippocampal slices. The objective of this work is to determine whether Cu perfusion can perturb synaptic transmission in hippocampal slices derived from pilocarpine treated epileptic rats. Field potential (FP) recordings of the CA1 neurons of rats with chronic epilepsy showed voltage and response duration decrease following copper sulfate perfusion. However, voltage and response duration were higher after removing copper by washing. The discharge frequency of the CA1 neurons of hippocampal slices from non-epileptic control rats was increased after acute perfusion of 10 μM of pilocarpine. This increase was blocked by administering copper sulphate 10 μM. Krebs-Ringer solution washing re-established the discharges, with a higher frequency than that provoked by pilocarpine perfusion. We discuss the blocking effect of copper and the synaptic hyper-excitability generated by its removal. PMID:27548095

  14. Effects of polarization induced by non-weak electric fields on the excitability of elongated neurons with active dendrites.

    PubMed

    Reznik, Robert I; Barreto, Ernest; Sander, Evelyn; So, Paul

    2016-02-01

    An externally-applied electric field can polarize a neuron, especially a neuron with elongated dendrites, and thus modify its excitability. Here we use a computational model to examine, predict, and explain these effects. We use a two-compartment Pinsky-Rinzel model neuron polarized by an electric potential difference imposed between its compartments, and we apply an injected ramp current. We vary three model parameters: the magnitude of the applied potential difference, the extracellular potassium concentration, and the rate of current injection. A study of the Time-To-First-Spike (TTFS) as a function of polarization leads to the identification of three regions of polarization strength that have different effects. In the weak region, the TTFS increases linearly with polarization. In the intermediate region, the TTFS increases either sub- or super-linearly, depending on the current injection rate and the extracellular potassium concentration. In the strong region, the TTFS decreases. Our results in the weak and strong region are consistent with experimental observations, and in the intermediate region, we predict novel effects that depend on experimentally-accessible parameters. We find that active channels in the dendrite play a key role in these effects. Our qualitative results were found to be robust over a wide range of inter-compartment conductances and the ratio of somatic to dendritic membrane areas. In addition, we discuss preliminary results where synaptic inputs replace the ramp injection protocol. The insights and conclusions were found to extend from our polarized PR model to a polarized PR model with I h dendritic currents. Finally, we discuss the degree to which our results may be generalized. PMID:26560333

  15. Intravenous Cocaine Induces Rapid, Transient Excitation of Striatal Neurons via its Action on Peripheral Neural Elements: Single-cell, Iontophoretic Study in Awake and Anesthetized Rats

    PubMed Central

    Kiyatkin, Eugene A.; Brown, Paul Leon

    2007-01-01

    Cocaine’s (COC) direct interaction with the dopamine (DA) transporter is usually considered the most important action underlying the psychomotor stimulant and reinforcing effects of this drug. However, some physiological, behavioral and psycho-emotional effects of COC are very rapid and brief and they remain intact during DA receptor blockade, suggesting possible involvement of peripheral non-DA neural mechanisms. To assess this issue, single-unit recording with microiontophoresis was used to examine changes in impulse activity of dorsal and ventral striatal neurons to intravenous (iv) COC (0.25–0.5 mg/kg) in the same rats under two conditions: awake with dopamine (DA) receptor blockade and anesthetized with urethane. In the awake preparation ~70% striatal neurons showed rapid and transient (latency ~ 6 s, duration ~15 s) COC-induced excitations. These effects were stronger in ventral than dorsal striatum. During anesthesia, these phasic effects were fully blocked and COC slowly decreased neuronal discharge rate. COC-methiodide (COC-M), a derivative that cannot cross the blood-brain barrier, also caused phasic excitations in the awake, but not anesthetized condition. In contrast to regular COC, COC-M had no tonic effect on discharge rate in either preparation. Most striatal neurons that were phasically excited by both COC forms also showed short-latency excitations during tail-touch and tail-pinch in the awake preparation, an effect strongly attenuated during anesthesia. Finally, most striatal neurons that in awake conditions were phasically excited by somato-sensory stimuli and COC salts were also excited by iontophoretic glutamate (GLU). Although striatal neurons were sensitive to GLU in both preparations, the response magnitude at the same GLU current was higher in awake than anesthetized conditions. These data suggest that in awake animals iv COC, like somato-sensory stimuli, transiently excites striatal neurons via its action on peripheral neural elements

  16. Hyperbaric hyperoxia and normobaric reoxygenation increase excitability and activate oxygen-induced potentiation in CA1 hippocampal neurons.

    PubMed

    Garcia, Alfredo J; Putnam, Robert W; Dean, Jay B

    2010-09-01

    Breathing hyperbaric oxygen (HBO) is common practice in hyperbaric and diving medicine. The benefits of breathing HBO, however, are limited by the risk of central nervous system O2 toxicity, which presents as seizures. We tested the hypothesis that excitability increases in CA1 neurons of the rat hippocampal slice (400 microm) over a continuum of hyperoxia that spans normobaric and hyperbaric pressures. Amplitude changes of the orthodromic population spike were used to assess neuronal O2 sensitivity before, during, and following exposure to 0, 0.6, 0.95 (control), 2.84, and 4.54 atmospheres absolute (ATA) O2. Polarographic O2 electrodes were used to measure tissue slice PO2 (PtO2). In 0.95 ATA O2, core PtO2 at 200 microm deep was 115±16 Torr (mean±SE). Increasing O2 to 2.84 and 4.54 ATA increased core PtO2 to 1,222±77 and 2,037±157 Torr, respectively. HBO increased the orthodromic population spike amplitude and usually induced hyperexcitability (i.e., secondary population spikes) and, in addition, a long-lasting potentiation of the orthodromic population spike that we have termed "oxygen-induced potentiation" (OxIP). Exposure to 0.60 ATA O2 and hypoxia (0.00 ATA) decreased core PtO2 to 84±6 and 20±4 Torr, respectively, and abolished the orthodromic response. Reoxygenation from 0.0 or 0.6 ATA O2, however, usually produced a response similar to that of HBO: hyperexcitability and activation of OxIP. We conclude that CA1 neurons exhibit increased excitability and neural plasticity over a broad range of PtO2, which can be activated by a single, hyperoxic stimulus. We postulate that transient acute hyperoxia stimulus, whether caused by breathing HBO or reoxygenation following hypoxia (e.g., disordered breathing), is a powerful stimulant for orthodromic activity and neural plasticity in the CA1 hippocampus. PMID:20558753

  17. Excitability parameters and sensitivity to anemone toxin ATX-II in rat small diameter primary sensory neurones discriminated by Griffonia simplicifolia isolectin IB4

    PubMed Central

    Snape, Alistair; Pittaway, James F; Baker, Mark D

    2010-01-01

    Sensory neurone subtypes (≤ 25 μm apparent diameter) express a variety of Na+ channels, where expression is linked to action potential duration, and associated with differential IB4-lectin binding. We hypothesized that sensitivity to ATX-II might also discriminate neurones and report that 1 μm has negligible or small effects on action potentials in IB4 +ve, but dramatically increased action potential duration in IB4 −ve, neurones. The toxin did not act on tetrodotoxin-resistant (TTX-r) NaV1.8 currents; discrimination was based on tetrodotoxin-sensitive (TTX-s) Na+ channel expression. We also explored the effects of varying the holding potential on current threshold, and the effect of repetitive activation on action currents in IB4 +ve and −ve neurones. IB4 +ve neurones became more excitable with depolarization over the range −100 to −20 mV, but IB4 −ve neurones exhibited peak excitability near −55 mV, and were inexcitable at −20 mV. Eliciting action potentials at 2 Hz, we found that peak inward action current in IB4 +ve neurones was reduced, whereas changes in the current amplitude were negligible in most IB4 −ve neurones. Our findings are consistent with relatively toxin-insensitive channels including NaV1.7 being expressed in IB4 +ve neurones, whereas toxin sensitivity indicates that IB4 −ve neurones may express NaV1.1 or NaV1.2, or both. The retention of excitability at low membrane potentials, and the responses to repetitive stimulation are explained by the known preferential expression of NaV1.8 in IB4 +ve neurones, and the reduction in action current in IB4 +ve neurones with repetitive stimulation supports a novel hypothesis explaining the slowing of conduction velocity in C-fibres by the build-up of Na+ channel inactivation. PMID:19900960

  18. HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study

    PubMed Central

    Ruiz, Rocío; Pérez-Villegas, Eva María; Bachiller, Sara; Rosa, José Luis; Armengol, José Angel

    2016-01-01

    The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity. PMID:27147983

  19. HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study.

    PubMed

    Ruiz, Rocío; Pérez-Villegas, Eva María; Bachiller, Sara; Rosa, José Luis; Armengol, José Angel

    2016-01-01

    The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity. PMID:27147983

  20. Elevated Neuronal Excitability Due to Modulation of the Voltage-Gated Sodium Channel Nav1.6 by Aβ1−42

    PubMed Central

    Wang, Xi; Zhang, Xiao-Gang; Zhou, Ting-Ting; Li, Na; Jang, Chun-Yan; Xiao, Zhi-Cheng; Ma, Quan-Hong; Li, Shao

    2016-01-01

    Aberrant increases in neuronal network excitability may contribute to the cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability are not fully understood. Such overexcitation of neuronal networks has been detected in the brains of APP/PS1 mice. In the present study, using current-clamp recording techniques, we observed that 12 days in vitro (DIV) primary cultured pyramidal neurons from P0 APP/PS1 mice exhibited a more prominent action potential burst and a lower threshold than WT littermates. Moreover, after treatment with Aβ1−42 peptide, 12 DIV primary cultured neurons showed similar changes, to a greater degree than in controls. Voltage-clamp recordings revealed that the voltage-dependent sodium current density of neurons incubated with Aβ1−42 was significantly increased, without change in the voltage-dependent sodium channel kinetic characteristics. Immunohistochemistry and western blot results showed that, after treatment with Aβ1−42, expressions of Nav and Nav1.6 subtype increased in cultured neurons or APP/PS1 brains compared to control groups. The intrinsic neuronal hyperexcitability of APP/PS1 mice might thus be due to an increased expression of voltage-dependent sodium channels induced by Aβ1−42. These results may illuminate the mechanism of aberrant neuronal networks in AD. PMID:27013956

  1. Neuronal Dysregulation in Stroke-Associated Pseudobulbar Affect (PBA): Diagnostic Scales and Current Treatment Options

    PubMed Central

    Lapchak, Paul A

    2015-01-01

    Until recently there was little understanding of the exact pathophysiology and treatment choices for stroke patients with Pseudobulbar affect (PBA). PBA is typically characterized by outbursts or uncontrollable laughing or crying and in the majority of patients, the outbursts being involuntary and incompatible with the patients’ emotional state. PBA is a behavioral syndrome reported to be displayed in 28–52% of stroke patients with first or multiple strokes, and incidence may be higher in patients who have had prior stroke events, and higher in females. There is typically involvement of glutaminergic, serotoninergic and dopaminergic neuronal circuits of the corticolimbic-subcorticothalamic-pontocerebellar network. PBA is now understood to be a disinhibition syndrome in which specific pathways involving serotonin and glutamate are disrupted or modulated causing reduced cortical inhibition of a cerebellar/brainstem-situated “emotional” laughing or crying focal center. Stroke-induced disruption of one or more neuronal pathway circuits may “disinhibit” voluntary laughing and crying making the process involuntary. With a “new” treatment currently being marketed to treat PBA patients, this article will delve into the neurological and physiological basis for PBA in stroke, and review progress with the diagnosis and treatment of PBA. PMID:26693049

  2. MIR137 variants identified in psychiatric patients affect synaptogenesis and neuronal transmission gene sets.

    PubMed

    Strazisar, M; Cammaerts, S; van der Ven, K; Forero, D A; Lenaerts, A-S; Nordin, A; Almeida-Souza, L; Genovese, G; Timmerman, V; Liekens, A; De Rijk, P; Adolfsson, R; Callaerts, P; Del-Favero, J

    2015-04-01

    Sequence analysis of 13 microRNA (miRNA) genes expressed in the human brain and located in genomic regions associated with schizophrenia and/or bipolar disorder, in a northern Swedish patient/control population, resulted in the discovery of two functional variants in the MIR137 gene. On the basis of their location and the allele frequency differences between patients and controls, we explored the hypothesis that the discovered variants impact the expression of the mature miRNA and consequently influence global mRNA expression affecting normal brain functioning. Using neuronal-like SH-SY5Y cells, we demonstrated significantly reduced mature miR-137 levels in the cells expressing the variant miRNA gene. Subsequent transcriptome analysis showed that the reduction in miR-137 expression led to the deregulation of gene sets involved in synaptogenesis and neuronal transmission, all implicated in psychiatric disorders. Our functional findings add to the growing data, which implicate that miR-137 has an important role in the etiology of psychiatric disorders and emphasizes its involvement in nervous system development and proper synaptic function. PMID:24888363

  3. Macoilin, a Conserved Nervous System–Specific ER Membrane Protein That Regulates Neuronal Excitability

    PubMed Central

    Couto, Africa; Cheung, Benny H. H.; Labouesse, Michel; de Bono, Mario

    2011-01-01

    Genome sequence comparisons have highlighted many novel gene families that are conserved across animal phyla but whose biological function is unknown. Here, we functionally characterize a member of one such family, the macoilins. Macoilins are characterized by several highly conserved predicted transmembrane domains towards the N-terminus and by coiled-coil regions C-terminally. They are found throughout Eumetazoa but not in other organisms. Mutants for the single Caenorhabditis elegans macoilin, maco-1, exhibit a constellation of behavioral phenotypes, including defects in aggregation, O2 responses, and swimming. MACO-1 protein is expressed broadly and specifically in the nervous system and localizes to the rough endoplasmic reticulum; it is excluded from dendrites and axons. Apart from subtle synapse defects, nervous system development appears wild-type in maco-1 mutants. However, maco-1 animals are resistant to the cholinesterase inhibitor aldicarb and sensitive to levamisole, suggesting pre-synaptic defects. Using in vivo imaging, we show that macoilin is required to evoke Ca2+ transients, at least in some neurons: in maco-1 mutants the O2-sensing neuron PQR is unable to generate a Ca2+ response to a rise in O2. By genetically disrupting neurotransmission, we show that pre-synaptic input is not necessary for PQR to respond to O2, indicating that the response is mediated by cell-intrinsic sensory transduction and amplification. Disrupting the sodium leak channels NCA-1/NCA-2, or the N-,P/Q,R-type voltage-gated Ca2+ channels, also fails to disrupt Ca2+ responses in the PQR cell body to O2 stimuli. By contrast, mutations in egl-19, which encodes the only Caenorhabditis elegans L-type voltage-gated Ca2+ channel α1 subunit, recapitulate the Ca2+ response defect we see in maco-1 mutants, although we do not see defects in localization of EGL-19. Together, our data suggest that macoilin acts in the ER to regulate assembly or traffic of ion channels or ion channel

  4. Alpha-Synuclein affects neurite morphology, autophagy, vesicle transport and axonal degeneration in CNS neurons

    PubMed Central

    Koch, J C; Bitow, F; Haack, J; d'Hedouville, Z; Zhang, J-N; Tönges, L; Michel, U; Oliveira, L M A; Jovin, T M; Liman, J; Tatenhorst, L; Bähr, M; Lingor, P

    2015-01-01

    Many neuropathological and experimental studies suggest that the degeneration of dopaminergic terminals and axons precedes the demise of dopaminergic neurons in the substantia nigra, which finally results in the clinical symptoms of Parkinson disease (PD). The mechanisms underlying this early axonal degeneration are, however, still poorly understood. Here, we examined the effects of overexpression of human wildtype alpha-synuclein (αSyn-WT), a protein associated with PD, and its mutant variants αSyn-A30P and -A53T on neurite morphology and functional parameters in rat primary midbrain neurons (PMN). Moreover, axonal degeneration after overexpression of αSyn-WT and -A30P was analyzed by live imaging in the rat optic nerve in vivo. We found that overexpression of αSyn-WT and of its mutants A30P and A53T impaired neurite outgrowth of PMN and affected neurite branching assessed by Sholl analysis in a variant-dependent manner. Surprisingly, the number of primary neurites per neuron was increased in neurons transfected with αSyn. Axonal vesicle transport was examined by live imaging of PMN co-transfected with EGFP-labeled synaptophysin. Overexpression of all αSyn variants significantly decreased the number of motile vesicles and decelerated vesicle transport compared with control. Macroautophagic flux in PMN was enhanced by αSyn-WT and -A53T but not by αSyn-A30P. Correspondingly, colocalization of αSyn and the autophagy marker LC3 was reduced for αSyn-A30P compared with the other αSyn variants. The number of mitochondria colocalizing with LC3 as a marker for mitophagy did not differ among the groups. In the rat optic nerve, both αSyn-WT and -A30P accelerated kinetics of acute axonal degeneration following crush lesion as analyzed by in vivo live imaging. We conclude that αSyn overexpression impairs neurite outgrowth and augments axonal degeneration, whereas axonal vesicle transport and autophagy are severely altered. PMID:26158517

  5. Orexin-A modulates excitatory synaptic transmission and neuronal excitability in the spinal cord substantia gelatinosa.

    PubMed

    Jeon, Younghoon; Park, Ki Bum; Pervin, Rokeya; Kim, Tae Wan; Youn, Dong-ho

    2015-09-14

    Although intrathecal orexin-A has been known to be antinociceptive in various pain models, the role of orexin-A in antinociception is not well characterized. In the present study, we examined whether orexin-A modulates primary afferent fiber-mediated or spontaneous excitatory synaptic transmission using transverse spinal cord slices with attached dorsal root. Bath-application of orexin-A (100nM) reduced the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation of Aδ- or C-primary afferent fibers. The magnitude of reduction was much larger for EPSCs evoked by polysynaptic C-fibers than polysynaptic Aδ-fibers, whereas it was similar in EPSCs evoked by monosynaptic Aδ- or C-fibers. SB674042, an orexin-1 receptor antagonist, but not EMPA, an orexin-2 receptor antagonist, significantly inhibited the orexin-A-induced reduction in EPSC amplitude from mono- or polysynaptic Aδ-fibers, as well as from mono- or polysynaptic C-fibers. Furthermore, orexin-A significantly increased the frequency of spontaneous EPSCs but not the amplitude. This increase was almost completely blocked by both SB674042 and EMPA. On the other hand, orexin-A produced membrane oscillations and inward currents in the SG neurons that were partially or completely inhibited by SB674042 or EMPA, respectively. Thus, this study suggests that the spinal actions of orexin-A underlie orexin-A-induced antinociceptive effects via different subtypes of orexin receptors. PMID:26254164

  6. Expression in cultured human neuroblastoma cells of epitopes associated with affected neurons in Alzheimer's disease.

    PubMed Central

    Ko, L. W.; Sheu, K. F.; Young, O.; Thaler, H.; Blass, J. P.

    1990-01-01

    Of three human neuroblastoma lines tested, IMR32K (and IMR32 parental line) was the only cell line that, after its exposure to a differentiation medium, consistently developed materials recognized immunocytochemically by a panel of antibodies against paired helical filaments (PHF). Ultrastructurally, these cells accumulated, at their perikarya and neuritic extensions, spatially discrete arrays of fibrils, which occasionally occurred in twisted pairs. When these fibrillar structures appeared as paired helices, they exhibited dimensions and configurations reminiscent of PHF found in affected Alzheimer neurons, although less compact. Immunoelectron microscope examinations of the fibrillar structures in these neuroblastoma cells with one of these anti-PHF immunoprobes revealed that only subsets of fibrillar structures that appeared thickened or aggregated to form bundles were selectively immunolabeled. Cultures of these immortal neuroblastoma lines may provide a convenient model for studying aspects of PHF formation that are hard to examine in Alzheimer brain obtained at autopsy. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:1691594

  7. Serotonin and insulin-like peptides modulate leucokinin-producing neurons that affect feeding and water homeostasis in Drosophila.

    PubMed

    Liu, Yiting; Luo, Jiangnan; Carlsson, Mikael A; Nässel, Dick R

    2015-08-15

    Metabolic homeostasis and water balance is maintained by tight hormonal and neuronal regulation. In Drosophila, insulin-like peptides (DILPs) are key regulators of metabolism, and the neuropeptide leucokinin (LK) is a diuretic hormone that also modulates feeding. However, it is not known whether LK and DILPs act together to regulate feeding and water homeostasis. Because LK neurons express the insulin receptor (dInR), we tested functional links between DILP and LK signaling in feeding and water balance. Thus, we performed constitutive and conditional manipulations of activity in LK neurons and insulin-producing cells (IPCs) in adult flies and monitored food intake, responses to desiccation, and peptide expression levels. We also measured in vivo changes in LK and DILP levels in neurons in response to desiccation and drinking. Our data show that activated LK cells stimulate diuresis in vivo, and that LK and IPC signaling affect food intake in opposite directions. Overexpression of the dInR in LK neurons decreases the LK peptide levels, but only caused a subtle decrease in feeding, and had no effect on water balance. Next we demonstrated that LK neurons express the serotonin receptor 5-HT1B . Knockdown of this receptor in LK neurons diminished LK expression, increased desiccation resistance, and diminished food intake. Live calcium imaging indicates that serotonin inhibits spontaneous activity in abdominal LK neurons. Our results suggest that serotonin via 5-HT1B diminishes activity in the LK neurons and thereby modulates functions regulated by LK peptide, but the action of the dInR in these neurons remains less clear. PMID:25732325

  8. Increased intrinsic excitability of muscle vasoconstrictor preganglionic neurons may contribute to the elevated sympathetic activity in hypertensive rats

    PubMed Central

    Briant, Linford J. B.; Stalbovskiy, Alexey O.; Nolan, Matthew F.; Champneys, Alan R.

    2014-01-01

    Hypertension is associated with pathologically increased sympathetic drive to the vasculature. This has been attributed to increased excitatory drive to sympathetic preganglionic neurons (SPN) from brainstem cardiovascular control centers. However, there is also evidence supporting increased intrinsic excitability of SPN. To test this hypothesis, we made whole cell recordings of muscle vasoconstrictor-like (MVClike) SPN in the working-heart brainstem preparation of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats. The MVClike SPN have a higher spontaneous firing frequency in the SH rat (3.85 ± 0.4 vs. 2.44 ± 0.4 Hz in WKY; P = 0.011) with greater respiratory modulation of their activity. The action potentials of SH SPN had smaller, shorter afterhyperpolarizations (AHPs) and showed diminished transient rectification indicating suppression of an A-type potassium conductance (IA). We developed mathematical models of the SPN to establish if changes in their intrinsic properties in SH rats could account for their altered firing. Reduction of the maximal conductance density of IA by 15–30% changed the excitability and output of the model from the WKY to a SH profile, with increased firing frequency, amplified respiratory modulation, and smaller AHPs. This change in output is predominantly a consequence of altered synaptic integration. Consistent with these in silico predictions, we found that intrathecal 4-aminopyridine (4-AP) increased sympathetic nerve activity, elevated perfusion pressure, and augmented Traube-Hering waves. Our findings indicate that IA acts as a powerful filter on incoming synaptic drive to SPN and that its diminution in the SH rat is potentially sufficient to account for the increased sympathetic output underlying hypertension. PMID:25122704

  9. Increased intrinsic excitability of muscle vasoconstrictor preganglionic neurons may contribute to the elevated sympathetic activity in hypertensive rats.

    PubMed

    Briant, Linford J B; Stalbovskiy, Alexey O; Nolan, Matthew F; Champneys, Alan R; Pickering, Anthony E

    2014-12-01

    Hypertension is associated with pathologically increased sympathetic drive to the vasculature. This has been attributed to increased excitatory drive to sympathetic preganglionic neurons (SPN) from brainstem cardiovascular control centers. However, there is also evidence supporting increased intrinsic excitability of SPN. To test this hypothesis, we made whole cell recordings of muscle vasoconstrictor-like (MVClike) SPN in the working-heart brainstem preparation of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats. The MVClike SPN have a higher spontaneous firing frequency in the SH rat (3.85 ± 0.4 vs. 2.44 ± 0.4 Hz in WKY; P = 0.011) with greater respiratory modulation of their activity. The action potentials of SH SPN had smaller, shorter afterhyperpolarizations (AHPs) and showed diminished transient rectification indicating suppression of an A-type potassium conductance (IA). We developed mathematical models of the SPN to establish if changes in their intrinsic properties in SH rats could account for their altered firing. Reduction of the maximal conductance density of IA by 15-30% changed the excitability and output of the model from the WKY to a SH profile, with increased firing frequency, amplified respiratory modulation, and smaller AHPs. This change in output is predominantly a consequence of altered synaptic integration. Consistent with these in silico predictions, we found that intrathecal 4-aminopyridine (4-AP) increased sympathetic nerve activity, elevated perfusion pressure, and augmented Traube-Hering waves. Our findings indicate that IA acts as a powerful filter on incoming synaptic drive to SPN and that its diminution in the SH rat is potentially sufficient to account for the increased sympathetic output underlying hypertension. PMID:25122704

  10. Premature changes in neuronal excitability account for hippocampal network impairment and autistic-like behavior in neonatal BTBR T+tf/J mice

    PubMed Central

    Cellot, Giada; Maggi, Laura; Di Castro, Maria Amalia; Catalano, Myriam; Migliore, Rosanna; Migliore, Michele; Scattoni, Maria Luisa; Calamandrei, Gemma; Cherubini, Enrico

    2016-01-01

    Coherent network oscillations (GDPs), generated in the immature hippocampus by the synergistic action of GABA and glutamate, both depolarizing and excitatory, play a key role in the construction of neuronal circuits. In particular, GDPs-associated calcium transients act as coincident detectors for enhancing synaptic efficacy at emerging GABAergic and glutamatergic synapses. Here, we show that, immediately after birth, in the CA3 hippocampal region of the BTBR T+tf/J mouse, an animal model of idiopathic autism, GDPs are severely impaired. This effect was associated with an increased GABAergic neurotransmission and a reduced neuronal excitability. In spite its depolarizing action on CA3 pyramidal cells (in single channel experiments EGABA was positive to Em), GABA exerted at the network level an inhibitory effect as demonstrated by isoguvacine-induced reduction of neuronal firing. We implemented a computational model in which experimental findings could be interpreted as the result of two competing effects: a reduction of the intrinsic excitability of CA3 principal cells and a reduction of the shunting activity in GABAergic interneurons projecting to principal cells. It is therefore likely that premature changes in neuronal excitability within selective hippocampal circuits of BTBR mice lead to GDPs dysfunction and behavioral deficits reminiscent of those found in autistic patients. PMID:27526668

  11. Premature changes in neuronal excitability account for hippocampal network impairment and autistic-like behavior in neonatal BTBR T+tf/J mice.

    PubMed

    Cellot, Giada; Maggi, Laura; Di Castro, Maria Amalia; Catalano, Myriam; Migliore, Rosanna; Migliore, Michele; Scattoni, Maria Luisa; Calamandrei, Gemma; Cherubini, Enrico

    2016-01-01

    Coherent network oscillations (GDPs), generated in the immature hippocampus by the synergistic action of GABA and glutamate, both depolarizing and excitatory, play a key role in the construction of neuronal circuits. In particular, GDPs-associated calcium transients act as coincident detectors for enhancing synaptic efficacy at emerging GABAergic and glutamatergic synapses. Here, we show that, immediately after birth, in the CA3 hippocampal region of the BTBR T+tf/J mouse, an animal model of idiopathic autism, GDPs are severely impaired. This effect was associated with an increased GABAergic neurotransmission and a reduced neuronal excitability. In spite its depolarizing action on CA3 pyramidal cells (in single channel experiments EGABA was positive to Em), GABA exerted at the network level an inhibitory effect as demonstrated by isoguvacine-induced reduction of neuronal firing. We implemented a computational model in which experimental findings could be interpreted as the result of two competing effects: a reduction of the intrinsic excitability of CA3 principal cells and a reduction of the shunting activity in GABAergic interneurons projecting to principal cells. It is therefore likely that premature changes in neuronal excitability within selective hippocampal circuits of BTBR mice lead to GDPs dysfunction and behavioral deficits reminiscent of those found in autistic patients. PMID:27526668

  12. The effects of cAMP on the excitability and responses of defensive behavior command neurons in the common snail evoked by sensory stimuli.

    PubMed

    Nikitin, V P; Kozyrev, S A

    2000-01-01

    Experiments on snails showed that extracellular application of dibutyryl-cAMP (db-cAMP) or intracellular application of cAMP for 30 min evoked increases in excitability and synaptic facilitation in responses to sensory stimulation of defensive behavior command neurons LP11 and RP11. Excitability increased 45-60 min after the start of addition of db-cAMP or cAMP and remained elevated until the end of the experiment (3-4 h). Synaptic facilitation started 50-60 min after the onset of extracellular application of db-cAMP and remained detectable in the responses of neurons to tactile stimulation of the head for 1 h and to application of dilute quinine solution for 2-4 h. Application of db-cAMP produced no changes in responses to tactile stimulation of the foot or mantle ridge. Intracellular injection of cAMP induced facilitation of neuron responses only to weak quinine solutions. The responses of neurons to tactile stimulation of the head, foot, and mantle ridge did not change after injections of cAMP. It is suggested that cAMP is involved in the mechanisms controlling the excitability of neurons LP11 and RP11. In addition, cAMP is selectively involved in the postsynaptic mechanism inducing the transient stage of long-term facilitation of synaptic "inputs," which mediates excitation evoked by chemical stimuli. This set of effects of cAMP is similar to effects arising during the development of nociceptive sensitization and in response to serotonin. PMID:10981948

  13. Subthreshold receptive fields and baseline excitability of "silent" S1 callosal neurons in awake rabbits: contributions of AMPA/kainate and NMDA receptors.

    PubMed

    Swadlow, H A; Hicks, T P

    1997-07-01

    The contribution of NMDA and non-NMDA receptors to excitatory subthreshold receptive fields was examined in callosal efferent neurons (CC neurons) in primary somatosensory cortex of the fully awake rabbit. Only neurons showing no traditional (suprathreshold) receptive fields were examined. Subthreshold responses were examined by monitoring the thresholds of efferent neurons to juxtasomal current pulses (JSCPs) delivered through the recording microelectrode. Changes in threshold following a peripheral conditioning stimulus signify a subthreshold response. Using this method, excitatory postsynaptic potentials and inhibitory postsynaptic potentials are manifested as decreases and increases in JSCP threshold, respectively. NMDA and non-NMDA agonists and antagonists were administered iontophoretically via a multibarrel micropipette assembly attached to the recording/stimulating microelectrode. Receptor-selective doses of both AMPA/kainate and NMDA antagonists decreased the excitability of CC neurons in the absence of any peripheral stimulation. Threshold to JSCPs rose by a mean of 20% for both classes of antagonist. Despite the similar effects of NMDA and non-NMDA antagonists on baseline excitability, these antagonists had dramatically different effects on the subthreshold excitatory response to activation of the receptive field. Whereas receptor-selective doses of AMPA/kainate antagonists either eliminated or severely attenuated the subthreshold excitatory responses to peripheral stimulation, NMDA antagonists had little or no effect on the subthreshold evoked response. PMID:9262195

  14. Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons.

    PubMed

    Khodr, Christina E; Chen, Lihua; Dave, Sonya; Al-Harthi, Lena; Hu, Xiu-Ti

    2016-10-01

    Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca(2+) channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca(2+) potentials (Ca(2+) influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K(+) influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca(2+) influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca(2+) potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca(2+) influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca(2+) dysregulation in the mPFC. PMID:27326669

  15. Gq Protein-Coupled Membrane-Initiated Estrogen Signaling Rapidly Excites Corticotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus in Female Mice.

    PubMed

    Hu, Pu; Liu, Ji; Yasrebi, Ali; Gotthardt, Juliet D; Bello, Nicholas T; Pang, Zhiping P; Roepke, Troy A

    2016-09-01

    CRH neurons in the hypothalamic paraventricular nucleus (PVN) play a central role in regulating the hypothalamus-pituitary-adrenal (HPA) axis and are directly influenced by 17β-estradiol (E2). Although compelling evidence has suggested the existence of membrane-associated estrogen receptors (mERs) in hypothalamic and other central nervous system neurons, it remains unknown whether E2 impacts CRH neuronal excitability through this mechanism. The purpose of the current study is to examine the existence and function of mER signaling in PVN CRH neurons. Whole-cell recordings were made from CRH neurons identified by Alexa Fluor 594 labeling and post hoc immunostaining in ovariectomized female mice. E2 (100nM) rapidly suppressed the M-current (a voltage-dependent K(+) current) and potentiated glutamatergic excitatory postsynaptic currents. The putative Gq-coupled mER (Gq-mER) characterized in hypothalamic proopiomelanocortin neurons initiates a phospholipase C-protein kinase C-protein kinase A pathway; therefore, we examined the involvement of this pathway using selective inhibitors. Indeed, the ER antagonist ICI 182780 and inhibitors of Gq-phospholipase C-protein kinase C-protein kinase A blocked E2's actions, suggesting dependence on the Gq-mER. Furthermore, STX, a selective ligand for the Gq-mER, mimicked E2's actions. Finally, to examine the in vivo effect of Gq-mER activation, E2 or STX injection increased c-fos expression in CRH neurons in the PVN, suggesting CRH neuronal activation. This corresponded to an increase in plasma corticosterone. We conclude that the Gq-mER plays a critical role in the rapid regulation of CRH neuronal activity and the HPA axis. Our findings provide a potential underlying mechanism for E2's involvement in the pathophysiology of HPA-associated mood disorders. PMID:27387482

  16. Neurons in the lateral part of the lumbar spinal cord show distinct novel axon trajectories and are excited by short propriospinal ascending inputs.

    PubMed

    Antal, Zs; Luz, L L; Safronov, B V; Antal, M; Szücs, Peter

    2016-05-01

    The role of spinal dorsal horn propriospinal connections in nociceptive processing is not yet established. Recently described, rostrocaudally oriented axon collaterals of lamina I projection and local-circuit neurons (PNs and LCNs) running in the dorsolateral funiculus (DLF) may serve as the anatomical substrate for intersegmental processing. Putative targets of these axons include lateral dendrites of superficial dorsal horn neurons, including PNs, and also neurons in the lateral spinal nucleus (LSN) that are thought to be important integrator units receiving, among others, visceral sensory information. Here we used an intact spinal cord preparation to study intersegmental connections within the lateral part of the superficial dorsal horn. We detected brief monosynaptic and prolonged polysynaptic excitation of lamina I and LSN neurons when stimulating individual dorsal horn neurons located caudally, even in neighboring spinal cord segments. These connections, however, were infrequent. We also revealed that some projection neurons outside the dorsal grey matter and in the LSN have distinct, previously undescribed course of their projection axon. Our findings indicate that axon collaterals of lamina I PNs and LCNs in the DLF rarely form functional connections with other lamina I and LSN neurons and that the majority of their targets are on other elements of the dorsal horn. The unique axon trajectories of neurons in the dorsolateral aspect of the spinal cord, including the LSN do not fit our present understanding of midline axon guidance and suggest that their function and development differ from the neurons inside lamina I. These findings emphasize the importance of understanding the connectivity matrix of the superficial dorsal horn in order to decipher spinal sensory information processing. PMID:25912439

  17. Partial weight support differentially affects corticomotor excitability across muscles of the upper limb

    PubMed Central

    Runnalls, Keith D.; Anson, Greg; Wolf, Steven L.; Byblow, Winston D.

    2014-01-01

    Abstract Partial weight support may hold promise as a therapeutic adjuvant during rehabilitation after stroke by providing a permissive environment for reducing the expression of abnormal muscle synergies that cause upper limb impairment. We explored the neurophysiological effects of upper limb weight support in 13 healthy young adults by measuring motor‐evoked potentials (MEPs) from transcranial magnetic stimulation (TMS) of primary motor cortex and electromyography from anterior deltoid (AD), biceps brachii (BB), extensor carpi radialis (ECR), and first dorsal interosseous (FDI). Five levels of weight support, varying from none to full, were provided to the arm using a commercial device (Saebo Mobile Arm Support). For each level of support, stimulus–response (SR) curves were derived from MEPs across a range of TMS intensities. Weight support affected background EMG activity in each of the four muscles examined (P <0.0001 for each muscle). Tonic background activity was primarily reduced in the AD. Weight support had a differential effect on the size of MEPs across muscles. After curve fitting, the SR plateau for ECR increased at the lowest support level (P =0.004). For FDI, the SR plateau increased at the highest support level (P =0.0003). These results indicate that weight support of the proximal upper limb modulates corticomotor excitability across the forearm and hand. The findings support a model of integrated control of the upper limb and may inform the use of weight support in clinical settings. PMID:25501435

  18. 17β-Estradiol increases persistent Na(+) current and excitability of AVPV/PeN Kiss1 neurons in female mice.

    PubMed

    Zhang, Chunguang; Bosch, Martha A; Qiu, Jian; Rønnekleiv, Oline K; Kelly, Martin J

    2015-04-01

    In vitro slice studies have revealed that there are significant differences in the spontaneous firing activity between anteroventral periventricular/periventricular preoptic nucleus (AVPV/PeN) and arcuate nucleus (ARC) kisspeptin (Kiss1) neurons in females. Although both populations express similar endogenous conductances, we have discovered that AVPV/PeN Kiss1 neurons express a subthreshold, persistent sodium current (INaP) that dramatically alters their firing activity. Based on whole-cell recording of Kiss1-Cre-green fluorescent protein (GFP) neurons, INaP was 4-fold greater in AVPV/PeN vs ARC Kiss1 neurons. An LH surge-producing dose of 17β-estradiol (E2) that increased Kiss1 mRNA expression in the AVPV/PeN, also augmented INaP in AVPV/PeN neurons by 2-fold. Because the activation threshold for INaP was close to the resting membrane potential (RMP) of AVPV/PeN Kiss1 neurons (-54 mV), it rendered them much more excitable and spontaneously active vs ARC Kiss1 neurons (RMP = -66 mV). Single-cell RT-PCR revealed that AVPV/PeN Kiss1 neurons expressed the requisite sodium channel α-subunit transcripts, NaV1.1, NaV1.2, and NaV1.6 and β subunits, β2 and β4. Importantly, NaV1.1α and -β2 transcripts in AVPV/PeN, but not ARC, were up-regulated 2- to 3-fold by a surge-producing dose of E2, similar to the transient calcium current channel subunit Cav3.1. The transient calcium current collaborates with INaP to generate burst firing, and selective blockade of INaP by riluzole significantly attenuated rebound burst firing and spontaneous activity. Therefore, INaP appears to play a prominent role in AVPV/PeN Kiss1 neurons to generate spontaneous, repetitive burst firing, which is required for the high-frequency-stimulated release of kisspeptin for exciting GnRH neurons and potentially generating the GnRH surge. PMID:25734516

  19. Aggressive experience affects the sensitivity of neurons towards pharmacological treatment in the hypothalamic attack area.

    PubMed

    Haller, J; Abrahám, I; Zelena, D; Juhász, G; Makara, G B; Kruk, M R

    1998-09-01

    Early investigators of brain stimulation-evoked complex behaviours (attack, escape, feeding, self-grooming, sexual behaviour) reported that experience may affect the behavioural outcome of brain stimulation. This intriguing example of functional neuronal plasticity was later totally neglected. The present experiment investigated the behavioural outcome of in vivo microdialysis perfusion of the glutamate agonist kainate and/or the GABAA antagonist bicuculline into the hypothalamic attack area (HAA) of (1) animals naive to dyadic encounters; (2) animals with a recent aggressive experience (the probe being implanted 6-24 h after the last of a series of dyadic encounters); and (3) animals with an earlier aggressive experience (probe being implanted 2 weeks after the last aggressive experience). On the experimental day, rats received two 5-min infusions during a dyadic encounter lasting 35 min with an unknown opponent. Flow rate was 1.5-2 microliters/min, drug concentrations were 1.8 x 10(-5) and 1.5 x 10(-5) M for kainate and bicuculline, respectively. Behaviour was analysed before, during and after perfusions. Only the combined kainate + bicuculline treatment had significant effects on behaviour at the doses studied. A significant increase in aggressive behaviour was elicited only in animals with a recent aggressive experience, while naive animals and with an earlier experience responded to the treatments by grooming. These results appear to support early observations indicating that one important aspect of brain stimulation effects is previous experience. PMID:9832932

  20. Background complexity affects response of a looming-sensitive neuron to object motion.

    PubMed

    Silva, Ana C; McMillan, Glyn A; Santos, Cristina P; Gray, John R

    2015-01-01

    An increasing number of studies show how stimulus complexity affects the responses of looming-sensitive neurons across multiple animal taxa. Locusts contain a well-described, descending motion-sensitive pathway that is preferentially looming sensitive. However, the lobula giant movement detector/descending contralateral movement detector (LGMD/DCMD) pathway responds to more than simple objects approaching at constant, predictable trajectories. In this study, we presented Locusta migratoria with a series of complex three-dimensional visual stimuli presented while simultaneously recording DCMD activity extracellularly. In addition to a frontal looming stimulus, we used a combination of compound trajectories (nonlooming transitioning to looming) presented at different velocities and onto a simple, scattered, or progressive flow field background. Regardless of stimulus background, DCMD responses to looming were characteristic and related to previously described effects of azimuthal approach angle and velocity of object expansion. However, increasing background complexity caused reduced firing rates, delayed peaks, shorter rise phases, and longer fall phases. DCMD responded to transitions to looming with a characteristic drop in a firing rate that was relatively invariant across most stimulus combinations and occurred regardless of stimulus background. Spike numbers were higher in the presence of the scattered background and reduced in the flow field background. We show that DCMD response time to a transition depends on unique expansion parameters of the moving stimulus irrespective of background complexity. Our results show how background complexity shapes DCMD responses to looming stimuli, which is explained within a behavioral context. PMID:25274344

  1. Osmotic Edema Rapidly Increases Neuronal Excitability Through Activation of NMDA Receptor-Dependent Slow Inward Currents in Juvenile and Adult Hippocampus.

    PubMed

    Lauderdale, Kelli; Murphy, Thomas; Tung, Tina; Davila, David; Binder, Devin K; Fiacco, Todd A

    2015-01-01

    Cellular edema (cell swelling) is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techniques, we report that one of the first effects of osmotic edema on excitability of CA1 pyramidal cells is the generation of slow inward currents (SICs), which initiate after approximately 1 min. Frequency of SICs increased as osmolarity decreased in a dose-dependent manner. Imaging of real-time volume changes in astrocytes revealed that neuronal SICs occurred while astrocytes were still in the process of swelling. SICs evoked by cell swelling were mainly nonsynaptic in origin and NMDA receptor-dependent. To better understand the relationship between SICs and changes in neuronal excitability, recordings were performed in increasingly physiological conditions. In the absence of any added pharmacological reagents or imposed voltage clamp, osmotic edema induced excitatory postsynaptic potentials and burst firing over the same timecourse as SICs. Like SICs, action potentials were blocked by NMDAR antagonists. Effects were more pronounced in adult (8-20 weeks old) compared with juvenile (P15-P21) mice. Together, our results indicate that cell swelling triggered by reduced osmolarity rapidly increases neuronal excitability through activation of NMDA receptors. Our findings have important implications for understanding nonsynaptic mechanisms of epilepsy in relation to cell swelling and reduction of the extracellular space. PMID:26489684

  2. Osmotic Edema Rapidly Increases Neuronal Excitability Through Activation of NMDA Receptor-Dependent Slow Inward Currents in Juvenile and Adult Hippocampus

    PubMed Central

    Lauderdale, Kelli; Murphy, Thomas; Tung, Tina; Davila, David; Binder, Devin K.

    2015-01-01

    Cellular edema (cell swelling) is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techniques, we report that one of the first effects of osmotic edema on excitability of CA1 pyramidal cells is the generation of slow inward currents (SICs), which initiate after approximately 1 min. Frequency of SICs increased as osmolarity decreased in a dose-dependent manner. Imaging of real-time volume changes in astrocytes revealed that neuronal SICs occurred while astrocytes were still in the process of swelling. SICs evoked by cell swelling were mainly nonsynaptic in origin and NMDA receptor-dependent. To better understand the relationship between SICs and changes in neuronal excitability, recordings were performed in increasingly physiological conditions. In the absence of any added pharmacological reagents or imposed voltage clamp, osmotic edema induced excitatory postsynaptic potentials and burst firing over the same timecourse as SICs. Like SICs, action potentials were blocked by NMDAR antagonists. Effects were more pronounced in adult (8–20 weeks old) compared with juvenile (P15–P21) mice. Together, our results indicate that cell swelling triggered by reduced osmolarity rapidly increases neuronal excitability through activation of NMDA receptors. Our findings have important implications for understanding nonsynaptic mechanisms of epilepsy in relation to cell swelling and reduction of the extracellular space. PMID:26489684

  3. Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1.

    PubMed

    Rannals, Matthew D; Hamersky, Gregory R; Page, Stephanie Cerceo; Campbell, Morganne N; Briley, Aaron; Gallo, Ryan A; Phan, BaDoi N; Hyde, Thomas M; Kleinman, Joel E; Shin, Joo Heon; Jaffe, Andrew E; Weinberger, Daniel R; Maher, Brady J

    2016-04-01

    Transcription Factor 4 (TCF4) is a clinically pleiotropic gene associated with schizophrenia and Pitt-Hopkins syndrome (PTHS). To gain insight about the neurobiology of TCF4, we created an in vivo model of PTHS by suppressing Tcf4 expression in rat prefrontal neurons immediately prior to neurogenesis. This cell-autonomous genetic insult attenuated neuronal spiking by increasing the afterhyperpolarization. At the molecular level, using a novel technique called iTRAP that combined in utero electroporation and translating ribosome affinity purification, we identified increased translation of two ion channel genes, Kcnq1 and Scn10a. These ion channel candidates were validated by pharmacological rescue and molecular phenocopy. Remarkably, similar excitability deficits were observed in prefrontal neurons from a Tcf4(+/tr) mouse model of PTHS. Thus, we identify TCF4 as a regulator of neuronal intrinsic excitability in part by repression of Kcnq1 and Scn10a and suggest that this molecular function may underlie pathophysiology associated with neuropsychiatric disorders. PMID:26971948

  4. Change in excitability of a putative decision-making neuron in Aplysia serves as a mechanism in the decision not feed following food satiation

    PubMed Central

    Dickinson, Kathy J.; Wainwright, Marcy L.; Mozzachiodi, Riccardo

    2014-01-01

    Although decision making is a ubiquitous function, the understanding of its underlying mechanisms remains limited, particularly at the single-cell level. In this study, we used the decision not to feed that follows satiation in the marine mollusk Aplysia to examine the role of putative decision-making neuron B51 in this process. B51 is a neuron in the feeding neural circuit that exhibits decision-making characteristics in vitro, which bias the circuit toward producing the motor programs responsible for biting behavior. Once satiated, Aplysia decided not to bite for a prolonged period of time (≥ 24 h) when presented with a food stimulus that normally elicits feeding in non-satiated animals. Twenty-four hours after satiation, suppressed feeding was accompanied by a significant decrease of B51 excitability compared to the control group of unfed animals. No differences were measured in B51 resting membrane properties or synaptic input to B51 between the satiated and control groups. When B51 properties were measured at a time point in which feeding had recovered from the suppressive effects of satiation (i.e., 96 h after satiation), no difference in B51 excitability was observed between satiated and control groups. These findings indicate that B51 excitability changes in a manner that is coherent with the modifications in biting resulting from food satiation, thus implicating this neuron as a site of plasticity underlying the decision not to bite following food satiation in Aplysia. PMID:25527117

  5. Selective silencing of NaV1.7 decreases excitability and conduction in vagal sensory neurons

    PubMed Central

    Muroi, Yukiko; Ru, Fei; Kollarik, Marian; Canning, Brendan J; Hughes, Stephen A; Walsh, Stacey; Sigg, Martin; Carr, Michael J; Undem, Bradley J

    2011-01-01

    Abstract There has been much information learned in recent years about voltage gated sodium channel (NaV) subtypes in somatosensory pain signalling, but much less is known about the role of specific sodium channel subtypes in the vagal sensory system. In this study, we developed a technique using adeno-associated viruses (AAVs) to directly introduce shRNA against NaV1.7 subtype gene into the vagal sensory ganglia of guinea pigsin vivo. NaV1.7 gene expression in nodose ganglia was effectively and selectively reduced without influencing the expression of other sodium channel subtype genes including NaV1.1, 1.2, 1.3 1.6, 1.8, or 1.9. Using a whole cell patch-clamp technique, this effect on NaV1.7 gene expression coincided with a reduction in tetrodotoxin-sensitive sodium current, a requirement for much larger depolarizing stimulus to initiate action potentials, and reduction in repetitive action potential discharge. Extracellular recordings in the isolated vagus nerve revealed that the conduction of action potentials in sensory A- and C-fibres in many neurons was effectively abolished after NaV1.7 shRNA introduction. Moreover, bilateral NaV1.7 shRNA injected animals survived for several months and the vagal reflex behaviour, exemplified by citric acid-induced coughing, was significantly suppressed. These data indicate that selectively silencing NaV1.7 ion channel expression leads to a substantial decrease in neural excitability and conduction block in vagal afferent nerves. PMID:22005676

  6. pigk Mutation underlies macho behavior and affects Rohon-Beard cell excitability

    PubMed Central

    Carmean, V.; Yonkers, M. A.; Tellez, M. B.; Willer, J. R.; Willer, G. B.; Gregg, R. G.; Geisler, R.; Neuhauss, S. C.

    2015-01-01

    The study of touch-evoked behavior allows investigation of both the cells and circuits that generate a response to tactile stimulation. We investigate a touch-insensitive zebrafish mutant, macho (maco), previously shown to have reduced sodium current amplitude and lack of action potential firing in sensory neurons. In the genomes of mutant but not wild-type embryos, we identify a mutation in the pigk gene. The encoded protein, PigK, functions in attachment of glycophosphatidylinositol anchors to precursor proteins. In wild-type embryos, pigk mRNA is present at times when mutant embryos display behavioral phenotypes. Consistent with the predicted loss of function induced by the mutation, knock-down of PigK phenocopies maco touch insensitivity and leads to reduced sodium current (INa) amplitudes in sensory neurons. We further test whether the genetic defect in pigk underlies the maco phenotype by overexpressing wild-type pigk in mutant embryos. We find that ubiquitous expression of wild-type pigk rescues the touch response in maco mutants. In addition, for maco mutants, expression of wild-type pigk restricted to sensory neurons rescues sodium current amplitudes and action potential firing in sensory neurons. However, expression of wild-type pigk limited to sensory cells of mutant embryos does not allow rescue of the behavioral touch response. Our results demonstrate an essential role for pigk in generation of the touch response beyond that required for maintenance of proper INa density and action potential firing in sensory neurons. PMID:26133798

  7. Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin

    PubMed Central

    Mansuroglu, Zeyni; Benhelli-Mokrani, Houda; Marcato, Vasco; Sultan, Audrey; Violet, Marie; Chauderlier, Alban; Delattre, Lucie; Loyens, Anne; Talahari, Smail; Bégard, Séverine; Nesslany, Fabrice; Colin, Morvane; Souès, Sylvie; Lefebvre, Bruno; Buée, Luc; Galas, Marie-Christine; Bonnefoy, Eliette

    2016-01-01

    Pericentromeric heterochromatin (PCH) gives rise to highly dense chromatin sub-structures rich in the epigenetic mark corresponding to the trimethylated form of lysine 9 of histone H3 (H3K9me3) and in heterochromatin protein 1α (HP1α), which regulate genome expression and stability. We demonstrate that Tau, a protein involved in a number of neurodegenerative diseases including Alzheimer’s disease (AD), binds to and localizes within or next to neuronal PCH in primary neuronal cultures from wild-type mice. Concomitantly, we show that the clustered distribution of H3K9me3 and HP1α, two hallmarks of PCH, is disrupted in neurons from Tau-deficient mice (KOTau). Such altered distribution of H3K9me3 that could be rescued by overexpressing nuclear Tau protein was also observed in neurons from AD brains. Moreover, the expression of PCH non-coding RNAs, involved in PCH organization, was disrupted in KOTau neurons that displayed an abnormal accumulation of stress-induced PCH DNA breaks. Altogether, our results demonstrate a new physiological function of Tau in directly regulating neuronal PCH integrity that appears disrupted in AD neurons. PMID:27605042

  8. Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin.

    PubMed

    Mansuroglu, Zeyni; Benhelli-Mokrani, Houda; Marcato, Vasco; Sultan, Audrey; Violet, Marie; Chauderlier, Alban; Delattre, Lucie; Loyens, Anne; Talahari, Smail; Bégard, Séverine; Nesslany, Fabrice; Colin, Morvane; Souès, Sylvie; Lefebvre, Bruno; Buée, Luc; Galas, Marie-Christine; Bonnefoy, Eliette

    2016-01-01

    Pericentromeric heterochromatin (PCH) gives rise to highly dense chromatin sub-structures rich in the epigenetic mark corresponding to the trimethylated form of lysine 9 of histone H3 (H3K9me3) and in heterochromatin protein 1α (HP1α), which regulate genome expression and stability. We demonstrate that Tau, a protein involved in a number of neurodegenerative diseases including Alzheimer's disease (AD), binds to and localizes within or next to neuronal PCH in primary neuronal cultures from wild-type mice. Concomitantly, we show that the clustered distribution of H3K9me3 and HP1α, two hallmarks of PCH, is disrupted in neurons from Tau-deficient mice (KOTau). Such altered distribution of H3K9me3 that could be rescued by overexpressing nuclear Tau protein was also observed in neurons from AD brains. Moreover, the expression of PCH non-coding RNAs, involved in PCH organization, was disrupted in KOTau neurons that displayed an abnormal accumulation of stress-induced PCH DNA breaks. Altogether, our results demonstrate a new physiological function of Tau in directly regulating neuronal PCH integrity that appears disrupted in AD neurons. PMID:27605042

  9. Enhanced excitability and suppression of A-type K+ currents in joint sensory neurons in a murine model of antigen-induced arthritis

    PubMed Central

    Qu, Lintao; Caterina, Michael J.

    2016-01-01

    Pain is a dominant symptom of rheumatoid arthritis (RA) and its adequate treatment represents a major unmet need. However, the cellular mechanisms that drive arthritis pain are largely unexplored. Here, we examined the changes in the activity of joint sensory neurons and the associated ionic mechanisms using an animal model of antigen-induced arthritis (AIA). Methylated-bovine serum albumin (mBSA), but not vehicle challenge, in the ankle of previously immunized mice produced time-dependent symptoms of arthritis, including joint inflammation, primary mechanical hyperalgesia in the ipsilateral ankle, and secondary mechanical and heat hyperalgesia in the ipsilateral hindpaw. In vivo electrophysiological recordings revealed that Dil-labeled joint sensory neurons in AIA mice exhibited a greater incidence of spontaneous activity, mechanically evoked after-discharges, and/or increased responses to mechanical stimulation of their receptive fields, compared to control animals. Whole-cell recordings in vitro showed that AIA enhanced the excitability of joint sensory neurons. These signs of neuronal hyperexcitability were associated with a significant reduction in the density of A-type K+ currents. Thus, our data suggest that neuronal hyperexcitability, brought about in part by reduced A-type K+ currents, may contribute to pain-related behaviors that accompany antigen-induced arthritis and/or other antigen-mediated diseases. PMID:27363579

  10. Enhanced excitability and suppression of A-type K(+) currents in joint sensory neurons in a murine model of antigen-induced arthritis.

    PubMed

    Qu, Lintao; Caterina, Michael J

    2016-01-01

    Pain is a dominant symptom of rheumatoid arthritis (RA) and its adequate treatment represents a major unmet need. However, the cellular mechanisms that drive arthritis pain are largely unexplored. Here, we examined the changes in the activity of joint sensory neurons and the associated ionic mechanisms using an animal model of antigen-induced arthritis (AIA). Methylated-bovine serum albumin (mBSA), but not vehicle challenge, in the ankle of previously immunized mice produced time-dependent symptoms of arthritis, including joint inflammation, primary mechanical hyperalgesia in the ipsilateral ankle, and secondary mechanical and heat hyperalgesia in the ipsilateral hindpaw. In vivo electrophysiological recordings revealed that Dil-labeled joint sensory neurons in AIA mice exhibited a greater incidence of spontaneous activity, mechanically evoked after-discharges, and/or increased responses to mechanical stimulation of their receptive fields, compared to control animals. Whole-cell recordings in vitro showed that AIA enhanced the excitability of joint sensory neurons. These signs of neuronal hyperexcitability were associated with a significant reduction in the density of A-type K(+) currents. Thus, our data suggest that neuronal hyperexcitability, brought about in part by reduced A-type K(+) currents, may contribute to pain-related behaviors that accompany antigen-induced arthritis and/or other antigen-mediated diseases. PMID:27363579

  11. Prenatal Hypoxia in Different Periods of Embryogenesis Differentially Affects Cell Migration, Neuronal Plasticity, and Rat Behavior in Postnatal Ontogenesis.

    PubMed

    Vasilev, Dmitrii S; Dubrovskaya, Nadezhda M; Tumanova, Natalia L; Zhuravin, Igor A

    2016-01-01

    Long-term effects of prenatal hypoxia on embryonic days E14 or E18 on the number, type and localization of cortical neurons, density of labile synaptopodin-positive dendritic spines, and parietal cortex-dependent behavioral tasks were examined in the postnatal ontogenesis of rats. An injection of 5'ethynyl-2'deoxyuridine to pregnant rats was used to label neurons generated on E14 or E18 in the fetuses. In control rat pups a majority of cells labeled on E14 were localized in the lower cortical layers V-VI while the cells labeled on E18 were mainly found in the superficial cortical layers II-III. It was shown that hypoxia both on E14 and E18 results in disruption of neuroblast generation and migration but affects different cell populations. In rat pups subjected to hypoxia on E14, the total number of labeled cells in the parietal cortex was decreased while the number of labeled neurons scattered within the superficial cortical layers was increased. In rat pups subjected to hypoxia on E18, the total number of labeled cells in the parietal cortex was also decreased but the number of scattered labeled neurons was higher in the lower cortical layers. It can be suggested that prenatal hypoxia both on E14 and E18 causes a disruption in neuroblast migration but with a different outcome. Only in rats subjected to hypoxia on E14 did we observe a reduction in the total number of pyramidal cortical neurons and the density of labile synaptopodin-positive dendritic spines in the molecular cortical layer during the first month after birth which affected development of the cortical functions. As a result, rats subjected to hypoxia on E14, but not on E18, had impaired development of the whisker-placing reaction and reduced ability to learn reaching by a forepaw. The data obtained suggest that hypoxia on E14 in the period of generation of the cells, which later differentiate into the pyramidal cortical neurons of the V-VI layers and form cortical minicolumns, affects formation of

  12. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?

    PubMed Central

    Deng, Wei; Aimone, James B.; Gage, Fred H.

    2010-01-01

    The integration of adult-born neurons into the circuitry of the adult hippocampus suggests an important role for adult hippocampal neurogenesis in learning and memory, but its specific function in these processes has remained elusive. In this article, we summarize recent progress in this area, including advances based on behavioural studies and insights provided by computational modelling. Increasingly, evidence suggests that newborn neurons might be involved in hippocampal functions that are particularly dependent on the dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different maturation stages may make distinct contributions to learning and memory. In particular, computational studies suggest that, before newborn neurons are fully mature, they might function as a pattern integrator by introducing a degree of similarity to the encoding of events that occur closely in time. PMID:20354534

  13. The activity of isolated snail neurons controlling locomotion is affected by glucose

    PubMed Central

    Dyakonova, Varvara; Hernádi, László; Ito, Etsuro; Dyakonova, Taisia; Zakharov, Igor; Sakharov, Dmitri

    2015-01-01

    The involvement of serotonin in mediating hunger-related changes in behavioral state has been described in many invertebrates. However, the mechanisms by which hunger signals to serotonergic cells remain unknown. We tested the hypothesis that serotonergic neurons can directly sense the concentration of glucose, a metabolic indicator of nutritional state. In the snail Lymnaea stagnalis, we demonstrate that completely isolated pedal serotonergic neurons that control locomotion changed their biophysical characteristics in response to glucose application by lowering membrane potential and decreasing the firing rate. Additionally, the excitatory response of the isolated serotonergic neurons to the neuroactive microenvironment of the pedal ganglia was significantly lowered by glucose application. Because hunger has been reported to increase the activity of select neurons and their responses to the pedal ganglia microenvironment, these responses to glucose are in accordance with the hypothesis that direct glucose signaling is involved in the mediation of the hunger-related behavioral state. PMID:27493515

  14. Chloride Accumulators NKCC1 and AE2 in Mouse GnRH Neurons: Implications for GABAA Mediated Excitation.

    PubMed

    Taylor-Burds, Carol; Cheng, Paul; Wray, Susan

    2015-01-01

    A developmental "switch" in chloride transporters occurs in most neurons resulting in GABAA mediated hyperpolarization in the adult. However, several neuronal cell subtypes maintain primarily depolarizing responses to GABAA receptor activation. Among this group are gonadotropin-releasing hormone-1 (GnRH) neurons, which control puberty and reproduction. NKCC1 is the primary chloride accumulator in neurons, expressed at high levels early in development and contributes to depolarization after GABAA receptor activation. In contrast, KCC2 is the primary chloride extruder in neurons, expressed at high levels in the adult and contributes to hyperpolarization after GABAA receptor activation. Anion exchangers (AEs) are also potential modulators of responses to GABAA activation since they accumulate chloride and extrude bicarbonate. To evaluate the mechanism(s) underlying GABAA mediated depolarization, GnRH neurons were analyzed for 1) expression of chloride transporters and AEs in embryonic, pre-pubertal, and adult mice 2) responses to GABAA receptor activation in NKCC1-/- mice and 3) function of AEs in these responses. At all ages, GnRH neurons were immunopositive for NKCC1 and AE2 but not KCC2 or AE3. Using explants, calcium imaging and gramicidin perforated patch clamp techniques we found that GnRH neurons from NKCC1-/- mice retained relatively normal responses to the GABAA agonist muscimol. However, acute pharmacological inhibition of NKCC1 with bumetanide eliminated the depolarization/calcium response to muscimol in 40% of GnRH neurons from WT mice. In the remaining GnRH neurons, HCO3- mediated mechanisms accounted for the remaining calcium responses to muscimol. Collectively these data reveal mechanisms responsible for maintaining depolarizing GABAA mediated transmission in GnRH neurons. PMID:26110920

  15. Chloride Accumulators NKCC1 and AE2 in Mouse GnRH Neurons: Implications for GABAA Mediated Excitation

    PubMed Central

    Taylor-Burds, Carol; Cheng, Paul; Wray, Susan

    2015-01-01

    A developmental “switch” in chloride transporters occurs in most neurons resulting in GABAA mediated hyperpolarization in the adult. However, several neuronal cell subtypes maintain primarily depolarizing responses to GABAA receptor activation. Among this group are gonadotropin-releasing hormone-1 (GnRH) neurons, which control puberty and reproduction. NKCC1 is the primary chloride accumulator in neurons, expressed at high levels early in development and contributes to depolarization after GABAA receptor activation. In contrast, KCC2 is the primary chloride extruder in neurons, expressed at high levels in the adult and contributes to hyperpolarization after GABAA receptor activation. Anion exchangers (AEs) are also potential modulators of responses to GABAA activation since they accumulate chloride and extrude bicarbonate. To evaluate the mechanism(s) underlying GABAA mediated depolarization, GnRH neurons were analyzed for 1) expression of chloride transporters and AEs in embryonic, pre-pubertal, and adult mice 2) responses to GABAA receptor activation in NKCC1-/- mice and 3) function of AEs in these responses. At all ages, GnRH neurons were immunopositive for NKCC1 and AE2 but not KCC2 or AE3. Using explants, calcium imaging and gramicidin perforated patch clamp techniques we found that GnRH neurons from NKCC1-/- mice retained relatively normal responses to the GABAA agonist muscimol. However, acute pharmacological inhibition of NKCC1 with bumetanide eliminated the depolarization/calcium response to muscimol in 40% of GnRH neurons from WT mice. In the remaining GnRH neurons, HCO3- mediated mechanisms accounted for the remaining calcium responses to muscimol. Collectively these data reveal mechanisms responsible for maintaining depolarizing GABAA mediated transmission in GnRH neurons. PMID:26110920

  16. Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol.

    PubMed

    Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J; Woodward, John J

    2016-03-01

    Alcoholism is associated with changes in brain reward and control systems, including the prefrontal cortex. In prefrontal areas, the orbitofrontal cortex (OFC) has been suggested to have an important role in the development of alcohol-abuse disorders and studies from this laboratory demonstrate that OFC-mediated behaviors are impaired in alcohol-dependent animals. However, it is not known whether chronic alcohol (ethanol) exposure alters the fundamental properties of OFC neurons. In this study, mice were exposed to repeated cycles of chronic intermittent ethanol (CIE) exposure to induce dependence and whole-cell patch-clamp electrophysiology was used to examine the effects of CIE treatment on lateral OFC (lOFC) neuron excitability, synaptic transmission, and plasticity. Repeated cycles of CIE exposure and withdrawal enhanced current-evoked action potential (AP) spiking and this was accompanied by a reduction in the after-hyperpolarization and a decrease in the functional activity of SK channels. CIE mice also showed an increase in the AMPA/NMDA ratio, and this was associated with an increase in GluA1/GluA2 AMPA receptor expression and a decrease in GluN2B NMDA receptor subunits. Following CIE treatment, lOFC neurons displayed a persistent long-term potentiation of glutamatergic synaptic transmission following a spike-timing-dependent protocol. Lastly, CIE treatment diminished the inhibitory effect of acute ethanol on AP spiking of lOFC neurons and reduced expression of the GlyT1 transporter. Taken together, these results suggest that chronic exposure to ethanol leads to enhanced intrinsic excitability and glutamatergic synaptic signaling of lOFC neurons. These alterations may contribute to the impairment of OFC-dependent behaviors in alcohol-dependent individuals. PMID:26286839

  17. Excitability of the infraspinatus, but not the middle deltoid, is affected by shoulder elevation angle.

    PubMed

    Lin, Yin-Liang; Christie, Anita; Karduna, Andrew

    2015-06-01

    Although both the rotator cuff and deltoid muscle serve as shoulder abductors, they play different roles in shoulder movement. While the deltoid is a primary abductor, the rotator cuff is a stabilizer. They have different anatomic structures for force production and demonstrate different neuromuscular control at different shoulder angles, as measured by electromyographic activity. Corticospinal excitability may be associated with different neuromuscular control of the deltoid and rotator cuff at different angles. The purpose of this study was to investigate how shoulder joint position influences the corticospinal excitability of the deltoid and rotator cuff muscles. Transcranial magnetic stimulation was used to measure the corticospinal excitability of the middle deltoid and infraspinatus at 0° and 90° of arm elevation. Three parameters, a plateau value, exponential parameter, and threshold, were calculated from the input-output curve of the corticospinal pathway. The plateau value of the infraspinatus was significantly higher at 90° of arm elevation, while there is no difference in the excitability in the middle deltoid between elevation angles. The plateau value of the middle deltoid at 90° was 5 % lower than that at 0°, but the plateau value of infraspinatus at 90° was 55 % higher than that at 0°. This suggests that the modulation of excitability varies with shoulder angle and reveals different neurological mechanism for the roles of the deltoid and rotator cuff. PMID:25814379

  18. CREBBP re-arrangements affect protein function and lead to aberrant neuronal differentiation.

    PubMed

    Sharma, Neeti; Jadhav, Shweta P; Bapat, Sharmila A

    2010-01-01

    Biallelic inactivation of the CREB-binding protein (CREBBP) a transcriptional co-activator produces an embryonic lethal phenotype in mice. In humans, re-arrangements in CREBBP are associated with the Rubinstein-Taybi Syndrome (RSTS) that is characterised by craniofacial, skeletal and neuronal symptoms. Neuronal defects in RSTS can be attributed to genetic re-arrangements in CREBBP, which has been implicated in synaptic plasticity and long-term memory. The present study was designed to investigate the role of CREBBP re-arrangements during neuronal differentiation. Towards this, deletion constructs of pCREBBP, viz. pDeltaCB-HAT and pDeltaHAT-CT were generated and transfected into NT2 cells. Expression profiling of the components of Notch, Wnt, SHH and Retinoid signaling along with screening of the neuronal markers was carried out in the NT2 cells and their mutant derivatives. ChIP-PCRs along with co-immunoprecipitations were also performed in these cells to investigate defects due to inappropriate interaction of mutated CREEBP with the corresponding transcription factor and other transcription regulatory proteins both at steady state as well as during differentiation. Mutant NT2 cells lacking the CREB, BROMO and HAT domains (CB-HAT) were highly proliferative and showed limited differentiation; while mutant NT2 cells expressing CREBBP lacking the HAT and CTAD domains (HAT-CT) are proliferation deficient and differentiate rapidly albeit generating an insufficient number of neurons. Altered CREBBP structure resulted in changes in HAT activity, cell cycle profiles and expression of basal levels of components of Notch, SHH, Wnt and retinoid pathways known to be critical in the proliferation and differentiation of neuronal progenitors. At the chromatin level, aberrant signaling correlated with altered binding affinities of the (CREBBP-transcription factor) complexes to promoter regions of components of these pathways. Thus, differentiation defects are manifested early at

  19. On the properties of input-to-output transformations in neuronal networks.

    PubMed

    Olypher, Andrey; Vaillant, Jean

    2016-06-01

    Information processing in neuronal networks in certain important cases can be considered as maps of binary vectors, where ones (spikes) and zeros (no spikes) of input neurons are transformed into spikes and no spikes of output neurons. A simple but fundamental characteristic of such a map is how it transforms distances between input vectors into distances between output vectors. We advanced earlier known results by finding an exact solution to this problem for McCulloch-Pitts neurons. The obtained explicit formulas allow for detailed analysis of how the network connectivity and neuronal excitability affect the transformation of distances in neurons. As an application, we explored a simple model of information processing in the hippocampus, a brain area critically implicated in learning and memory. We found network connectivity and neuronal excitability parameter values that optimize discrimination between similar and distinct inputs. A decrease of neuronal excitability, which in biological neurons may be associated with decreased inhibition, impaired the optimality of discrimination. PMID:27106188

  20. Multinodular and vacuolating neuronal tumor affecting amygdala and hippocampus: A quasi-tumor?

    PubMed

    Yamaguchi, Maki; Komori, Takashi; Nakata, Yasuhiro; Yagishita, Akira; Morino, Michiharu; Isozaki, Eiji

    2016-01-01

    Multinodular and vacuolating neuronal tumors (MVNT) have been referred to as distinctive neuronal tumors whose characteristic features include multiple nodules localized in the subcortical white matter. MVNT are composed of vacuolating dysplastic neurons reactive to HuC/HuD. A significant overexpression of alpha-internexin (INA) limited to the stroma of nodules was reported in one tumor. Since genetic analyses have failed to demonstrate any consistent alterations, the nosological position as well as the nature of MVNT, namely, neoplastic or dysplastic, remains unclear. We herein present another example of MVNT involving the amygdala and anterior hippocampus in a 41-year-old man. In addition to the nodular lesions described earlier, we found INA-positive ribbon-like lesions that replaced neuropil and extended along the hippocampal gray matter. We also identified dysplastic neurons infiltrating into the CA4 hilus of the hippocampus. Intense INA expression was present in the stroma as well as the cytoplasmic membrane of dysplastic neurons and their processes. While the invasiveness suggested a neoplasm, a relatively restrictive, either nodular or ribbon-like growth pattern with INA-positive abnormal neuropil suggested a hamartoma. Such quasi-tumors should be accommodated in the World Health Organization classification of tumors of the central nervous system, as are dysembryoplastic neuroepithelial tumor and Lhermitte-Duclos disease. PMID:26644357

  1. Excitability and Burst Generation of AVPV Kisspeptin Neurons Are Regulated by the Estrous Cycle Via Multiple Conductances Modulated by Estradiol Action123

    PubMed Central

    Wang, Luhong

    2016-01-01

    Abstract The preovulatory secretory surge of gonadotropin-releasing hormone (GnRH) is crucial for fertility and is regulated by a switch of estradiol feedback action from negative to positive. GnRH neurons likely receive estradiol feedback signals via ERα-expressing afferents. Kisspeptin neurons in anteroventral periventricular nucleus (AVPV) are thought to be critical for estradiol-positive feedback induction of the GnRH surge. We examined the electrophysiological properties of GFP-identified AVPV kisspeptin neurons in brain slices from mice on the afternoon of diestrus (negative feedback) and proestrus (positive feedback, time of surge). Extracellular recordings revealed increased firing frequency and action potential bursts on proestrus versus diestrus. Whole-cell recordings were used to study the intrinsic mechanisms of bursting. Upon depolarization, AVPV kisspeptin neurons exhibited tonic firing or depolarization-induced bursts (DIB). Both tonic and DIB cells exhibited bursts induced by rebound from hyperpolarization. DIB occurred similarly on both cycle stages, but rebound bursts were observed more often on proestrus. DIB and rebound bursts were both sensitive to Ni2+, suggesting that T-type Ca2+ currents (ITs) are involved. IT current density was greater on proestrus versus diestrus. In addition to IT, persistent sodium current (INaP) facilitated rebound bursting. On diestrus, 4-aminopyridine-sensitive potassium currents contributed to reduced rebound bursts in both tonic and DIB cells. Manipulation of specific sex steroids suggests that estradiol induces the changes that enhance AVPV kisspeptin neuron excitability on proestrus. These observations indicate cycle-driven changes in circulating estradiol increased overall action potential generation and burst firing in AVPV kisspeptin neurons on proestrus versus diestrus by regulating multiple intrinsic currents. PMID:27280155

  2. Transient receptor potential canonical 3 (TRPC3) is required for IgG immune complex-induced excitation of the rat dorsal root ganglion neurons

    PubMed Central

    Qu, Lintao; Li, Yumei; Pan, Xinghua; Zhang, Pu; LaMotte, Robert H.; Ma, Chao

    2012-01-01

    Chronic pain may accompany immune-related disorders with an elevated level of serum IgG immune complex (IgG-IC) but the underlying mechanisms are obscure. We previously demonstrated that IgG-IC directly excited a subpopulation of dorsal root ganglion (DRG) neurons through the neuronal Fc-gamma receptor I (FcγRI). This might be a mechanism linking IgG-IC to pain and hyperalgesia. The purpose of this study was to investigate the signaling pathways and transduction channels activated downstream of IgG-IC and FcγRI. In whole-cell recordings, IgG-IC induced a non-selective cation current (IIC) in the rat DRG neurons, carried by Ca2+ and Na+. The IIC was potentiated or attenuated by respectively lowering or increasing the intracellular Ca2+ buffering capacity, suggesting that this current was regulated by intracellular calcium. Single-cell RT-PCR revealed that transient receptor potential canonical 3 (TRPC3) mRNA was always coexpressed with FcγRI mRNA in the same DRG neuron. Moreover, ruthenium red (a general TRP channel blocker), BTP2 (a general TRPC channel inhibitor) or pyrazole-3 (a selective TRPC3 blocker), each potently inhibited the IIC. Specific knockdown of TRPC3 using small interfering RNA attenuated the IgG-IC-induced Ca2+ response and the IIC. Additionally, the IIC was blocked by the tyrosine kinase Syk inhibitor OXSI-2, the phospholipase C (PLC) inhibitor neomycin, or either the IP3 receptor antagonist 2-aminoethyldiphenylborinate or heparin. These results indicated that the activation of neuronal FcγRI triggers TRPC channels through the Syk-PLC-IP3 pathway, and that TRPC3 is a key molecular target for the excitatory effect of IgG-IC on DRG neurons. PMID:22787041

  3. Acute Effects of Transforming Growth Factor-β1 on Neuronal Excitability and Involvement in the Pain of Rats with Chronic Pancreatitis

    PubMed Central

    Zhang, Xiaoyu; Zheng, Hang; Zhu, Hong-Yan; Hu, Shufen; Wang, Shusheng; Jiang, Xinghong; Xu, Guang-Yin

    2016-01-01

    Background/Aims This study was to investigate whether transforming growth factor-β1 (TGF-β1) plays a role in hyperalgesia in chronic pancreatitis (CP) and the underlying mechanisms. Methods CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Abdominal hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. Dil dye injected into the pancreas was used to label pancreas-specific dorsal root ganglion (DRG) neurons. Whole cell patch clamp recordings and calcium imaging were performed to examine the effect of TGF-β1 on acutely isolated pancreas-specific DRG neurons. Western blot analysis was carried out to measure the expression of TGF-β1 and its receptors. Results TNBS injection significantly upregulated expression of TGF-β1 in the pancreas and DRGs, and TGF-β1 receptors in DRGs (T9-T13) in CP rats. Intrathecal injection of TGF-β receptor I antagonist SB431542 attenuated abdominal hyperalgesia in CP rats. TGF-β1 application depolarized the membrane potential and caused firing activity of DRG neurons. TGF-β1 application also reduced rheobase, hyperpolarized action potential threshold, and increased numbers of action potentials evoked by current injection of pancreas-specific DRG neurons. TGF-β1 application also increased the concentration of intracellular calcium of DRG neurons, which was inhibited by SB431542. Furthermore, intrathecal injection of TGF-β1 produced abdominal hyperalgesia in healthy rats. Conclusions These results suggest that TGF-β1 enhances neuronal excitability and increases the concentration of intracellular calcium. TGF-β1 and its receptors are involved in abdominal hyperalgesia in CP. This and future study might identify a potentially novel target for the treatment of abdominal pain in CP. PMID:26645248

  4. [Changes in the intragastric contents during sleep affect the statistical characteristics of the neuronal activity in cerebral cortex].

    PubMed

    Pigarev, I N; Bibikov, N G; Busygina, I I

    2014-06-01

    Firing activity in somatosensory cortical area was analyzed in cats during slow wave sleep. Statistical characteristics of the background activity were calculated before and after changes of the intragastric contents (introduction of 50 ml of water into stomach). This procedure did not affect the depth of sleep. There were no changes of the mean firing frequency and the local variation coefficients. To evaluate the degree of chaos in neuronal firing before and after changes of the intragastric contents, the dependence of the Fano factor from the length of the intervals of analysis was calculated. This dependence before water infusion for 40 neurons expressed as a power function with index of power > 0.2 what indicated on fractal nature of the background activity. The changes of the gastric contents in 18 neurons lead to considerable changes of the indexes of power of this function. It is known that in wakefulness for cortical neurons these indexes are dependent on the specific sensory stimulation. Thus, our results can be considered as an indication that during slow wave sleep signals from stomach are included in the afferent flow to the cortical areas, which in wakefulness are involved in somatosensory functions. PMID:25665397

  5. Conditional Knockout of Tumor Overexpressed Gene in Mouse Neurons Affects RNA Granule Assembly, Granule Translation, LTP and Short Term Habituation

    PubMed Central

    Barbarese, Elisa; Ifrim, Marius F.; Hsieh, Lawrence; Guo, Caiying; Tatavarty, Vedakumar; Maggipinto, Michael J.; Korza, George; Tutolo, Jessica W.; Giampetruzzi, Anthony; Le, Hien; Ma, Xin-Ming; Levine, Eric; Bishop, Brian; Kim, Duck O.; Kuwada, Shigeyuki; Carson, John H.

    2013-01-01

    In neurons, specific RNAs are assembled into granules, which are translated in dendrites, however the functional consequences of granule assembly are not known. Tumor overexpressed gene (TOG) is a granule-associated protein containing multiple binding sites for heterogeneous nuclear ribonucleoprotein (hnRNP) A2, another granule component that recognizes cis-acting sequences called hnRNP A2 response elements (A2REs) present in several granule RNAs. Translation in granules is sporadic, which is believed to reflect monosomal translation, with occasional bursts, which are believed to reflect polysomal translation. In this study, TOG expression was conditionally knocked out (TOG cKO) in mouse hippocampal neurons using cre/lox technology. In TOG cKO cultured neurons granule assembly and bursty translation of activity-regulated cytoskeletal associated (ARC) mRNA, an A2RE RNA, are disrupted. In TOG cKO brain slices synaptic sensitivity and long term potentiation (LTP) are reduced. TOG cKO mice exhibit hyperactivity, perseveration and impaired short term habituation. These results suggest that in hippocampal neurons TOG is required for granule assembly, granule translation and synaptic plasticity, and affects behavior. PMID:23936366

  6. Dynorphin-Dependent Reduction of Excitability and Attenuation of Inhibitory Afferents of NPS Neurons in the Pericoerulear Region of Mice

    PubMed Central

    Jüngling, Kay; Blaesse, Peter; Goedecke, Lena; Pape, Hans-Christian

    2016-01-01

    The Neuropeptide S system, consisting of the 20-amino acid peptide neuropeptide S (NPS) and its G-protein coupled receptor (NPSR), modulates arousal, wakefulness, anxiety, and fear-extinction in mice. In addition, recent evidence indicates that the NPS system attenuates stress-dependent impairment of fear extinction, and that NPS-expressing neurons in close proximity to the locus coeruleus region (LC; pericoerulear, periLC) are activated by stress. Furthermore, periLC NPS neurons receive afferents from neurons of the centrolateral nucleus of the amygdala (CeL), of which a substantial population expresses the kappa opioid receptor (KOR) ligand precursor prodynorphin. This study aims to identify the effect of the dynorphinergic system on NPS neurons in the periLC via pre- and postsynaptic mechanisms. Using electrophysiological recordings in mouse brain slices, we provide evidence that NPS neurons in the periLC region are directly inhibited by dynorphin A (DynA) via activation of κ-opioid receptor 1 (KOR1) and a subsequent increase of potassium conductances. Thus, the dynorphinergic system is suited to inactivate NPS neurons in the periLC. In addition to this direct, somatic effect, DynA reduces the efficacy of GABAergic synapses on NPS neurons via KOR1 and KOR2. In conclusion, the present study provides evidence for the interaction of the NPS and the kappa opioid system in the periLC. Therefore, the endogenous opioid dynorphin is suited to inhibit NPS neurons with a subsequent decrease in NPS release in putative target regions leading to a variety of physiological consequences such as increased anxiety or vulnerability to stress exposure. PMID:27013974

  7. NPY-Induced Phase Shifts of PER2::LUC Rhythms are Mediated by Long-Term Suppression of Neuronal Excitability in a Phase-Specific Manner

    PubMed Central

    Besing, Rachel C.; Hablitz, Lauren M.; Paul, Jodi R.; Johnson, Russell L.; Prosser, Rebecca A.; Gamble, Karen L.

    2013-01-01

    Endogenous circadian rhythms are entrained to the 24-h light/dark cycle by both light and nonphotic stimuli. During the day, nonphotic stimuli, such as novel-wheel induced exercise, produce large phase advances. Neuropeptide Y (NPY) release from the thalamus onto suprachiasmatic nucleus (SCN) neurons at least partially mediates this nonphotic signal. We examined the hypothesis that NPY-induced phase advances are accompanied by suppression of PER2 and are mediated by long-term depression of neuronal excitability in a phase-specific manner. First, we found that NPY-induced phase advances in PER2::LUC SCN cultures are largest when NPY (2.35 µM) is given in the early part of the day (circadian time [CT] 0–6). In addition, PER2::LUC levels in NPY-treated (compared to vehicle-treated) samples were suppressed beginning 6–7 h after treatment. Similar NPY application to organotypic Per1::GFP SCN cultures resulted in long-term suppression of spike rate of GFP+ cells when slices were treated with NPY during the early or middle of the day (zeitgeber time [ZT] 2 or 6), but not during the late day (ZT 10). Furthermore, 1-h bath application of NPY to acute SCN brain slices decreased general neuronal activity measured through extracellular recordings. Finally, NPY-induced phase advances of PER2::LUC rhythms were blocked by latent depolarization with 34.5 mM [K+] 3 h after NPY application. These results suggest that NPY-induced phase advances may be mediated by long-term depression of neuronal excitability. This model is consistent with findings in other brain regions that NPY-induced persistent hyperpolarization underlies mechanisms of energy homeostasis, anxiety-related behavior, and thalamocortical synchronous firing. PMID:22324550

  8. Astrocytes are involved in long-term facilitation of neuronal excitation in the anterior cingulate cortex of mice with inflammatory pain.

    PubMed

    Ikeda, Hiroshi; Mochizuki, Keiichi; Murase, Kazuyuki

    2013-12-01

    Neuronal plasticity in the pain-processing pathway is thought to be a mechanism underlying pain hypersensitivity and negative emotions occurring during a pain state. Recent evidence suggests that the activation of astrocytes in the anterior cingulate cortex (ACC) contributes to the development of negative emotions during pain hypersensitivity after peripheral inflammation. However, it is unknown whether these activated astrocytes contribute to neuronal plasticity in the ACC. In this study, by using optical imaging with voltage- and Ca(2+)-sensitive dyes, we examined the long-term facilitation of neuronal excitation induced by high-frequency conditioning stimulation (HFS) in ACC slices of control mice and mice with peripheral inflammation induced by the injection of complete Freund adjuvant (CFA) to the hind paw. Immunoreactivity of glial fibrillary acidic protein in laminae II-III of the ACC in the CFA-injected mice was higher than in the control mice. Neuronal excitation in ACC slices from the CFA-injected mice was gradually increased by HFS, and the magnitude of this long-term facilitation was greater than in the control mice. The long-term facilitation in the CFA-injected mice was inhibited by the astroglial toxin, the N-methyl-d-aspartate (NMDA) receptor antagonist and NMDA receptor glycine binding site antagonist. The increase of intracellular Ca(2+) concentration in astrocytes during HFS was higher in the CFA-injected mice than in the control mice and was inhibited by l-α-aminoadipate (l-α-AA). These results suggest that the activation of astrocytes in the ACC plays a crucial role in the development of negative emotions and LTP during pain hypersensitivity after peripheral inflammation. PMID:23988365

  9. Dietary Restriction Affects Neuronal Response Property and GABA Synthesis in the Primary Visual Cortex.

    PubMed

    Yang, Jinfang; Wang, Qian; He, Fenfen; Ding, Yanxia; Sun, Qingyan; Hua, Tianmiao; Xi, Minmin

    2016-01-01

    Previous studies have reported inconsistent effects of dietary restriction (DR) on cortical inhibition. To clarify this issue, we examined the response properties of neurons in the primary visual cortex (V1) of DR and control groups of cats using in vivo extracellular single-unit recording techniques, and assessed the synthesis of inhibitory neurotransmitter GABA in the V1 of cats from both groups using immunohistochemical and Western blot techniques. Our results showed that the response of V1 neurons to visual stimuli was significantly modified by DR, as indicated by an enhanced selectivity for stimulus orientations and motion directions, decreased visually-evoked response, lowered spontaneous activity and increased signal-to-noise ratio in DR cats relative to control cats. Further, it was shown that, accompanied with these changes of neuronal responsiveness, GABA immunoreactivity and the expression of a key GABA-synthesizing enzyme GAD67 in the V1 were significantly increased by DR. These results demonstrate that DR may retard brain aging by increasing the intracortical inhibition effect and improve the function of visual cortical neurons in visual information processing. This DR-induced elevation of cortical inhibition may favor the brain in modulating energy expenditure based on food availability. PMID:26863207

  10. Affect Regulation, Mirror Neurons, and the Third Hand: Formulating Mindful Empathic Art Interventions

    ERIC Educational Resources Information Center

    Franklin, Michael

    2010-01-01

    Visual empathy through empathic art interventions are discussed in this article with respect to attachment theory; recent research on the mirror neuron system; art, empathy, and mindfulness; and an artistic strategy for crafting third-hand interventions (Kramer, 1986). A case vignette demonstrates the art therapist's applied use of visual art…

  11. Dietary Restriction Affects Neuronal Response Property and GABA Synthesis in the Primary Visual Cortex

    PubMed Central

    Sun, Qingyan; Hua, Tianmiao; Xi, Minmin

    2016-01-01

    Previous studies have reported inconsistent effects of dietary restriction (DR) on cortical inhibition. To clarify this issue, we examined the response properties of neurons in the primary visual cortex (V1) of DR and control groups of cats using in vivo extracellular single-unit recording techniques, and assessed the synthesis of inhibitory neurotransmitter GABA in the V1 of cats from both groups using immunohistochemical and Western blot techniques. Our results showed that the response of V1 neurons to visual stimuli was significantly modified by DR, as indicated by an enhanced selectivity for stimulus orientations and motion directions, decreased visually-evoked response, lowered spontaneous activity and increased signal-to-noise ratio in DR cats relative to control cats. Further, it was shown that, accompanied with these changes of neuronal responsiveness, GABA immunoreactivity and the expression of a key GABA-synthesizing enzyme GAD67 in the V1 were significantly increased by DR. These results demonstrate that DR may retard brain aging by increasing the intracortical inhibition effect and improve the function of visual cortical neurons in visual information processing. This DR-induced elevation of cortical inhibition may favor the brain in modulating energy expenditure based on food availability. PMID:26863207

  12. Class IIa histone deacetylases affect neuronal remodeling and functional outcome after stroke.

    PubMed

    Kassis, Haifa; Shehadah, Amjad; Li, Chao; Zhang, Yi; Cui, Yisheng; Roberts, Cynthia; Sadry, Neema; Liu, Xianshuang; Chopp, Michael; Zhang, Zheng Gang

    2016-06-01

    We have previously demonstrated that stroke induces nuclear shuttling of class IIa histone deacetylase 4 (HDAC4). Stroke-induced nuclear shuttling of HDAC4 is positively and significantly correlated with improved indices of neuronal remodeling in the peri-infarct cortex. In this study, using a rat model for middle cerebral artery occlusion (MCAO), we tested the effects of selective inhibition of class IIa HDACs on functional recovery and neuronal remodeling when administered 24hr after stroke. Adult male Wistar rats (n = 15-17/group) were subjected to 2 h MCAO and orally gavaged with MC1568 (a selective class IIa HDAC inhibitor), SAHA (a non-selective HDAC inhibitor), or vehicle-control for 7 days starting 24 h after MCAO. A battery of behavioral tests was performed. Lesion volume measurement and immunohistochemistry were performed 28 days after MCAO. We found that stroke increased total HDAC activity in the ipsilateral hemisphere compared to the contralateral hemisphere. Stroke-increased HDAC activity was significantly decreased by the administration of SAHA as well as by MC1568. However, SAHA significantly improved functional outcome compared to vehicle control, whereas selective class IIa inhibition with MC1568 increased mortality and lesion volume and did not improve functional outcome. In addition, MC1568 decreased microtubule associated protein 2 (MAP2, dendrites), phosphorylated neurofilament heavy chain (pNFH, axons) and myelin basic protein (MBP, myelination) immunoreactivity in the peri-infarct cortex. Quantitative RT-PCR of cortical neurons isolated by laser capture microdissection revealed that MC1568, but not SAHA, downregulated CREB and c-fos expression. Additionally, MC1568 decreased the expression of phosphorylated CREB (active) in neurons. Taken together, these findings demonstrate that selective inhibition of class IIa HDACs impairs neuronal remodeling and neurological outcome. Inactivation of CREB and c-fos by MC1568 likely contributes to

  13. Two-photon-excitation scanning microscopy of living neurons with a saturable Bragg reflector mode-locked diode-pumped Cr:LiSrAlFl laser.

    PubMed

    Svoboda, K; Denk, W; Knox, W H; Tsuda, S

    1996-09-01

    A Cr:LiSrAlFl laser, pumped with a diffraction-limited laser diode and mode locked with a saturable Bragg reflector, produces 90-fs pulses at 860 nm with a cw power as high as 88 mW in two beams. It is shown that this recently developed, compact, solid-state laser can be used as an excitation source for two-photon laser scanning microscopy. Morphological and functional images of neocortical and cerebellar neurons were obtained with submicrometer three-dimensional resolution. Single dendritic spines could easily be resolved deep in scattering tissue. PMID:19876369

  14. Heat Shock Protein 70.1 (Hsp70.1) Affects Neuronal Cell Fate by Regulating Lysosomal Acid Sphingomyelinase*

    PubMed Central

    Zhu, Hong; Yoshimoto, Tanihiro; Yamashima, Tetsumori

    2014-01-01

    The inducible expression of heat shock protein 70.1 (Hsp70.1) plays cytoprotective roles in its molecular chaperone function. Binding of Hsp70 to an endolysosomal phospholipid, bis(monoacylglycero)phosphate (BMP), has been recently shown to stabilize lysosomal membranes by enhancing acid sphingomyelinase (ASM) activity in cancer cells. Using the monkey experimental paradigm, we have reported that calpain-mediated cleavage of oxidized Hsp70.1 causes neurodegeneration in the hippocampal cornu ammonis 1 (CA1), whereas expression of Hsp70.1 in the motor cortex without calpain activation contributes to neuroprotection. However, the molecular mechanisms of the lysosomal destabilization/stabilization determining neuronal cell fate have not been elucidated. To elucidate whether regulation of lysosomal ASM could affect the neuronal fate, we analyzed Hsp70.1-BMP binding and ASM activity by comparing the motor cortex and the CA1. We show that Hsp70.1 being localized at the lysosomal membrane, lysosomal lipid BMP levels, and the lipid binding domain of Hsp70.1 are crucial for Hsp70.1-BMP binding. In the postischemic motor cortex, Hsp70.1 being localized at the lysosomal membrane could bind to BMP without calpain activation and decreased BMP levels, resulting in increasing ASM activity and lysosomal stability. However, in the postischemic CA1, calpain activation and a concomitant decrease in the lysosomal membrane localization of Hsp70.1 and BMP levels may diminish Hsp70.1-BMP binding, resulting in decreased ASM activity and lysosomal rupture with leakage of cathepsin B into the cytosol. A TUNEL assay revealed the differential neuronal vulnerability between the CA1 and the motor cortex. These results suggest that regulation of ASM activation in vivo by Hsp70.1-BMP affects lysosomal stability and neuronal survival or death after ischemia/reperfusion. PMID:25074941

  15. Decreased excitability and voltage-gated sodium currents in aortic baroreceptor neurons contribute to the impairment of arterial baroreflex in cirrhotic rats.

    PubMed

    Lee, Choong-Ku; Park, Kwang-Hwa; Baik, Soon-Koo; Jeong, Seong-Woo

    2016-06-01

    Cardiovascular autonomic dysfunction, which is manifested by an impairment of the arterial baroreflex, is prevalent irrespective of etiology and contributes to the increased morbidity and mortality in cirrhotic patients. However, the cellular mechanisms that underlie the cirrhosis-impaired arterial baroreflex remain unknown. In the present study, we examined whether the cirrhosis-impaired arterial baroreflex is attributable to the dysfunction of aortic baroreceptor (AB) neurons. Biliary and nonbiliary cirrhotic rats were generated via common bile duct ligation (CBDL) and intraperitoneal injections of thioacetamide (TAA), respectively. Histological and molecular biological examinations confirmed the development of fibrosis in the livers of both cirrhotic rat models. The heart rate changes during phenylephrine-induced baroreceptor activation indicated that baroreflex sensitivity was blunted in the CBDL and TAA rats. Under the current-clamp mode of the patch-clamp technique, cell excitability was recorded in DiI-labeled AB neurons. The number of action potential discharges in the A- and C-type AB neurons was significantly decreased because of the increased rheobase and threshold potential in the CBDL and TAA rats compared with sham-operated rats. Real-time PCR and Western blotting indicated that the NaV1.7, NaV1.8, and NaV1.9 transcripts and proteins were significantly downregulated in the nodose ganglion neurons from the CBDL and TAA rats compared with the sham-operated rats. Consistent with these molecular data, the tetrodotoxin-sensitive NaV currents and the tetrodotoxin-resistant NaV currents were significantly decreased in A- and C-type AB neurons, respectively, from the CBDL and TAA rats compared with the sham-operated rats. Taken together, these findings implicate a key cellular mechanism in the cirrhosis-impaired arterial baroreflex. PMID:26984890

  16. Distribution of transition times in a stochastic model of excitable cell: Insights into the cell-intrinsic mechanisms of randomness in neuronal interspike intervals

    NASA Astrophysics Data System (ADS)

    Requena-Carrión, Jesús; Requena-Carrión, Víctor J.

    2016-04-01

    In this paper, we develop an analytical approach to studying random patterns of activity in excitable cells. Our analytical approach uses a two-state stochastic model of excitable system based on the electrophysiological properties of refractoriness and restitution, which characterize cell recovery after excitation. By applying the notion of probability density flux, we derive the distributions of transition times between states and the distribution of interspike interval (ISI) durations for a constant applied stimulus. The derived ISI distribution is unimodal and, provided that the time spent in the excited state is constant, can be approximated by a Rayleigh peak followed by an exponential tail. We then explore the role of the model parameters in determining the shape of the derived distributions and the ISI coefficient of variation. Finally, we use our analytical results to study simulation results from the stochastic Morris-Lecar neuron and from a three-state extension of the proposed stochastic model, which is capable of reproducing multimodal ISI histograms.

  17. Early developmental stress negatively affects neuronal recruitment to avian song system nucleus HVC.

    PubMed

    Honarmand, Mariam; Thompson, Christopher K; Schatton, Adriana; Kipper, Silke; Scharff, Constance

    2016-01-01

    Adverse environmental conditions can impact the life history trajectory of animals. Adaptive responses enable individuals to cope with unfavorable conditions, but altered metabolism and resource allocation can bear long-term costs. In songbirds, early developmental stress can cause lifelong changes in learned song, a culturally transmitted trait, and nestlings experiencing developmental stress develop smaller song control nucleus HVCs. We investigated whether nutrition-related developmental stress impacts neurogenesis in HVC, which may explain how poor nutrition leads to smaller HVC volume. We provided different quality diets (LOW and HIGH) by varying the husks-to-seeds ratio to zebra finch families for the first 35 days after the young hatched (PHD). At PHD14-18 and again at nutritional independence (PHD35), juveniles were injected with different cell division markers. To monitor growth, we took body measures at PHD10, 17, and 35. At PHD35 the number of newly recruited neurons in HVC and the rate of proliferation in the adjacent ventricular zone (VZ) were counted. Males raised on the LOW diet for their first weeks of life had significantly fewer new neurons in HVC than males raised on the HIGH diet. At the time when these new HVC neurons were born and labeled in the VZ (PHD17) the birds exposed to the LOW diet had significantly lower body mass. At PHD35 body mass or neuronal proliferation no longer differed. Our study shows that even transitory developmental stress can have negative consequences on the cellular processes underlying the development of neural circuits. PMID:25980802

  18. Drosophila Ten-m and Filamin Affect Motor Neuron Growth Cone Guidance

    PubMed Central

    Zheng, Lihua; Michelson, Yehudit; Freger, Vita; Avraham, Ziva; Venken, Koen J. T.; Bellen, Hugo J.; Justice, Monica J.; Wides, Ron

    2011-01-01

    The Drosophila Ten-m (also called Tenascin-major, or odd Oz (odz)) gene has been associated with a pair-rule phenotype. We identified and characterized new alleles of Drosophila Ten-m to establish that this gene is not responsible for segmentation defects but rather causes defects in motor neuron axon routing. In Ten-m mutants the inter-segmental nerve (ISN) often crosses segment boundaries and fasciculates with the ISN in the adjacent segment. Ten-m is expressed in the central nervous system and epidermal stripes during the stages when the growth cones of the neurons that form the ISN navigate to their targets. Over-expression of Ten-m in epidermal cells also leads to ISN misrouting. We also found that Filamin, an actin binding protein, physically interacts with the Ten-m protein. Mutations in cheerio, which encodes Filamin, cause defects in motor neuron axon routing like those of Ten-m. During embryonic development, the expression of Filamin and Ten-m partially overlap in ectodermal cells. These results suggest that Ten-m and Filamin in epidermal cells might together influence growth cone progression. PMID:21857973

  19. Maneb-induced dopaminergic neuronal death is not affected by loss of mitochondrial complex I activity: Results from primary mesencephalic dopaminergic neurons cultured from individual Ndufs4+/+ and Ndufs4-/- mouse embryos

    PubMed Central

    Choi, Won-Seok; Xia, Zhengui

    2014-01-01

    Primary cultures from embryonic mouse ventral mesencephalon are widely used for investigating the mechanisms of dopaminergic neuronal death in Parkinson's disease models. Specifically, single mouse or embryo cultures from littermates can be very useful for comparative studies involving transgenic mice when the neuron cultures are to be prepared before genotyping. However, preparing single mouse embryo culture is technically challenging because of the small number of cells present in the mesencephalon of each embryo (150,000-300,000), of which only 0.5-5% are tyrosine hydroxylase (TH) -positive, dopaminergic neurons. In this study, we optimized the procedure for preparing primary mesencephalic neuron cultures from individual mouse embryos. Mesencephalic neurons that are dissociated delicately, plated on Aclar film coverslips, and incubated in DMEM supplemented with FBS for 5 days and then N2 supplement for 1 day resulted in the best survival of dopaminergic neurons from each embryo. Using this optimized method, we prepared mesencephalic neuron cultures from single Ndufs4+/+ or Ndufs4-/- embryos, and investigated the role of mitochondrial complex I in maneb-induced dopamine neuron death. Our results suggest that maneb toxicity to dopamine neurons is not affected by loss of mitochondrial complex I activity in Ndufs4-/- cultures. PMID:25275677

  20. Activation of neurotensin receptor 1 facilitates neuronal excitability and spatial learning and memory in the entorhinal cortex: beneficial actions in an Alzheimer's disease model.

    PubMed

    Xiao, Zhaoyang; Cilz, Nicholas I; Kurada, Lalitha; Hu, Binqi; Yang, Chuanxiu; Wada, Etsuko; Combs, Colin K; Porter, James E; Lesage, Florian; Lei, Saobo

    2014-05-14

    Neurotensin (NT) is a tridecapeptide distributed in the CNS, including the entorhinal cortex (EC), a structure that is crucial for learning and memory and undergoes the earliest pathological alterations in Alzheimer's disease (AD). Whereas NT has been implicated in modulating cognition, the cellular and molecular mechanisms by which NT modifies cognitive processes and the potential therapeutic roles of NT in AD have not been determined. Here we examined the effects of NT on neuronal excitability and spatial learning in the EC, which expresses high density of NT receptors. Brief application of NT induced persistent increases in action potential firing frequency, which could last for at least 1 h. NT-induced facilitation of neuronal excitability was mediated by downregulation of TREK-2 K(+) channels and required the functions of NTS1, phospholipase C, and protein kinase C. Microinjection of NT or NTS1 agonist, PD149163, into the EC increased spatial learning as assessed by the Barnes Maze Test. Activation of NTS1 receptors also induced persistent increases in action potential firing frequency and significantly improved the memory status in APP/PS1 mice, an animal model of AD. Our study identifies a cellular substrate underlying learning and memory and suggests that NTS1 agonists may exert beneficial actions in an animal model of AD. PMID:24828655

  1. Activation of Neurotensin Receptor 1 Facilitates Neuronal Excitability and Spatial Learning and Memory in the Entorhinal Cortex: Beneficial Actions in an Alzheimer's Disease Model

    PubMed Central

    Xiao, Zhaoyang; Cilz, Nicholas I.; Kurada, Lalitha; Hu, Binqi; Yang, Chuanxiu; Wada, Etsuko; Combs, Colin K.; Porter, James E.; Lesage, Florian

    2014-01-01

    Neurotensin (NT) is a tridecapeptide distributed in the CNS, including the entorhinal cortex (EC), a structure that is crucial for learning and memory and undergoes the earliest pathological alterations in Alzheimer's disease (AD). Whereas NT has been implicated in modulating cognition, the cellular and molecular mechanisms by which NT modifies cognitive processes and the potential therapeutic roles of NT in AD have not been determined. Here we examined the effects of NT on neuronal excitability and spatial learning in the EC, which expresses high density of NT receptors. Brief application of NT induced persistent increases in action potential firing frequency, which could last for at least 1 h. NT-induced facilitation of neuronal excitability was mediated by downregulation of TREK-2 K+ channels and required the functions of NTS1, phospholipase C, and protein kinase C. Microinjection of NT or NTS1 agonist, PD149163, into the EC increased spatial learning as assessed by the Barnes Maze Test. Activation of NTS1 receptors also induced persistent increases in action potential firing frequency and significantly improved the memory status in APP/PS1 mice, an animal model of AD. Our study identifies a cellular substrate underlying learning and memory and suggests that NTS1 agonists may exert beneficial actions in an animal model of AD. PMID:24828655

  2. GABAergic neurons of the medial septum play a nodal role in facilitation of nociception-induced affect

    PubMed Central

    Ang, Seok Ting; Lee, Andy Thiam Huat; Foo, Fang Chee; Ng, Lynn; Low, Chian-Ming; Khanna, Sanjay

    2015-01-01

    The present study explored the functional details of the influence of medial septal region (MSDB) on spectrum of nociceptive behaviours by manipulating intraseptal GABAergic mechanisms. Results showed that formalin-induced acute nociception was not affected by intraseptal microinjection of bicuculline, a GABAA receptor antagonist, or on selective lesion of septal GABAergic neurons. Indeed, the acute nociceptive responses were dissociated from the regulation of sensorimotor behaviour and generation of theta-rhythm by the GABAergic mechanisms in MSDB. The GABAergic lesion attenuated formalin-induced unconditioned cellular response in the anterior cingulate cortex (ACC) and blocked formalin-induced conditioned place avoidance (F-CPA), and as well as the contextual fear induced on conditioning with brief footshock. The effects of lesion on nociceptive-conditioned cellular responses were, however, variable. Interestingly, the lesion attenuated the conditioned representation of experimental context in dorsal hippocampus field CA1 in the F-CPA task. Collectively, the preceding suggests that the MSDB is a nodal centre wherein the GABAergic neurons mediate nociceptive affect-motivation by regulating cellular mechanisms in ACC that confer an aversive value to the noxious stimulus. Further, in conjunction with a modulatory influence on hippocampal contextual processing, MSDB may integrate affect with context as part of associative learning in the F-CPA task. PMID:26487082

  3. Isolation Rearing Reduces Neuronal Excitability in Dentate Gyrus Granule Cells of Adolescent C57BL/6J Mice: Role of GABAergic Tonic Currents and Neurosteroids.

    PubMed

    Talani, Giuseppe; Biggio, Francesca; Licheri, Valentina; Locci, Valentina; Biggio, Giovanni; Sanna, Enrico

    2016-01-01

    Early-life exposure to stress, by impacting on a brain still under development, is considered a critical factor for the increased vulnerability to psychiatric disorders and abuse of psychotropic substances during adulthood. As previously reported, rearing C57BL/6J weanling mice in social isolation (SI) from their peers for several weeks, a model of prolonged stress, is associated with a decreased plasma and brain levels of neuroactive steroids such as 3α,5α-THP, with a parallel up-regulation of extrasynaptic GABAA receptors (GABAAR) in dentate gyrus (DG) granule cells compared to group-housed (GH) mice. In the present study, together with the SI-induced decrease in plasma concentration of both progesterone and 3α,5α-THP, and an increase in THIP-stimulated GABAergic tonic currents, patch-clamp analysis of DG granule cells revealed a significant decrease in membrane input resistance and action potential (AP) firing rate, in SI compared to GH mice, suggesting that SI exerts an inhibitory action on neuronal excitability of these neurons. Voltage-clamp recordings of glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) revealed a SI-associated decrease in frequency as well as a shift from paired-pulse (PP) depression to PP facilitation (PPF) of evoked EPSCs, indicative of a reduced probability of glutamate release. Daily administration of progesterone during isolation reverted the changes in plasma 3α,5α-THP as well as in GABAergic tonic currents and neuronal excitability caused by SI, but it had only a limited effect on the changes in the probability of presynaptic glutamate release. Overall, the results obtained in this work, together with those previously published, indicate that exposure of mice to SI during adolescence reduces neuronal excitability of DG granule cells, an effect that may be linked to the increased GABAergic tonic currents as a consequence of the sustained decrease in plasma and hippocampal levels of neurosteroids. All these

  4. Isolation Rearing Reduces Neuronal Excitability in Dentate Gyrus Granule Cells of Adolescent C57BL/6J Mice: Role of GABAergic Tonic Currents and Neurosteroids

    PubMed Central

    Talani, Giuseppe; Biggio, Francesca; Licheri, Valentina; Locci, Valentina; Biggio, Giovanni; Sanna, Enrico

    2016-01-01

    Early-life exposure to stress, by impacting on a brain still under development, is considered a critical factor for the increased vulnerability to psychiatric disorders and abuse of psychotropic substances during adulthood. As previously reported, rearing C57BL/6J weanling mice in social isolation (SI) from their peers for several weeks, a model of prolonged stress, is associated with a decreased plasma and brain levels of neuroactive steroids such as 3α,5α-THP, with a parallel up-regulation of extrasynaptic GABAA receptors (GABAAR) in dentate gyrus (DG) granule cells compared to group-housed (GH) mice. In the present study, together with the SI-induced decrease in plasma concentration of both progesterone and 3α,5α-THP, and an increase in THIP-stimulated GABAergic tonic currents, patch-clamp analysis of DG granule cells revealed a significant decrease in membrane input resistance and action potential (AP) firing rate, in SI compared to GH mice, suggesting that SI exerts an inhibitory action on neuronal excitability of these neurons. Voltage-clamp recordings of glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) revealed a SI-associated decrease in frequency as well as a shift from paired-pulse (PP) depression to PP facilitation (PPF) of evoked EPSCs, indicative of a reduced probability of glutamate release. Daily administration of progesterone during isolation reverted the changes in plasma 3α,5α-THP as well as in GABAergic tonic currents and neuronal excitability caused by SI, but it had only a limited effect on the changes in the probability of presynaptic glutamate release. Overall, the results obtained in this work, together with those previously published, indicate that exposure of mice to SI during adolescence reduces neuronal excitability of DG granule cells, an effect that may be linked to the increased GABAergic tonic currents as a consequence of the sustained decrease in plasma and hippocampal levels of neurosteroids. All these

  5. Cofilin 1-Mediated Biphasic F-Actin Dynamics of Neuronal Cells Affect Herpes Simplex Virus 1 Infection and Replication

    PubMed Central

    Xiang, Yangfei; Zheng, Kai; Ju, Huaiqiang; Wang, Shaoxiang; Pei, Ying; Ding, Weichao; Chen, Zhenping; Wang, Qiaoli; Qiu, Xianxiu; Zhong, Meigong; Zeng, Fanli; Ren, Zhe; Qian, Chuiwen; Liu, Ge

    2012-01-01

    Herpes simplex virus 1 (HSV-1) invades the nervous system and causes pathological changes. In this study, we defined the remodeling of F-actin and its possible mechanisms during HSV-1 infection of neuronal cells. HSV-1 infection enhanced the formation of F-actin-based structures in the early stage of infection, which was followed by a continuous decrease in F-actin during the later stages of infection. The disruption of F-actin dynamics by chemical inhibitors significantly reduced the efficiency of viral infection and intracellular HSV-1 replication. The active form of the actin-depolymerizing factor cofilin 1 was found to increase at an early stage of infection and then to continuously decrease in a manner that corresponded to the remodeling pattern of F-actin, suggesting that cofilin 1 may be involved in the biphasic F-actin dynamics induced by HSV-1 infection. Knockdown of cofilin 1 impaired HSV-1-induced F-actin assembly during early infection and inhibited viral entry; however, overexpression of cofilin 1 did not affect F-actin assembly or viral entry during early infection but decreased intracellular viral reproduction efficiently. Our results, for the first time, demonstrated the biphasic F-actin dynamics in HSV-1 neuronal infection and confirmed the association of F-actin with the changes in the expression and activity of cofilin 1. These results may provide insight into the mechanism by which HSV-1 productively infects neuronal cells and causes pathogenesis. PMID:22623803

  6. Phthalates Induce Neurotoxicity Affecting Locomotor and Thermotactic Behaviors and AFD Neurons through Oxidative Stress in Caenorhabditis elegans

    PubMed Central

    Tseng, I-Ling; Yang, Ying-Fei; Yu, Chan-Wei; Li, Wen-Hsuan; Liao, Vivian Hsiu-Chuan

    2013-01-01

    Background Phthalate esters are ubiquitous environmental contaminants and numerous organisms are thus exposed to various levels of phthalates in their natural habitat. Considering the critical, but limited, research on human neurobehavioral outcomes in association with phthalates exposure, we used the nematode Caenorhabditis elegans as an in vivo model to evaluate phthalates-induced neurotoxicity and the possible associated mechanisms. Principal Findings Exposure to phthalates (DEHP, DBP, and DIBP) at the examined concentrations induced behavioral defects, including changes in body bending, head thrashing, reversal frequency, and thermotaxis in C. elegans. Moreover, phthalates (DEHP, DBP, and DIBP) exposure caused toxicity, affecting the relative sizes of cell body fluorescent puncta, and relative intensities of cell bodies in AFD neurons. The mRNA levels of the majority of the genes (TTX-1, TAX-2, TAX-4, and CEH-14) that are required for the differentiation and function of AFD neurons were decreased upon DEHP exposure. Furthermore, phthalates (DEHP, DBP, and DIBP) exposure at the examined concentrations produced elevated intracellular reactive oxygen species (ROS) in C. elegans. Finally, pretreatment with the antioxidant ascorbic acid significantly lowered the intracellular ROS level, ameliorated the locomotor and thermotactic behavior defects, and protected the damage of AFD neurons by DEHP exposure. Conclusions Our study suggests that oxidative stress plays a critical role in the phthalate esters-induced neurotoxic effects in C. elegans. PMID:24349328

  7. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease

    PubMed Central

    Balez, Rachelle; Steiner, Nicole; Engel, Martin; Muñoz, Sonia Sanz; Lum, Jeremy Stephen; Wu, Yizhen; Wang, Dadong; Vallotton, Pascal; Sachdev, Perminder; O’Connor, Michael; Sidhu, Kuldip; Münch, Gerald; Ooi, Lezanne

    2016-01-01

    Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, yet current therapeutic treatments are inadequate due to a complex disease pathogenesis. The plant polyphenol apigenin has been shown to have anti-inflammatory and neuroprotective properties in a number of cell and animal models; however a comprehensive assessment has not been performed in a human model of AD. Here we have used a human induced pluripotent stem cell (iPSC) model of familial and sporadic AD, in addition to healthy controls, to assess the neuroprotective activity of apigenin. The iPSC-derived AD neurons demonstrated a hyper-excitable calcium signalling phenotype, elevated levels of nitrite, increased cytotoxicity and apoptosis, reduced neurite length and increased susceptibility to inflammatory stress challenge from activated murine microglia, in comparison to control neurons. We identified that apigenin has potent anti-inflammatory properties with the ability to protect neurites and cell viability by promoting a global down-regulation of cytokine and nitric oxide (NO) release in inflammatory cells. In addition, we show that apigenin is able to protect iPSC-derived AD neurons via multiple means by reducing the frequency of spontaneous Ca2+ signals and significantly reducing caspase-3/7 mediated apoptosis. These data demonstrate the broad neuroprotective action of apigenin against AD pathogenesis in a human disease model. PMID:27514990

  8. Eugenol and carvacrol excite first- and second-order trigeminal neurons and enhance their heat-evoked responses

    PubMed Central

    Klein, Amanda H.; Joe, Christopher L.; Davoodi, Auva; Takechi, Kenichi; Carstens, Mirela Iodi; Carstens, E

    2014-01-01

    Eugenol and carvacrol from clove and oregano, respectively, are agonists of the warmth-sensitive transient receptor potential channel TRPV3 and the irritant-sensitive TRPA1. Eugenol and carvacrol induce oral irritation that rapidly desensitizes, accompanied by brief enhancement of innocuous warmth and heat pain in humans. We presently investigated if eugenol and carvacrol activate nociceptive primary afferent and higher-order trigeminal neurons and enhance their heat-evoked responses, using calcium imaging of cultured trigeminal ganglion (TG) and dorsal root ganglion (DRG) neurons, and in vivo single-unit recordings in trigeminal subnucleus caudalis (Vc) of rats. Eugenol and carvacrol activated 20-30% of TG and 7-20% of DRG cells, the majority of which additionally responded to menthol, mustard oil and/or capsaicin. TG cell responses to innocuous (39°) and noxious (42°C) heating were enhanced by eugenol and carvacrol. We identified dorsomedial Vc neurons responsive to noxious heating of the tongue in pentobarbital-anesthetized rats. Eugenol and carvacrol dose-dependently elicited desensitizing responses in 55% and 73% of heat-sensitive units, respectively. Responses to noxious heat were briefly enhanced by eugenol and carvacrol. Many eugenol- and carvacrol-responsive units also responded to menthol, cinnamaldehyde and capsaicin. These data support a peripheral site for eugenol and carvacrol to enhance warmth- and noxious heat-evoked responses of trigeminal neurons, and are consistent with the observation that these agonists briefly enhance warmth and heat pain on the human tongue. PMID:24759772

  9. Induction of an Isoelectric Brain State to Investigate the Impact of Endogenous Synaptic Activity on Neuronal Excitability In Vivo.

    PubMed

    Altwegg-Boussac, Tristan; Mahon, Séverine; Chavez, Mario; Charpier, Stéphane; Schramm, Adrien E

    2016-01-01

    The way neurons process information depends both on their intrinsic membrane properties and on the dynamics of the afferent synaptic network. In particular, endogenously-generated network activity, which strongly varies as a function of the state of vigilance, significantly modulates neuronal computation. To investigate how different spontaneous cerebral dynamics impact single neurons' integrative properties, we developed a new experimental strategy in the rat consisting in suppressing in vivo all cerebral activity by means of a systemic injection of a high dose of sodium pentobarbital. Cortical activities, continuously monitored by combined electrocorticogram (ECoG) and intracellular recordings are progressively slowed down, leading to a steady isoelectric profile. This extreme brain state, putting the rat into a deep comatose, was carefully monitored by measuring the physiological constants of the animal throughout the experiments. Intracellular recordings allowed us to characterize and compare the integrative properties of the same neuron embedded into physiologically relevant cortical dynamics, such as those encountered in the sleep-wake cycle, and when the brain was fully silent. PMID:27078163

  10. A tale of two receptors: Dual roles for ionotropic acetylcholine receptors in regulating motor neuron excitation and inhibition.

    PubMed

    Philbrook, Alison; Barbagallo, Belinda; Francis, Michael M

    2013-07-01

    Nicotinic or ionotropic acetylcholine receptors (iAChRs) mediate excitatory signaling throughout the nervous system, and the heterogeneity of these receptors contributes to their multifaceted roles. Our recent work has characterized a single iAChR subunit, ACR-12, which contributes to two distinct iAChR subtypes within the C. elegans motor circuit. These two receptor subtypes regulate the coordinated activity of excitatory (cholinergic) and inhibitory (GABAergic) motor neurons. We have shown that the iAChR subunit ACR-12 is differentially expressed in both cholinergic and GABAergic motor neurons within the motor circuit. In cholinergic motor neurons, ACR-12 is incorporated into the previously characterized ACR-2 heteromeric receptor, which shows non-synaptic localization patterns and plays a modulatory role in controlling circuit function.(1) In contrast, a second population of ACR-12-containing receptors in GABAergic motor neurons, ACR-12GABA, shows synaptic expression and regulates inhibitory signaling.(2) Here, we discuss the two ACR-12-containing receptor subtypes, their distinct expression patterns, and functional roles in the C. elegans motor circuit. We anticipate our continuing studies of iAChRs in the C. elegans motor circuit will lead to novel insights into iAChR function in the nervous system as well as mechanisms for their regulation. PMID:24778941

  11. A General Odorant Background Affects the Coding of Pheromone Stimulus Intermittency in Specialist Olfactory Receptor Neurones

    PubMed Central

    Rouyar, Angela; Party, Virginie; Prešern, Janez; Blejec, Andrej; Renou, Michel

    2011-01-01

    In nature the aerial trace of pheromone used by male moths to find a female appears as a train of discontinuous pulses separated by gaps among a complex odorant background constituted of plant volatiles. We investigated the effect of such background odor on behavior and coding of temporal parameters of pheromone pulse trains in the pheromone olfactory receptor neurons of Spodoptera littoralis. Effects of linalool background were tested by measuring walking behavior towards a source of pheromone. While velocity and orientation index did drop when linalool was turned on, both parameters recovered back to pre-background values after 40 s with linalool still present. Photo-ionization detector was used to characterize pulse delivery by our stimulator. The photo-ionization detector signal reached 71% of maximum amplitude at 50 ms pulses and followed the stimulus period at repetition rates up to 10 pulses/s. However, at high pulse rates the concentration of the odorant did not return to base level during inter-pulse intervals. Linalool decreased the intensity and shortened the response of receptor neurons to pulses. High contrast (>10 dB) in firing rate between pulses and inter-pulse intervals was observed for 1 and 4 pulses/s, both with and without background. Significantly more neurons followed the 4 pulses/s pattern when delivered over linalool; at the same time the information content was preserved almost to the control values. Rapid recovery of behavior shows that change of perceived intensity is more important than absolute stimulus intensity. While decreasing the response intensity, background odor preserved the temporal parameters of the specific signal. PMID:22028879

  12. Interleukin-6 Deficiency Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutation

    PubMed Central

    Han, Yongmei; Ripley, Barry; Serada, Satoshi; Naka, Tetsuji; Fujimoto, Minoru

    2016-01-01

    Background & Aim Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease. Recent evidence indicates that inflammation is associated with many neurodegenerative diseases including ALS. Previously, abnormal levels of inflammatory cytokines including IL-1β, IL-6 and TNF-α were described in ALS patients and/or in mouse ALS models. In addition, one study showed that blocking IL-1β could slow down progression of ALS-like symptoms in mice. In this study, we examined a role for IL-6 in ALS, using an animal model for familial ALS. Methods Mice with mutant SOD1 (G93A) transgene, a model for familial ALS, were used in this study. The expression of the major inflammatory cytokines, IL-6, IL-1β and TNF-α, in spinal cords of these SOD1 transgenic (TG) mice were assessed by real time PCR. Mice were then crossed with IL-6(-/-) mice to generate SOD1TG/IL-6(-/-) mice. SOD1 TG/IL-6(-/-) mice (n = 17) were compared with SOD1 TG/IL-6(+/-) mice (n = 18), SOD1 TG/IL-6(+/+) mice (n = 11), WT mice (n = 15), IL-6(+/-) mice (n = 5) and IL-6(-/-) mice (n = 8), with respect to neurological disease severity score, body weight and the survival. We also histologically compared the motor neuron loss in lumber spinal cords and the atrophy of hamstring muscles between these mouse groups. Results Levels of IL-6, IL-1β and TNF-α in spinal cords of SOD1 TG mice was increased compared to WT mice. However, SOD1 TG/IL-6(-/-) mice exhibited weight loss, deterioration in motor function and shortened lifespan (167.55 ± 11.52 days), similarly to SOD1 TG /IL-6(+/+) mice (164.31±12.16 days). Motor neuron numbers and IL-1β and TNF-α levels in spinal cords were not significantly different in SOD1 TG /IL-6(-/-) mice and SOD1 TG /IL-6 (+/+) mice. Conclusion These results provide compelling preclinical evidence indicating that IL-6 does not directly contribute to motor neuron disease caused by SOD1 mutations. PMID:27070121

  13. Etiology of distinct membrane excitability in pre- and posthearing auditory neurons relies on activity of Cl− channel TMEM16A

    PubMed Central

    Zhang, Xiao-Dong; Lee, Jeong-Han; Lv, Ping; Chen, Wei Chun; Kim, Hyo Jeong; Wei, Dongguang; Wang, Wenying; Sihn, Choong-Ryoul; Doyle, Karen Jo; Rock, Jason R.; Chiamvimonvat, Nipavan; Yamoah, Ebenezer N.

    2015-01-01

    The developmental rehearsal for the debut of hearing is marked by massive changes in the membrane properties of hair cells (HCs) and spiral ganglion neurons (SGNs). Whereas the underlying mechanisms for the developing HC transition to mature stage are understood in detail, the maturation of SGNs from hyperexcitable prehearing to quiescent posthearing neurons with broad dynamic range is unknown. Here, we demonstrated using pharmacological approaches, caged-Ca2+ photolysis, and gramicidin patch recordings that the prehearing SGN uses Ca2+-activated Cl− conductance to depolarize the resting membrane potential and to prime the neurons in a hyperexcitable state. Immunostaining of the cochlea preparation revealed the identity and expression of the Ca2+-activated Cl− channel transmembrane member 16A (TMEM16A) in SGNs. Moreover, null deletion of TMEM16A reduced the Ca2+-activated Cl− currents and action potential firing in SGNs. To determine whether Cl− ions and TMEM16A are involved in the transition between pre- and posthearing features of SGNs we measured the intracellular Cl− concentration [Cl−]i in SGNs. Surprisingly, [Cl−]i in SGNs from prehearing mice was ∼90 mM, which was significantly higher than posthearing neurons, ∼20 mM, demonstrating discernible altered roles of Cl− channels in the developing neuron. The switch in [Cl−]i stems from delayed expression of the development of intracellular Cl− regulating mechanisms. Because the Cl− channel is the only active ion-selective conductance with a reversal potential that lies within the dynamic range of SGN action potentials, developmental alteration of [Cl−]i, and hence the equilibrium potential for Cl− (ECl), transforms pre- to posthearing phenotype. PMID:25675481

  14. Etiology of distinct membrane excitability in pre- and posthearing auditory neurons relies on activity of Cl- channel TMEM16A.

    PubMed

    Zhang, Xiao-Dong; Lee, Jeong-Han; Lv, Ping; Chen, Wei Chun; Kim, Hyo Jeong; Wei, Dongguang; Wang, Wenying; Sihn, Choong-Ryoul; Doyle, Karen Jo; Rock, Jason R; Chiamvimonvat, Nipavan; Yamoah, Ebenezer N

    2015-02-24

    The developmental rehearsal for the debut of hearing is marked by massive changes in the membrane properties of hair cells (HCs) and spiral ganglion neurons (SGNs). Whereas the underlying mechanisms for the developing HC transition to mature stage are understood in detail, the maturation of SGNs from hyperexcitable prehearing to quiescent posthearing neurons with broad dynamic range is unknown. Here, we demonstrated using pharmacological approaches, caged-Ca(2+) photolysis, and gramicidin patch recordings that the prehearing SGN uses Ca(2+)-activated Cl(-) conductance to depolarize the resting membrane potential and to prime the neurons in a hyperexcitable state. Immunostaining of the cochlea preparation revealed the identity and expression of the Ca(2+)-activated Cl(-) channel transmembrane member 16A (TMEM16A) in SGNs. Moreover, null deletion of TMEM16A reduced the Ca(2+)-activated Cl(-) currents and action potential firing in SGNs. To determine whether Cl(-) ions and TMEM16A are involved in the transition between pre- and posthearing features of SGNs we measured the intracellular Cl(-) concentration [Cl(-)]i in SGNs. Surprisingly, [Cl(-)]i in SGNs from prehearing mice was ∼90 mM, which was significantly higher than posthearing neurons, ∼20 mM, demonstrating discernible altered roles of Cl(-) channels in the developing neuron. The switch in [Cl(-)]i stems from delayed expression of the development of intracellular Cl(-) regulating mechanisms. Because the Cl(-) channel is the only active ion-selective conductance with a reversal potential that lies within the dynamic range of SGN action potentials, developmental alteration of [Cl(-)]i, and hence the equilibrium potential for Cl(-) (ECl), transforms pre- to posthearing phenotype. PMID:25675481

  15. Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons.

    PubMed

    Morte, Maria I; Carreira, Bruno P; Falcão, Maria J; Ambrósio, António F; Soares-da-Silva, Patrício; Araújo, Inês M; Carvalho, Caetana M

    2013-12-01

    In this study we evaluated the neurotoxicity of eslicarbazepine acetate (ESL), and of its in vivo metabolites eslicarbazepine (S-Lic) and R-licarbazepine (R-Lic), as compared to the structurally-related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), in an in vitro model of cultured rat hippocampal neurons. The non-related antiepileptic drugs (AEDs) lamotrigine (LTG) and sodium valproate (VPA) were also studied. We assessed whether AEDs modulate pro-survival/pro-apoptotic pathways, such as extracellular-regulated kinase (ERK1/2), Akt and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). We found that neither ESL nor its metabolites, CBZ or LTG, up to 0.3mM, for 24h of exposure, decreased cell viability. OXC was the most toxic drug decreasing cell viability in a concentration-dependent manner, leading to activation of caspase-3 and PARP cleavage. VPA caused the appearance of the apoptotic markers, but did not alter cell viability. ESL, S-Lic and OXC decreased the levels of phospho-ERK1/2 and of phospho-Akt, when compared to basal levels, whereas CBZ decreased phospho-SAPK/JNK and phospho-Akt levels. LTG and VPA increased the phosphorylation levels of SAPK/JNK. These results suggest that ESL and its main metabolite S-Lic, as well as CBZ, LTG and VPA, are less toxic to hippocampal neurons than OXC, which was the most toxic agent. PMID:24055897

  16. Inhibitory ryanodine prevents ryanodine receptor-mediated Ca²⁺ release without affecting endoplasmic reticulum Ca²⁺ content in primary hippocampal neurons.

    PubMed

    Adasme, Tatiana; Paula-Lima, Andrea; Hidalgo, Cecilia

    2015-02-27

    Ryanodine is a cell permeant plant alkaloid that binds selectively and with high affinity to ryanodine receptor (RyR) Ca(2+) release channels. Sub-micromolar ryanodine concentrations activate RyR channels while micromolar concentrations are inhibitory. Several reports indicate that neuronal synaptic plasticity, learning and memory require RyR-mediated Ca(2+)-release, which is essential for muscle contraction. The use of micromolar (inhibitory) ryanodine represents a common strategy to suppress RyR activity in neuronal cells: however, micromolar ryanodine promotes RyR-mediated Ca(2+) release and endoplasmic reticulum Ca(2+) depletion in muscle cells. Information is lacking in this regard in neuronal cells; hence, we examined here if addition of inhibitory ryanodine elicited Ca(2+) release in primary hippocampal neurons, and if prolonged incubation of primary hippocampal cultures with inhibitory ryanodine affected neuronal ER calcium content. Our results indicate that inhibitory ryanodine does not cause Ca(2+) release from the ER in primary hippocampal neurons, even though ryanodine diffusion should produce initially low intracellular concentrations, within the RyR activation range. Moreover, neurons treated for 1 h with inhibitory ryanodine had comparable Ca(2+) levels as control neurons. These combined findings imply that prolonged incubation with inhibitory ryanodine, which effectively abolishes RyR-mediated Ca(2+) release, preserves ER Ca(2+) levels and thus constitutes a sound strategy to suppress neuronal RyR function. PMID:25623539

  17. Eugenol and carvacrol excite first- and second-order trigeminal neurons and enhance their heat-evoked responses.

    PubMed

    Klein, A H; Joe, C L; Davoodi, A; Takechi, K; Carstens, M I; Carstens, E

    2014-06-20

    Eugenol and carvacrol from clove and oregano, respectively, are agonists of the warmth-sensitive transient receptor potential channel TRPV3 and the irritant-sensitive transient receptor potential ankyrin (TRPA)-1. Eugenol and carvacrol induce oral irritation that rapidly desensitizes, accompanied by brief enhancement of innocuous warmth and heat pain in humans. We presently investigated if eugenol and carvacrol activate nociceptive primary afferent and higher order trigeminal neurons and enhance their heat-evoked responses, using calcium imaging of cultured trigeminal ganglion (TG) and dorsal root ganglion (DRG) neurons, and in vivo single-unit recordings in trigeminal subnucleus caudalis (Vc) of rats. Eugenol and carvacrol activated 20-30% of TG and 7-20% of DRG cells, the majority of which additionally responded to menthol, mustard oil and/or capsaicin. TG cell responses to innocuous (39°) and noxious (42 °C) heating were enhanced by eugenol and carvacrol. We identified dorsomedial Vc neurons responsive to noxious heating of the tongue in pentobarbital-anesthetized rats. Eugenol and carvacrol dose-dependently elicited desensitizing responses in 55% and 73% of heat-sensitive units, respectively. Responses to noxious heat were briefly enhanced by eugenol and carvacrol. Many eugenol- and carvacrol-responsive units also responded to menthol, cinnamaldehyde and capsaicin. These data support a peripheral site for eugenol and carvacrol to enhance warmth- and noxious heat-evoked responses of trigeminal neurons, and are consistent with the observation that these agonists briefly enhance warmth and heat pain on the human tongue. PMID:24759772

  18. Computational models of neuron-astrocyte interaction in epilepsy

    PubMed Central

    Volman, Vladislav; Bazhenov, Maxim; Sejnowski, Terrence J.

    2012-01-01

    Astrocytes actively shape the dynamics of neurons and neuronal ensembles by affecting several aspects critical to neuronal function, such as regulating synaptic plasticity, modulating neuronal excitability, and maintaining extracellular ion balance. These pathways for astrocyte-neuron interaction can also enhance the information-processing capabilities of brains, but in other circumstances may lead the brain on the road to pathological ruin. In this article, we review the existing computational models of astrocytic involvement in epileptogenesis, focusing on their relevance to existing physiological data. PMID:23060780

  19. Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion

    PubMed Central

    Cimino, Irene; Casoni, Filippo; Liu, Xinhuai; Messina, Andrea; Parkash, Jyoti; Jamin, Soazik P.; Catteau-Jonard, Sophie; Collier, Francis; Baroncini, Marc; Dewailly, Didier; Pigny, Pascal; Prescott, Mel; Campbell, Rebecca; Herbison, Allan E.; Prevot, Vincent; Giacobini, Paolo

    2016-01-01

    Anti-Müllerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic–pituitary–gonadal axis remain unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining in vivo and in vitro experiments, we show that AMH increases GnRH-dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS. PMID:26753790

  20. Short Conduction Delays Cause Inhibition Rather than Excitation to Favor Synchrony in Hybrid Neuronal Networks of the Entorhinal Cortex

    PubMed Central

    Fernandez, Fernando R.; White, John A.; Canavier, Carmen C.

    2012-01-01

    How stable synchrony in neuronal networks is sustained in the presence of conduction delays is an open question. The Dynamic Clamp was used to measure phase resetting curves (PRCs) for entorhinal cortical cells, and then to construct networks of two such neurons. PRCs were in general Type I (all advances or all delays) or weakly type II with a small region at early phases with the opposite type of resetting. We used previously developed theoretical methods based on PRCs under the assumption of pulsatile coupling to predict the delays that synchronize these hybrid circuits. For excitatory coupling, synchrony was predicted and observed only with no delay and for delays greater than half a network period that cause each neuron to receive an input late in its firing cycle and almost immediately fire an action potential. Synchronization for these long delays was surprisingly tight and robust to the noise and heterogeneity inherent in a biological system. In contrast to excitatory coupling, inhibitory coupling led to antiphase for no delay, very short delays and delays close to a network period, but to near-synchrony for a wide range of relatively short delays. PRC-based methods show that conduction delays can stabilize synchrony in several ways, including neutralizing a discontinuity introduced by strong inhibition, favoring synchrony in the case of noisy bistability, and avoiding an initial destabilizing region of a weakly type II PRC. PRCs can identify optimal conduction delays favoring synchronization at a given frequency, and also predict robustness to noise and heterogeneity. PMID:22241969

  1. Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion.

    PubMed

    Cimino, Irene; Casoni, Filippo; Liu, Xinhuai; Messina, Andrea; Parkash, Jyoti; Jamin, Soazik P; Catteau-Jonard, Sophie; Collier, Francis; Baroncini, Marc; Dewailly, Didier; Pigny, Pascal; Prescott, Mel; Campbell, Rebecca; Herbison, Allan E; Prevot, Vincent; Giacobini, Paolo

    2016-01-01

    Anti-Müllerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic-pituitary-gonadal axis remain unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining in vivo and in vitro experiments, we show that AMH increases GnRH-dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS. PMID:26753790

  2. Clinically relevant concentration of pregabalin has no acute inhibitory effect on excitation of dorsal horn neurons under normal or neuropathic pain conditions: An intracellular calcium-imaging study in spinal cord slices from adult rats.

    PubMed

    Baba, Hiroshi; Petrenko, Andrey B; Fujiwara, Naoshi

    2016-10-01

    Pregabalin is thought to exert its therapeutic effect in neuropathic pain via binding to α2δ-1 subunits of voltage-gated calcium (Ca(2+)) channels. However, the exact analgesic mechanism after its binding to α2δ-1 subunits remains largely unknown. Whether a clinical concentration of pregabalin (≈10μM) can cause acute inhibition of dorsal horn neurons in the spinal cord is controversial. To address this issue, we undertook intracellular Ca(2+)-imaging studies using spinal cord slices with an intact attached L5 dorsal root, and examined if pregabalin acutely inhibits the primary afferent stimulation-evoked excitation of dorsal horn neurons in normal rats and in rats with streptozotocin-induced painful diabetic neuropathy. Under normal conditions, stimulation of a dorsal root evoked Ca(2+) signals predominantly in the superficial dorsal horn. Clinically relevant (10μM) and a very high concentration of pregabalin (100μM) did not affect the intensity or spread of dorsal root stimulation-evoked Ca(2+) signals, whereas an extremely high dose of pregabalin (300μM) slightly but significantly attenuated Ca(2+) signals in normal rats and in diabetic neuropathic (DN) rats. There was no difference between normal rats and DN rats with regard to the extent of signal attenuation at all concentrations tested. These results suggest that the activity of dorsal horn neurons in the spinal cord is not inhibited acutely by clinical doses of pregabalin under normal or DN conditions. It is very unlikely that an acute inhibitory action in the dorsal horn is the main analgesic mechanism of pregabalin in neuropathic pain states. PMID:27543338

  3. 916 MHz electromagnetic field exposure affects rat behavior and hippocampal neuronal discharge☆

    PubMed Central

    Hao, Dongmei; Yang, Lei; Chen, Su; Tian, Yonghao; Wu, Shuicai

    2012-01-01

    Wistar rats were exposed to a 916 MHz, 10 W/m2 mobile phone electromagnetic field for 6 hours a day, 5 days a week. Average completion times in an eight-arm radial maze were longer in the exposed rats than control rats after 4–5 weeks of exposure. Error rates in the exposed rats were greater than the control rats at 6 weeks. Hippocampal neurons from the exposed rats showed irregular firing patterns during the experiment, and they exhibited decreased spiking activity 6–9 weeks compared with that after 2–5 weeks of exposure. These results indicate that 916 MHz electromagnetic fields influence learning and memory in rats during exposure, but long-term effects are not obvious. PMID:25657684

  4. Oligodendrocyte ablation affects the coordinated interaction between granule and Purkinje neurons during cerebellum development

    SciTech Connect

    Collin, Ludovic; Doretto, Sandrine; Malerba, Monica; Ruat, Martial; Borrelli, Emiliana . E-mail: borrelli@uci.edu

    2007-08-01

    Oligodendrocytes (OLs) are the glial cells of the central nervous system (CNS) classically known to be devoted to the formation of myelin sheaths around most axons of the vertebrate brain. We have addressed the role of these cells during cerebellar development, by ablating OLs in vivo. Previous analyses had indicated that OL ablation during the first six postnatal days results into a striking cerebellar phenotype, whose major features are a strong reduction of granule neurons and aberrant Purkinje cells development. These two cell types are highly interconnected during cerebellar development through the production of molecules that help their proliferation, differentiation and maintenance. In this article, we present data showing that OL ablation has major effects on the physiology of Purkinje (PC) and granule cells (GC). In particular, OL ablation results into a reduction of sonic hedgehog (Shh), Brain Derived Neurotrophic Factor (BDNF), and Reelin (Rln) expression. These results indicate that absence of OLs profoundly alters the normal cerebellar developmental program.

  5. Effects of Aversive Stimuli beyond Defensive Neural Circuits: Reduced Excitability in an Identified Neuron Critical for Feeding in "Aplysia"

    ERIC Educational Resources Information Center

    Shields-Johnson, Maria E.; Hernandez, John S.; Torno, Cody; Adams, Katherine M.; Wainwright, Marcy L.; Mozzachiodi, Riccardo

    2013-01-01

    In "Aplysia," repeated trials of aversive stimuli produce long-term sensitization (LTS) of defensive reflexes and suppression of feeding. Whereas the cellular underpinnings of LTS have been characterized, the mechanisms of feeding suppression remained unknown. Here, we report that LTS training induced a long-term decrease in the excitability of…

  6. Biophysics of Active Vesicle Transport, an Intermediate Step That Couples Excitation and Exocytosis of Serotonin in the Neuronal Soma

    PubMed Central

    De-Miguel, Francisco F.; Santamaría-Holek, Iván; Noguez, Paula; Bustos, Carlos; Hernández-Lemus, Enrique; Rubí, J. Miguel

    2012-01-01

    Transmitter exocytosis from the neuronal soma is evoked by brief trains of high frequency electrical activity and continues for several minutes. Here we studied how active vesicle transport towards the plasma membrane contributes to this slow phenomenon in serotonergic leech Retzius neurons, by combining electron microscopy, the kinetics of exocytosis obtained from FM1-43 dye fluorescence as vesicles fuse with the plasma membrane, and a diffusion equation incorporating the forces of local confinement and molecular motors. Electron micrographs of neurons at rest or after stimulation with 1 Hz trains showed cytoplasmic clusters of dense core vesicles at 1.5±0.2 and 3.7±0.3 µm distances from the plasma membrane, to which they were bound through microtubule bundles. By contrast, after 20 Hz stimulation vesicle clusters were apposed to the plasma membrane, suggesting that transport was induced by electrical stimulation. Consistently, 20 Hz stimulation of cultured neurons induced spotted FM1-43 fluorescence increases with one or two slow sigmoidal kinetics, suggesting exocytosis from an equal number of vesicle clusters. These fluorescence increases were prevented by colchicine, which suggested microtubule-dependent vesicle transport. Model fitting to the fluorescence kinetics predicted that 52–951 vesicles/cluster were transported along 0.60–6.18 µm distances at average 11–95 nms−1 velocities. The ATP cost per vesicle fused (0.4–72.0), calculated from the ratio of the ΔGprocess/ΔGATP, depended on the ratio of the traveling velocity and the number of vesicles in the cluster. Interestingly, the distance-dependence of the ATP cost per vesicle was bistable, with low energy values at 1.4 and 3.3 µm, similar to the average resting distances of the vesicle clusters, and a high energy barrier at 1.6–2.0 µm. Our study confirms that active vesicle transport is an intermediate step for somatic serotonin exocytosis by Retzius neurons and provides a quantitative

  7. Presynaptic α4β2 nicotinic acetylcholine receptors increase glutamate release and serotonin neuron excitability in the dorsal raphe nucleus.

    PubMed

    Garduño, Julieta; Galindo-Charles, Luis; Jiménez-Rodríguez, Javier; Galarraga, Elvira; Tapia, Dagoberto; Mihailescu, Stefan; Hernandez-Lopez, Salvador

    2012-10-24

    Several behavioral effects of nicotine are mediated by changes in serotonin (5-HT) release in brain areas that receive serotonergic afferents from the dorsal raphe nucleus (DRN). In vitro experiments have demonstrated that nicotine increases the firing activity in the majority of DRN 5-HT neurons and that DRN contains nicotinic acetylcholine receptors (nAChRs) located at both somata and presynaptic elements. One of the most common presynaptic effects of nicotine is to increase glutamate release. Although DRN receives profuse glutamatergic afferents, the effect of nicotine on glutamate release in the DRN has not been studied in detail. Using whole-cell recording techniques, we investigated the effects of nicotine on the glutamatergic input to 5-HT DRN neurons in rat midbrain slices. Low nicotine concentrations, in the presence of bicuculline and tetrodotoxin (TTX), increased the frequency but did not change the amplitude of glutamate-induced EPSCs, recorded from identified 5-HT neurons. Nicotine-induced increase of glutamatergic EPSC frequency persisted 10-20 min after drug withdrawal. This nicotinic effect was mimicked by exogenous administration of acetylcholine (ACh) or inhibition of ACh metabolism. In addition, the nicotine-induced increase in EPSC frequency was abolished by blockade of α4β2 nAChRs, voltage-gated calcium channels, or intracellular calcium signaling but not by α7 nAChR antagonists. These data suggest that both nicotine and endogenous ACh can increase glutamate release through activation of presynaptic α4β2 but not α7 nAChRs in the DRN. The effect involves long-term changes in synaptic function, and it is dependent on voltage-gated calcium channels and presynaptic calcium stores. PMID:23100436

  8. Poliovirus Internal Ribosome Entry Segment Structure Alterations That Specifically Affect Function in Neuronal Cells: Molecular Genetic Analysis

    PubMed Central

    Malnou, Cécile E.; Pöyry, Tuija A. A.; Jackson, Richard J.; Kean, Katherine M.

    2002-01-01

    Translation of poliovirus RNA is driven by an internal ribosome entry segment (IRES) present in the 5′ noncoding region of the genomic RNA. This IRES is structured into several domains, including domain V, which contains a large lateral bulge-loop whose predicted secondary structure is unclear. The primary sequence of this bulge-loop is strongly conserved within enteroviruses and rhinoviruses: it encompasses two GNAA motifs which could participate in intrabulge base pairing or (in one case) could be presented as a GNRA tetraloop. We have begun to address the question of the significance of the sequence conservation observed among enterovirus reference strains and field isolates by using a comprehensive site-directed mutagenesis program targeted to these two GNAA motifs. Mutants were analyzed functionally in terms of (i) viability and growth kinetics in both HeLa and neuronal cell lines, (ii) structural analyses by biochemical probing of the RNA, and (iii) translation initiation efficiencies in vitro in rabbit reticulocyte lysates supplemented with HeLa or neuronal cell extracts. Phenotypic analyses showed that only viruses with both GNAA motifs destroyed were significantly affected in their growth capacities, which correlated with in vitro translation defects. The phenotypic defects were strongly exacerbated in neuronal cells, where a temperature-sensitive phenotype could be revealed at between 37 and 39.5°C. Biochemical probing of mutated domain V, compared to the wild type, demonstrated that such mutations lead to significant structural perturbations. Interestingly, revertant viruses possessed compensatory mutations which were distant from the primary mutations in terms of sequence and secondary structure, suggesting that intradomain tertiary interactions could exist within domain V of the IRES. PMID:12368304

  9. Defects in the COG complex and COG-related trafficking regulators affect neuronal Golgi function

    PubMed Central

    Climer, Leslie K.; Dobretsov, Maxim; Lupashin, Vladimir

    2015-01-01

    The Conserved Oligomeric Golgi (COG) complex is an evolutionarily conserved hetero-octameric protein complex that has been proposed to organize vesicle tethering at the Golgi apparatus. Defects in seven of the eight COG subunits are linked to Congenital Disorders of Glycosylation (CDG)-type II, a family of rare diseases involving misregulation of protein glycosylation, alterations in Golgi structure, variations in retrograde trafficking through the Golgi and system-wide clinical pathologies. A troublesome aspect of these diseases are the neurological pathologies such as low IQ, microcephaly, and cerebellar atrophy. The essential function of the COG complex is dependent upon interactions with other components of trafficking machinery, such as Rab-GTPases and SNAREs. COG-interacting Rabs and SNAREs have been implicated in neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Defects in Golgi maintenance disrupts trafficking and processing of essential proteins, frequently associated with and contributing to compromised neuron function and human disease. Despite the recent advances in molecular neuroscience, the subcellular bases for most neurodegenerative diseases are poorly understood. This article gives an overview of the potential contributions of the COG complex and its Rab and SNARE partners in the pathogenesis of different neurodegenerative disorders. PMID:26578865

  10. Social experience affects neuronal responses to male calls in adult female zebra finches.

    PubMed

    Menardy, F; Touiki, K; Dutrieux, G; Bozon, B; Vignal, C; Mathevon, N; Del Negro, C

    2012-04-01

    Plasticity studies have consistently shown that behavioural relevance can change the neural representation of sounds in the auditory system, but what occurs in the context of natural acoustic communication where significance could be acquired through social interaction remains to be explored. The zebra finch, a highly social songbird species that forms lifelong pair bonds and uses a vocalization, the distance call, to identify its mate, offers an opportunity to address this issue. Here, we recorded spiking activity in females while presenting distance calls that differed in their degree of familiarity: calls produced by the mate, by a familiar male, or by an unfamiliar male. We focused on the caudomedial nidopallium (NCM), a secondary auditory forebrain region. Both the mate's call and the familiar call evoked responses that differed in magnitude from responses to the unfamiliar call. This distinction between responses was seen both in single unit recordings from anesthetized females and in multiunit recordings from awake freely moving females. In contrast, control females that had not heard them previously displayed responses of similar magnitudes to all three calls. In addition, more cells showed highly selective responses in mated than in control females, suggesting that experience-dependent plasticity in call-evoked responses resulted in enhanced discrimination of auditory stimuli. Our results as a whole demonstrate major changes in the representation of natural vocalizations in the NCM within the context of individual recognition. The functional properties of NCM neurons may thus change continuously to adapt to the social environment. PMID:22512260

  11. Amphipathic amines affect membrane excitability in paramecium: role for bilayer couple.

    PubMed

    Browning, J L; Nelson, D L

    1976-02-01

    Amphipathic amines and local anesthetics stimulated reversal of the ciliary beating direction in wild-type Paramecium. Ca++ influx across the surface membrane and the consequent increase in internal Ca++ causes ciliary reversal and backward swimming. Mutant cells of the "Pawn" class, which lack a "gating" mechanism for regulating Ca++ influx, did not swim backwards in the presence of local anesthetics. Local anesthetics stimulated the passive efflux of K+ but had no effect on the active transport of K+ or Ca++. Apparently passive influx of Ca++ also was stimulated by local anesthetics as evidenced by their effects on swimming direction. These data can be interpreted in terms of the "bilayer couple" hypothesis of Sheetz and Singer [(1974) Proc. Nat. Acad. Sci. USA 71, 4457-4461]: amphipathic drugs affect cells by asymmetric insertion into one face of the lipid bilayer. As predicted by this hypothesis, the drugs' effects were seen only after a short time lag, and quaternary amines were less effective than tertiary amines. The effect on behavior was caused by any of several amphipathic cations, and the relative potency was a function of their hydrophobicity. Amphipathic anions, which according to the hypothesis would insert into the opposite face of the lipid bilayer, had little effect on ciliary reversal. Asymmetric perturbation of the lipid bilayer with amphipathic cations may trigger the opening of the Ca++ gate. PMID:1061147

  12. Ultrasonic excitation affects friction interactions between food materials and cutting tools.

    PubMed

    Schneider, Yvonne; Zahn, Susann; Schindler, Claudia; Rohm, Harald

    2009-06-01

    In the food industry, ultrasonic cutting is used to improve separation by a reduction of the cutting force. This reduction can be attributed to the modification of tool-workpiece interactions at the cutting edge and along the tool flanks because of the superposition of the cutting movement with ultrasonic vibration of the cutting tool. In this study, model experiments were used to analyze friction between the flanks of a cutting tool and the material to be cut. Friction force at a commercial cutting sonotrode was quantified using combined cutting-friction experiments, and sliding friction tests were carried out by adapting a standard draw-off assembly and using an ultrasonic welding sonotrode as sliding surface. The impact of material parameters, ultrasonic amplitude, and the texture of the contacting food surface on friction force was investigated. The results show that ultrasonic vibration significantly reduces the sliding friction force. While the amplitude showed no influence within the tested range, the texture of the contact surface of the food affects the intensity of ultrasonic transportation effects. These effects are a result of mechanical interactions and of changes in material properties of the contact layer, which are induced by the deformation of contact points, friction heating and absorption heating because of the dissipation of mechanical vibration energy. PMID:19342070

  13. Neurocognitive poetics: methods and models for investigating the neuronal and cognitive-affective bases of literature reception

    PubMed Central

    Jacobs, Arthur M.

    2015-01-01

    A long tradition of research including classical rhetoric, esthetics and poetics theory, formalism and structuralism, as well as current perspectives in (neuro)cognitive poetics has investigated structural and functional aspects of literature reception. Despite a wealth of literature published in specialized journals like Poetics, however, still little is known about how the brain processes and creates literary and poetic texts. Still, such stimulus material might be suited better than other genres for demonstrating the complexities with which our brain constructs the world in and around us, because it unifies thought and language, music and imagery in a clear, manageable way, most often with play, pleasure, and emotion (Schrott and Jacobs, 2011). In this paper, I discuss methods and models for investigating the neuronal and cognitive-affective bases of literary reading together with pertinent results from studies on poetics, text processing, emotion, or neuroaesthetics, and outline current challenges and future perspectives. PMID:25932010

  14. Neurocognitive poetics: methods and models for investigating the neuronal and cognitive-affective bases of literature reception.

    PubMed

    Jacobs, Arthur M

    2015-01-01

    A long tradition of research including classical rhetoric, esthetics and poetics theory, formalism and structuralism, as well as current perspectives in (neuro)cognitive poetics has investigated structural and functional aspects of literature reception. Despite a wealth of literature published in specialized journals like Poetics, however, still little is known about how the brain processes and creates literary and poetic texts. Still, such stimulus material might be suited better than other genres for demonstrating the complexities with which our brain constructs the world in and around us, because it unifies thought and language, music and imagery in a clear, manageable way, most often with play, pleasure, and emotion (Schrott and Jacobs, 2011). In this paper, I discuss methods and models for investigating the neuronal and cognitive-affective bases of literary reading together with pertinent results from studies on poetics, text processing, emotion, or neuroaesthetics, and outline current challenges and future perspectives. PMID:25932010

  15. Repetitive Peripheral Magnetic Stimulation (15 Hz RPMS) of the Human Soleus Muscle did not Affect Spinal Excitability.

    PubMed

    Behrens, Martin; Mau-Möller, Anett; Zschorlich, Volker; Bruhn, Sven

    2011-01-01

    The electric field induced by repetitive peripheral magnetic stimulation (RPMS) is able to activate muscles artificially due to the stimulation of deep intramuscular motor axons. RPMS applied to the muscle induces proprioceptive input to the central nervous system in different ways. Firstly, the indirect activation of mechanoreceptors and secondly, direct activation of afferent nerve fibers. The purpose of the study was to examine the effects of RPMS applied to the soleus. Thirteen male subjects received RPMS once and were investigated before and after the treatment regarding the parameters maximal M wave (Mmax), maximal H-reflex (Hmax), Hmax/Mmax-ratio, Hmax and Mmax onset latencies and plantar flexor peak twitch torque associated with Hmax (PTH). Eleven male subjects served as controls. No significant changes were observed for Hmax and PTH of the treatment group but the Hmax/Mmax-ratio increased significantly (p = 0.015) on account of a significantly decreased Mmax (p = 0.027). Hmax onset latencies were increased for the treatment group (p = 0.003) as well as for the control group (p = 0.011) while Mmax onset latencies did not change. It is concluded that the RPMS protocol did not affect spinal excitability but acted on the muscle fibres which are part of fast twitch units and mainly responsible for the generation of the maximal M wave. RPMS probably modified the integrity of neuromuscular propagation. Key pointsRPMS probably did not affect spinal excitability.Data suggested that RPMS likely acted on the muscle fibres which are part of fast twitch units and mainly responsible for the generation of the maximal M wave.RPMS probably modified the integrity of neuromuscular propagation. PMID:24149293

  16. Background visual motion affects responses of an insect motion-sensitive neuron to objects deviating from a collision course.

    PubMed

    Yakubowski, Jasmine M; McMillan, Glyn A; Gray, John R

    2016-05-01

    Stimulus complexity affects the response of looming sensitive neurons in a variety of animal taxa. The Lobula Giant Movement Detector/Descending Contralateral Movement Detector (LGMD/DCMD) pathway is well-characterized in the locust visual system. It responds to simple objects approaching on a direct collision course (i.e., looming) as well as complex motion defined by changes in stimulus velocity, trajectory, and transitions, all of which are affected by the presence or absence of background visual motion. In this study, we focused on DCMD responses to objects transitioning away from a collision course, which emulates a successful locust avoidance behavior. We presented each of 20 locusts with a sequence of complex three-dimensional visual stimuli in simple, scattered, and progressive flow field backgrounds while simultaneously recording DCMD activity extracellularly. DCMD responses to looming stimuli were generally characteristic irrespective of stimulus background. However, changing background complexity affected, peak firing rates, peak time, and caused changes in peak rise and fall phases. The DCMD response to complex object motion also varied with the azimuthal approach angle and the dynamics of object edge expansion. These data fit with an existing correlational model that relates expansion properties to firing rate modulation during trajectory changes. PMID:27207786

  17. KCNQ1, KCNE2, and Na+-Coupled Solute Transporters Form Reciprocally Regulating Complexes that Affect Neuronal Excitability

    PubMed Central

    Abbott, Geoffrey W.; Tai, Kwok-Keung; Neverisky, Daniel; Hansler, Alex; Hu, Zhaoyang; Roepke, Torsten K.; Lerner, Daniel J.; Chen, Qiuying; Liu, Li; Zupan, Bojana; Toth, Miklos; Haynes, Robin; Huang, Xiaoping; Demirbas, Didem; Buccafusca, Roberto; Gross, Steven S.; Kanda, Vikram A.; Berry, Gerard T.

    2014-01-01

    Na+-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. Here, we found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K+ channel β subunit, showed a reduction in the myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavorial responsiveness to stress and seizure susceptibility in Kcne2−/− mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na+-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K+ channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activity of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1, but suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk. PMID:24595108

  18. Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens

    PubMed Central

    Ma, Yao-Ying; Henley, Sandy M.; Toll, Jeff; Jentsch, James D.; Evans, Christopher J.; Levine, Michael S.; Cepeda, Carlos

    2013-01-01

    To examine the mechanisms of drug relapse, we first established a model for cocaine IVSA (intravenous self-administration) in mice, and subsequently examined electrophysiological alterations of MSNs (medium-sized spiny neurons) in the NAc (nucleus accumbens) before and after acute application of cocaine in slices. Three groups were included: master mice trained by AL (active lever) pressings followed by IV (intravenous) cocaine delivery, yoked mice that received passive IV cocaine administration initiated by paired master mice, and saline controls. MSNs recorded in the NAc shell in master mice exhibited higher membrane input resistances but lower frequencies and smaller amplitudes of sEPSCs (spontaneous excitatory postsynaptic currents) compared with neurons recorded from saline control mice, whereas cells in the NAc core had higher sEPSCs frequencies and larger amplitudes. Furthermore, sEPSCs in MSNs of the shell compartment displayed longer decay times, suggesting that both pre- and postsynaptic mechanisms were involved. After acute re-exposure to a low-dose of cocaine in vitro, an AP (action potential)-dependent, persistent increase in sEPSC frequency was observed in both NAc shell and core MSNs from master, but not yoked or saline control mice. Furthermore, re-exposure to cocaine induced membrane hyperpolarization, but concomitantly increased excitability of MSNs from master mice, as evidenced by increased membrane input resistance, decreased depolarizing current to generate APs, and a more negative Thr (threshold) for firing. These data demonstrate functional differences in NAc MSNs after chronic contingent versus non-contingent IV cocaine administration in mice, as well as synaptic adaptations of MSNs before and after acute re-exposure to cocaine. Reversing these functional alterations in NAc could represent a rational target for the treatment of some reward-related behaviors, including drug addiction. PMID:24000958

  19. Made for "anchorin": Kv7.2/7.3 (KCNQ2/KCNQ3) channels and the modulation of neuronal excitability in vertebrate axons.

    PubMed

    Cooper, Edward C

    2011-04-01

    Kv7.2 and Kv7.3 (encoded by KCNQ2 and KCNQ3) are homologous subunits forming a widely expressed neuronal voltage-gated K(+) (Kv) channel. Hypomorphic mutations in either KCNQ2 or KCNQ3 cause a highly penetrant, though transient, human phenotype-epilepsy during the first months of life. Some KCNQ2 mutations also cause involuntary muscle rippling, or myokymia, which is indicative of motoneuron axon hyperexcitability. Kv7.2 and Kv7.3 are concentrated at axonal initial segments (AISs), and at nodes of Ranvier in the central and peripheral nervous system. Kv7.2 and Kv7.3 share a novel ∼80 residue C-terminal domain bearing an "anchor" motif, which interacts with ankyrin-G and is required for channel AIS (and likely, nodal) localization. This domain includes the sequence IAEGES/TDTD, which is analogous (not homologous) to the ankyrin-G interaction motif of voltage-gated Na(+) (Na(V)) channels. The KCNQ subfamily is evolutionarily ancient, with two genes (KCNQ1 and KCNQ5) persisting as orthologues in extant bilaterian animals from worm to man. However, KCNQ2 and KCNQ3 arose much more recently, in the interval between the divergence of extant jawless and jawed vertebrates. This is precisely the interval during which myelin and saltatory conduction evolved. The natural selection for KCNQ2 and KCNQ3 appears to hinge on these subunits' unique ability to be coordinately localized with Na(V) channels by ankyrin-G, and the resulting enhancement in the reliability of neuronal excitability. PMID:20940059

  20. Brain-derived neurotrophic factor enhances the excitability of small-diameter trigeminal ganglion neurons projecting to the trigeminal nucleus interpolaris/caudalis transition zone following masseter muscle inflammation

    PubMed Central

    2013-01-01

    Background The trigeminal subnuclei interpolaris/caudalis transition zones (Vi/Vc) play an important role in orofacial deep pain, however, the role of primary afferent projections to the Vi/Vc remains to be determined. This study investigated the functional significance of hyperalgesia to the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (trkB) signaling system in trigeminal ganglion (TRG) neurons projecting to the Vi/Vc transition zone following masseter muscle (MM) inflammation. Results The escape threshold from mechanical stimulation applied to skin above the inflamed MM was significantly lower than in naïve rats. Fluorogold (FG) labeling was used to identify the TRG neurons innervating the MM, while microbeads (MB) were used to label neurons projecting to the Vi/Vc region. FG/MB-labeled TRG neurons were immunoreactive (IR) for BDNF and trkB. The mean number of BDNF/trkB-IR small/medium-diameter TRG neurons was significantly higher in inflamed rats than in naïve rats. In whole-cell current-clamp experiments, the majority of dissociated small-diameter TRG neurons showed a depolarization response to BDNF that was associated with spike discharge, and the concentration of BDNF that evoked a depolarizing response was significantly lower in the inflamed rats. In addition, the relative number of BDNF-induced spikes during current injection was significantly higher in inflamed rats. The BDNF-induced changes in TRG neuron excitability was abolished by tyrosine kinase inhibitor, K252a. Conclusion The present study provided evidence that BDNF enhances the excitability of the small-diameter TRG neurons projecting onto the Vi/Vc following MM inflammation. These findings suggest that ganglionic BDNF-trkB signaling is a therapeutic target for the treatment of trigeminal inflammatory hyperalgesia. PMID:24073832

  1. Hypoxic Preconditioning Differentially Affects GABAergic and Glutamatergic Neuronal Cells in the Injured Cerebellum of the Neonatal Rat

    PubMed Central

    Patterson, Sean I.; Muñoz, Estela M.; Seltzer, Alicia M.

    2014-01-01

    In this study we examined cerebellar alterations in a neonatal rat model of hypoxic-ischemic brain injury with or without hypoxic preconditioning (Pc). Between postnatal days 7 and 15, the cerebellum is still undergoing intense cellular proliferation, differentiation and migration, dendritogenesis and synaptogenesis. The expression of glutamate decarboxylase 1 (GAD67) and the differentiation factor NeuroD1 were examined as markers of Purkinje and granule cells, respectively. We applied quantitative immunohistochemistry to sagittal cerebellar slices, and Western blot analysis of whole cerebella obtained from control (C) rats and rats submitted to Pc, hypoxia-ischemia (L) and a combination of both treatments (PcL). We found that either hypoxia-ischemia or Pc perturbed the granule cells in the posterior lobes, affecting their migration and final placement in the internal granular layer. These effects were partially attenuated when the Pc was delivered prior to the hypoxia-ischemia. Interestingly, whole nuclear NeuroD1 levels in Pc animals were comparable to those in the C rats. However, a subset of Purkinje cells that were severely affected by the hypoxic-ischemic insult—showing signs of neuronal distress at the levels of the nucleus, cytoplasm and dendritic arborization—were not protected by Pc. A monoclonal antibody specific for GAD67 revealed a three-band pattern in cytoplasmic extracts from whole P15 cerebella. A ∼110 kDa band, interpreted as a potential homodimer of a truncated form of GAD67, was reduced in Pc and L groups while its levels were close to the control animals in PcL rats. Additionally we demonstrated differential glial responses depending on the treatment, including astrogliosis in hypoxiated cerebella and a selective effect of hypoxia-ischemia on the vimentin-immunolabeled intermediate filaments of the Bergmann glia. Thus, while both glutamatergic and GABAergic cerebellar neurons are compromised by the hypoxic-ischemic insult, the former are

  2. A neuronal disruption in redox homeostasis elicited by ammonia alters the glycine/glutamate (GABA) cycle and contributes to MMA-induced excitability.

    PubMed

    Royes, Luiz Fernando Freire; Gabbi, Patrícia; Ribeiro, Leandro Rodrigo; Della-Pace, Iuri Domingues; Rodrigues, Fernanda Silva; de Oliveira Ferreira, Ana Paula; da Silveira Junior, Mauro Eduardo Porto; da Silva, Luís Roberto Hart; Grisólia, Alan Barroso Araújo; Braga, Danielle Valente; Dobrachinski, Fernando; da Silva, Anderson Manoel Herculano Oliveira; Soares, Félix Alexandre Antunes; Marchesan, Sara; Furian, Ana Flavia; Oliveira, Mauro Schneider; Fighera, Michele Rechia

    2016-06-01

    Hyperammonemia is a common finding in children with methylmalonic acidemia. However, its contribution to methylmalonate-induced excitotoxicty is poorly understood. The aim of this study was to evaluate the mechanisms by which ammonia influences in the neurotoxicity induced by methylmalonate (MMA) in mice. The effects of ammonium chloride (NH4Cl 3, 6, and 12 mmol/kg; s.c.) on electroencephalographic (EEG) and behavioral convulsions induced by MMA (0.3, 0.66, and 1 µmol/2 µL, i.c.v.) were observed in mice. After, ammonia, TNF-α, IL1β, IL-6, nitrite/nitrate (NOx) levels, mitochondrial potential (ΔΨ), reactive oxygen species (ROS) generation, Methyl-Tetrazolium (MTT) reduction, succinate dehydrogenase (SDH), and Na(+), K(+)-ATPase activity levels were measured in the cerebral cortex. The binding of [(3)H]flunitrazepam, release of glutamate-GABA; glutamate decarboxylase (GAD) and glutamine synthetase (GS) activity and neuronal damage [opening of blood brain barrier (BBB) permeability and cellular death volume] were also measured. EEG recordings showed that an intermediate dose of NH4Cl (6 mmol/kg) increased the duration of convulsive episodes induced by MMA (0.66 μmol/2 μL i.c.v). NH4Cl (6 mmol/kg) administration also induced neuronal ammonia and NOx increase, as well as mitochondrial ROS generation throughout oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) to DCF-RS, followed by GS and GAD inhibition. The NH4Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the ΔΨ potential, reduced MTT, inhibited SDH activity, and increased Na(+), K(+)-ATPase activity. NH4Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, [(3)H]flunitrazepam binding, and GABA release after MMA injection. On the basis of our findings, the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine

  3. Altering the Balance between Excitation and Inhibition in Cultured Neural Networks

    NASA Astrophysics Data System (ADS)

    Dzakpasu, Rhonda

    2010-03-01

    How is the network temporal structure altered when the balance between excitation and inhibition is changed? Proper balance is essential for normal brain function, including cognitive processing, the representation of sensory information and motor control. When the balance is compromised, neurological disorders may result. We use a simple reduced experimental system to investigate how manipulating the number of inhibitory neurons in a network of cultured hippocampal neurons affects synchronized bursting activity, the most prominent temporal signature of cultured hippocampal networks. Inhibitory neurons are thought to control spike timing and modulate network excitability and their absence may lead to widespread synchronization. We culture dissociated hippocampal neurons with varying quantities of inhibitory neurons on an 8x8 grid of extracellular electrodes and study how inhibitory neurons modulate network temporal dynamics. We show that as the proportion of inhibitory neurons increase, there is a dramatic transition in the temporal pattern.

  4. Age and duration of inflammatory environment differentially affect the neuroimmune response and catecholaminergic neurons in the midbrain and brainstem.

    PubMed

    Bardou, Isabelle; Kaercher, Roxanne M; Brothers, Holly M; Hopp, Sarah C; Royer, Sarah; Wenk, Gary L

    2014-05-01

    Neuroinflammation and degeneration of ascending catecholaminergic systems occur early in the neurodegenerative process. Age and the duration of a pro-inflammatory environment induced by continuous intraventricular lipopolysaccharide (LPS) differentially affect the expression profile of pro- and anti-inflammatory genes and proteins as well as the number of activated microglia (express major histocompatibility complex II; MHC II) and the integrity and density of ascending catecholaminergic neural systems originating from the locus coeruleus (LC) and substantia nigra pars compacta (SNpc) in rats. LPS infusion increased gene expression and/or protein levels for both pro- and anti-inflammatory biomarkers. Although LPS infusion stimulated a robust increase in IL-1ß gene and protein expression, this increase was blunted with age. LPS infusion also increased the density of activated microglia cells throughout the midbrain and brainstem. Corresponding to the development of a pro-inflammatory environment, LC and SNpc neurons immunopositive for tyrosine-hydroxylase (the rate-limiting synthetic enzyme for dopamine and norepinephrine) decreased in number, along with a decrease in tyrosine-hydroxylase gene expression in the midbrain and/or brainstem region. Our data support the concept that continuous exposure to a pro-inflammatory environment drives exaggerated changes in the production and release of inflammatory mediators that interact with age to impair functional capacity of the SNpc and LC. PMID:24315728

  5. Asynchronous GABA Release Is a Key Determinant of Tonic Inhibition and Controls Neuronal Excitability: A Study in the Synapsin II−/− Mouse

    PubMed Central

    Medrihan, Lucian; Ferrea, Enrico; Greco, Barbara; Baldelli, Pietro; Benfenati, Fabio

    2015-01-01

    Idiopathic epilepsies have frequently been linked to mutations in voltage-gated channels (channelopathies); recently, mutations in several genes encoding presynaptic proteins have been shown to cause epilepsy in humans and mice, indicating that epilepsy can also be considered a synaptopathy. However, the functional mechanisms by which presynaptic dysfunctions lead to hyperexcitability and seizures are not well understood. We show that deletion of synapsin II (Syn II), a presynaptic protein contributing to epilepsy predisposition in humans, leads to a loss of tonic inhibition in mouse hippocampal slices due to a dramatic decrease in presynaptic asynchronous GABA release. We also show that the asynchronous GABA release reduces postsynaptic cell firing, and the parallel impairment of asynchronous GABA release and tonic inhibition results in an increased excitability at both single-neuron and network levels. Restoring tonic inhibition with THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; gaboxadol), a selective agonist of δ subunit-containing GABAA receptors, fully rescues the SynII−/− epileptic phenotype both ex vivo and in vivo. The results demonstrate a causal relationship between the dynamics of GABA release and the generation of tonic inhibition, and identify a novel mechanism of epileptogenesis generated by dysfunctions in the dynamics of release that can be effectively targeted by novel antiepileptic strategies. PMID:24962993

  6. Synaptic excitation and inhibition resulting from direct action of acetylcholine on two types of chemoreceptors on individual amphibian parasympathetic neurones

    PubMed Central

    Hartzell, H. Criss; Kuffler, Stephen W.; Stickgold, Robert; Yoshikami, Doju

    1977-01-01

    1. Synaptic transmission was studied in visually identified parasympathetic ganglion cells that modulate the heart beat of the mudpuppy Necturus maculosus). 2. The brief pulse of acetylcholine (ACh) released from terminals of the vagus nerve after each impulse can produce two distinct post-synaptic responses in individual principal cells of the ganglion: (i) within a milli-second of release, ACh generates a rapid and strong excitatory post-synaptic potential (e.p.s.p.) that normally initiates a post-synaptic impulse; (ii) this excitation is usually followed by a slow hyperpolarizing inhibitory post-synaptic potential (i.p.s.p.) that lasts for several seconds. The magnitude and time course of the i.p.s.p. depends on the frequency and number of vagal stimuli. When the hydrolysis of ACh is inhibited by prostigmine, a train of nerve stimuli may be followed by an i.p.s.p. lasting half a minute or longer. 3. The rapid e.p.s.p. and slow i.p.s.p. result from the direct action of ACh on two different types of chemoreceptors in the post-synaptic membrane of the principal cell. The e.p.s.p. can be preferentially blocked by the nicotinic antagonist dihydro-β-erythroidine (5 × 10-7 M), while the i.p.s.p. is selectively blocked by the muscarinic antagonist atropine (5 × 10-9 M). 4. Potentials resembling nerve-evoked e.p.s.p.s and i.p.s.p.s can be produced by iontophoretic release of ACh from micropipettes onto the post-synaptic membrane. Application of the muscarinic agonist bethanechol generates exclusively inhibitory responses. 5. The reversal potential for the i.p.s.p. is about -105 mV, which is approximately the equilibrium potential for potassium (EK). When the external K+ concentration is altered, the reversal potential for inhibition is shifted to the new value of EK as expected from the Nernst equation. Changes in the external Na+ and Cl- concentrations have no appreciable effect on the reversal potential. Thus, the i.p.s.p. is the result of a conductance increase for

  7. Transcranial magnetic stimulation intensity affects exercise-induced changes in corticomotoneuronal excitability and inhibition and voluntary activation.

    PubMed

    Bachasson, D; Temesi, J; Gruet, M; Yokoyama, K; Rupp, T; Millet, G Y; Verges, Samuel

    2016-02-01

    Transcranial magnetic stimulation (TMS) of the motor cortex during voluntary contractions elicits electrophysiological and mechanical responses in the target muscle. The effect of different TMS intensities on exercise-induced changes in TMS-elicited variables is unknown, impairing data interpretation. This study aimed to investigate TMS intensity effects on maximal voluntary activation (VATMS), motor-evoked potentials (MEPs), and silent periods (SPs) in the quadriceps muscles before, during, and after exhaustive isometric exercise. Eleven subjects performed sets of ten 5-s submaximal isometric quadriceps contractions at 40% of maximal voluntary contraction (MVC) strength until task failure. Three different TMS intensities (I100, I75, I50) eliciting MEPs of 53 ± 6%, 38 ± 5% and 25 ± 3% of maximal compound action potential (Mmax) at 20% MVC were used. MEPs and SPs were assessed at both absolute (40% baseline MVC) and relative (50%, 75%, and 100% MVC) force levels. VATMS was assessed with I100 and I75. When measured at absolute force level, MEP/Mmax increased during exercise at I50, decreased at I100 and remained unchanged at I75. No TMS intensity effect was observed at relative force levels. At both absolute and relative force levels, SPs increased at I100 and remained stable at I75 and I50. VATMS assessed at I75 tended to be lower than at I100. TMS intensity affects exercise-induced changes in MEP/Mmax (only when measured at absolute force level), SPs, and VATMS. These results indicate a single TMS intensity assessing maximal voluntary activation and exercise-induced changes in corticomotoneuronal excitability/inhibition may be inappropriate. PMID:26642805

  8. Corticospinal excitability as a predictor of functional gains at the affected upper limb following robotic training in chronic stroke survivors

    PubMed Central

    Milot, Marie-Hélène; Spencer, Steven J.; Chan, Vicky; Allington, James P.; Klein, Julius; Chou, Cathy; Pearson-Fuhrhop, Kristin; Bobrow, James E.; Reinkensmeyer, David J.; Cramer, Steven C.

    2014-01-01

    Background Robotic training can help improve function of a paretic limb following a stroke, but individuals respond differently to the training. A predictor of functional gains might improve the ability to select those individuals more likely to benefit from robot based therapy. Studies evaluating predictors of functional improvement after a robotic training are scarce. One study has found that white matter tract integrity predicts functional gains following a robotic training of the hand and wrist. Objective Determine the predictive ability of behavioral and brain measures to improve selection of individuals for robotic training. Methods Twenty subjects with chronic stroke participated in an 8-week course of robotic exoskeletal training for the arm. Before training, a clinical evaluation, fMRI, diffusion tensor imaging, and transcranial magnetic stimulation (TMS) were each measured as predictors. Final functional gain was defined as change in the Box and Block Test (BBT). Measures significant in bivariate analysis were fed into a multivariate linear regression model. Results Training was associated with an average gain of 6±5 blocks on the BBT (p<0.0001). Bivariate analysis revealed that lower baseline motor evoked potential (MEP) amplitude on TMS, and lower laterality M1 index on fMRI each significantly correlated with greater BBT change. In the multivariate linear regression analysis, baseline MEP magnitude was the only measure that remained significant. Conclusion Subjects with lower baseline MEP magnitude benefited the most from robotic training of the affected arm. These subjects might have reserve remaining for the training to boost corticospinal excitability, translating into functional gains. PMID:24642382

  9. Developmental exposure to chlorpyrifos and diazinon differentially affect passive avoidance performance and nitric oxide synthase-containing neurons in the basolateral complex of the amygdala.

    PubMed

    Vatanparast, Jafar; Naseh, Maryam; Baniasadi, Mansoureh; Haghdoost-Yazdi, Hashem

    2013-02-01

    Chronic exposure to low doses of organophosphates during brain development can induce persistent neurochemical and behavioral effects. This study sought to determine the long-lasting effects of developmental exposure to chlorpyrifos (CPF) and diazinon (DZN) on passive avoidance (PA) performance and neuronal nitric oxide synthase (nNOS)-containing neurons in the subnuclei within basolateral complex of amygdala (BLC). Developing rats were exposed to daily dose (1mg/kg) of CPF or DZN during gestational days 15-18 and postnatal days (PND) 1-4. PA performance was assessed in young adulthood (PND 60). Brain sections were also processed by NADPH-diaphorase (NADPH-d) and nNOS immunohistochemistry. Gestational exposure to CPF increased NADPH-d(+)/nNOS-immunoreactive (IR) neurons within the basolateral nucleus (BL) and medial paracapsular intercalated cluster, which was along with PA retention impairment in both male and female rats. Prenatal exposure to DZN did not significantly change the number of NADPH-d(+)/nNOS-IR neurons in the BLC while impaired PA retention in females. Postnatal exposure to CPF decreased NADPH-d(+)/NOS-IR neurons in the BL without affecting PA performance. Exposure to DZN during early postnatal period impaired PA retention in both sexes, albeit to a lesser extent in females, and was along with a considerable sex independent reduction of NADPH-d(+)/NOS-IR neurons in all BLC subnuclei. Our data suggest that developmental exposure to apparently subtoxic dose of CPF and DZN elicit long-lasting impairment in PA retention that are associated, but not necessarily correlated with effects on NADPH-d(+)/NOS-IR neurons in BLC of the amygdala. PMID:23219576

  10. Neuropilin 2 deficiency does not affect cortical neuronal viability in response to oxygen-glucose-deprivation and transient middle cerebral artery occlusion.

    PubMed

    Hou, Sheng T; Jiang, Susan X; Slinn, Jacqueline; O'Hare, Michael; Karchewski, Laurie

    2010-04-01

    Neuropilin 2 (NRP2) is a type I transmembrane protein that binds to distinct members of the class III secreted Semaphorin subfamily. NRP2 plays important roles in repulsive axon guidance, angiogenesis and vasculogenesis through partnering with co-receptors such as vascular endothelial growth factor receptors (VEGFRs) during development. Emerging evidence also suggests that NRP2 contributes to injury response and environment changes in adult brains. In this study, we examined the contribution of NRP2 gene to cerebral ischemia-induced brain injury using NRP2 deficient mouse. To our surprise, the lack of NRP2 expression does not affect the outcome of brain injury induced by transient occlusion of the middle cerebral artery (MCAO) in mouse. The cerebral vasculature in terms of the middle cerebral artery anatomy and microvessel density in the cerebral cortex of NRP2 deficient homozygous (NRP2(-/-)) mice are normal and almost identical to those of the heterozygous (NRP2(+/-)) and wild type (NRP2(+/+)) littermates. MCAO (1h) and 24h reperfusion caused a brain infarction of 23% (compared to the contralateral side) in NRP2(-/-) mice, which is not different from those in NRP2(+/- and +/+) mice at 22 and 21%, respectively (n=19, p>0.05). Correspondingly, NRP2(-/-) mouse also showed a similar level of deterioration of neurological functions after stroke compared with their NRP2(+/- and +/+) littermates. Oxygen-glucose-deprivation (OGD) caused a significant neuronal death in NRP2(-/-) cortical neurons, at the level similar to that in NRP(+/+) cortical neurons (72% death in NRP(-/-) neurons vs. 75% death in NRP2(+/+) neurons; n=4; p>0.05). Together, these loss-of-function studies demonstrated that despite of its critical role in neuronal guidance and vascular formation during development, NRP2 expression dose not affect adult brain response to cerebral ischemia. PMID:20036291

  11. Parent-of-origin genetic background affects the transcriptional levels of circadian and neuronal plasticity genes following sleep loss

    PubMed Central

    Tinarelli, Federico; Garcia-Garcia, Celina; Nicassio, Francesco; Tucci, Valter

    2014-01-01

    Sleep homoeostasis refers to a process in which the propensity to sleep increases as wakefulness progresses and decreases as sleep progresses. Sleep is tightly organized around the circadian clock and is regulated by genetic and epigenetic mechanisms. The homoeostatic response of sleep, which is classically triggered by sleep deprivation, is generally measured as a rebound effect of electrophysiological measures, for example delta sleep. However, more recently, gene expression changes following sleep loss have been investigated as biomarkers of sleep homoeostasis. The genetic background of an individual may affect this sleep-dependent gene expression phenotype. In this study, we investigated whether parental genetic background differentially modulates the expression of genes following sleep loss. We tested the progeny of reciprocal crosses of AKR/J and DBA/2J mouse strains and we show a parent-of-origin effect on the expression of circadian, sleep and neuronal plasticity genes following sleep deprivation. Thus, we further explored, by in silico, specific functions or upstream mechanisms of regulation and we observed that several upstream mechanisms involving signalling pathways (i.e. DICER1, PKA), growth factors (CSF3 and BDNF) and transcriptional regulators (EGR2 and ELK4) may be differentially modulated by parental effects. This is the first report showing that a behavioural manipulation (e.g. sleep deprivation) in adult animals triggers specific gene expression responses according to parent-of-origin genomic mechanisms. Our study suggests that the same mechanism may be extended to other behavioural domains and that the investigation of gene expression following experimental manipulations should take seriously into account parent-of-origin effects. PMID:24446504

  12. Effects of Morphology Constraint on Electrophysiological Properties of Cortical Neurons

    PubMed Central

    Zhu, Geng; Du, Liping; Jin, Lei; Offenhäusser, Andreas

    2016-01-01

    There is growing interest in engineering nerve cells in vitro to control architecture and connectivity of cultured neuronal networks or to build neuronal networks with predictable computational function. Pattern technologies, such as micro-contact printing, have been developed to design ordered neuronal networks. However, electrophysiological characteristics of the single patterned neuron haven’t been reported. Here, micro-contact printing, using polyolefine polymer (POP) stamps with high resolution, was employed to grow cortical neurons in a designed structure. The results demonstrated that the morphology of patterned neurons was well constrained, and the number of dendrites was decreased to be about 2. Our electrophysiological results showed that alterations of dendritic morphology affected firing patterns of neurons and neural excitability. When stimulated by current, though both patterned and un-patterned neurons presented regular spiking, the dynamics and strength of the response were different. The un-patterned neurons exhibited a monotonically increasing firing frequency in response to injected current, while the patterned neurons first exhibited frequency increase and then a slow decrease. Our findings indicate that the decrease in dendritic complexity of cortical neurons will influence their electrophysiological characteristics and alter their information processing activity, which could be considered when designing neuronal circuitries. PMID:27052791

  13. Effects of Morphology Constraint on Electrophysiological Properties of Cortical Neurons

    NASA Astrophysics Data System (ADS)

    Zhu, Geng; Du, Liping; Jin, Lei; Offenhäusser, Andreas

    2016-04-01

    There is growing interest in engineering nerve cells in vitro to control architecture and connectivity of cultured neuronal networks or to build neuronal networks with predictable computational function. Pattern technologies, such as micro-contact printing, have been developed to design ordered neuronal networks. However, electrophysiological characteristics of the single patterned neuron haven’t been reported. Here, micro-contact printing, using polyolefine polymer (POP) stamps with high resolution, was employed to grow cortical neurons in a designed structure. The results demonstrated that the morphology of patterned neurons was well constrained, and the number of dendrites was decreased to be about 2. Our electrophysiological results showed that alterations of dendritic morphology affected firing patterns of neurons and neural excitability. When stimulated by current, though both patterned and un-patterned neurons presented regular spiking, the dynamics and strength of the response were different. The un-patterned neurons exhibited a monotonically increasing firing frequency in response to injected current, while the patterned neurons first exhibited frequency increase and then a slow decrease. Our findings indicate that the decrease in dendritic complexity of cortical neurons will influence their electrophysiological characteristics and alter their information processing activity, which could be considered when designing neuronal circuitries.

  14. Effects of Morphology Constraint on Electrophysiological Properties of Cortical Neurons.

    PubMed

    Zhu, Geng; Du, Liping; Jin, Lei; Offenhäusser, Andreas

    2016-01-01

    There is growing interest in engineering nerve cells in vitro to control architecture and connectivity of cultured neuronal networks or to build neuronal networks with predictable computational function. Pattern technologies, such as micro-contact printing, have been developed to design ordered neuronal networks. However, electrophysiological characteristics of the single patterned neuron haven't been reported. Here, micro-contact printing, using polyolefine polymer (POP) stamps with high resolution, was employed to grow cortical neurons in a designed structure. The results demonstrated that the morphology of patterned neurons was well constrained, and the number of dendrites was decreased to be about 2. Our electrophysiological results showed that alterations of dendritic morphology affected firing patterns of neurons and neural excitability. When stimulated by current, though both patterned and un-patterned neurons presented regular spiking, the dynamics and strength of the response were different. The un-patterned neurons exhibited a monotonically increasing firing frequency in response to injected current, while the patterned neurons first exhibited frequency increase and then a slow decrease. Our findings indicate that the decrease in dendritic complexity of cortical neurons will influence their electrophysiological characteristics and alter their information processing activity, which could be considered when designing neuronal circuitries. PMID:27052791

  15. Deep mRNA Sequencing of the Tritonia diomedea Brain Transcriptome Provides Access to Gene Homologues for Neuronal Excitability, Synaptic Transmission and Peptidergic Signalling

    PubMed Central

    Senatore, Adriano; Edirisinghe, Neranjan; Katz, Paul S.

    2015-01-01

    Background The sea slug Tritonia diomedea (Mollusca, Gastropoda, Nudibranchia), has a simple and highly accessible nervous system, making it useful for studying neuronal and synaptic mechanisms underlying behavior. Although many important contributions have been made using Tritonia, until now, a lack of genetic information has impeded exploration at the molecular level. Results We performed Illumina sequencing of central nervous system mRNAs from Tritonia, generating 133.1 million 100 base pair, paired-end reads. De novo reconstruction of the RNA-Seq data yielded a total of 185,546 contigs, which partitioned into 123,154 non-redundant gene clusters (unigenes). BLAST comparison with RefSeq and Swiss-Prot protein databases, as well as mRNA data from other invertebrates (gastropod molluscs: Aplysia californica, Lymnaea stagnalis and Biomphalaria glabrata; cnidarian: Nematostella vectensis) revealed that up to 76,292 unigenes in the Tritonia transcriptome have putative homologues in other databases, 18,246 of which are below a more stringent E-value cut-off of 1x10-6. In silico prediction of secreted proteins from the Tritonia transcriptome shotgun assembly (TSA) produced a database of 579 unique sequences of secreted proteins, which also exhibited markedly higher expression levels compared to other genes in the TSA. Conclusions Our efforts greatly expand the availability of gene sequences available for Tritonia diomedea. We were able to extract full length protein sequences for most queried genes, including those involved in electrical excitability, synaptic vesicle release and neurotransmission, thus confirming that the transcriptome will serve as a useful tool for probing the molecular correlates of behavior in this species. We also generated a neurosecretome database that will serve as a useful tool for probing peptidergic signalling systems in the Tritonia brain. PMID:25719197

  16. Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43.

    PubMed

    Koyama, Akihide; Sugai, Akihiro; Kato, Taisuke; Ishihara, Tomohiko; Shiga, Atsushi; Toyoshima, Yasuko; Koyama, Misaki; Konno, Takuya; Hirokawa, Sachiko; Yokoseki, Akio; Nishizawa, Masatoyo; Kakita, Akiyoshi; Takahashi, Hitoshi; Onodera, Osamu

    2016-07-01

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons-especially neurons with mislocalized TDP-43-the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS. PMID:27257061

  17. [Sound duration and sound pattern affect the recovery cycles of inferior collicular neurons in leaf-nosed bat, Hipposideros armiger].

    PubMed

    Tang, Jia; Fu, Zi-Ying; Wu, Fei-Jian

    2010-10-25

    The effects of sound duration and sound pattern on the recovery cycles of inferior collicular (IC) neurons in constant frequency-frequency modulation (CF-FM) bats were explored in this study. Five leaf-nosed bats, Hipposideros armiger (4 males, 1 female, 43-50 g body weight), were used as subjects. The extracellular responses of IC neurons to paired sound stimuli with different duration and patterns were recorded, and the recovery was counted as the ratio of the second response to the first response. Totally, 169 sound-sensitive IC neurons were recorded in the experiment. According to the interpulse interval (IPI) of paired sounds when neurons reached 50% recovery (50% IPI), the recovery cycles of these IC neurons were classified into 3 types: fast recovery (F, the 50% IPI was less than 15 ms), short recovery (S, the 50% IPI was between 15.1 and 30 ms) and long recovery (L, the 50% IPI was more than 30 ms). When paired CF stimuli with 2 ms duration was used, the ratio of F neurons was 32.3%, and it decreased to 18.1% and 18.2% respectively when 5 and 7 ms CF stimuli were used. The ratios of S and L neurons were 41.5%, 33.7%, 29.1% and 26.2%, 48.2%, 52.7% respectively when 2, 5 and 7 ms CF stimuli were used. The average 50% IPI determined after stimulation with paired 2 ms, 5 ms and 7 ms CF sounds were (30.2 ± 27.6), (39.9 ± 29.1) and (49.4 ± 34.7) ms, respectively, and the difference among them was significant (P< 0.01). When the stimuli of paired 2 ms CF sounds were shifted to paired 2 ms FM sounds, the proportion of F, S and L neurons changed from 32.3%, 41.5%, 26.2% to 47.7%, 24.6%, 27.7%, respectively, and the average 50% IPI decreased from (30.2 ± 27.6) to (23.9 ± 19.0) ms (P< 0.05, n = 65). When paired 5+2 ms CF-FM pulses were used instead of 7 ms CF sounds, the proportion of F, S and L neurons changed from 18.2%, 29.1%, 52.7% to 29.1%, 27.3%, 43.6%, respectively, and the average 50% IPI decreased from (49.4 ± 34.7) to (36.3 ± 29.4) ms (P< 0.05, n = 55

  18. Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43

    PubMed Central

    Koyama, Akihide; Sugai, Akihiro; Kato, Taisuke; Ishihara, Tomohiko; Shiga, Atsushi; Toyoshima, Yasuko; Koyama, Misaki; Konno, Takuya; Hirokawa, Sachiko; Yokoseki, Akio; Nishizawa, Masatoyo; Kakita, Akiyoshi; Takahashi, Hitoshi; Onodera, Osamu

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons—especially neurons with mislocalized TDP-43—the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS. PMID:27257061

  19. Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the subcellular distribution of corticotropin releasing factor receptors

    PubMed Central

    Retson, T. A.; Reyes, B.A.; Van Bockstaele, E. J.

    2014-01-01

    Understanding the neurobiological bases for sex differences in alcohol dependence is needed to help guide the development of individualized therapies for alcohol abuse disorders. In the present study, alcohol-induced adaptations in (1) anxiety-like behavior, (2) patterns of c-Fos activation and (3) subcellular distribution of corticotropin releasing factor receptor in locus coeruleus (LC) neurons was investigated in male and female Sprague-Dawley rats that were chronically exposed to ethanol using a liquid diet. Results confirm and extend reports by others showing that chronic ethanol exposure produces an anxiogenic-like response in both male and female subjects. Ethanol-induced sex differences were observed with increased c-Fos expression in LC neurons of female ethanol-treated subjects compared to controls or male subjects. Results also reveal sex differences in the subcellular distribution of the CRFr in LC-noradrenergic neurons with female subjects exposed to ethanol exhibiting a higher frequency of plasmalemmal CRFrs. These adaptations have implications for LC neuronal activity and its neural targets across the sexes. Considering the important role of the LC in ethanol-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis, the present results indicate important sex differences in feed-forward regulation of the HPA axis that may render alcohol dependent females more vulnerable to subsequent stress exposure. PMID:25149913

  20. HMGB4 is expressed by neuronal cells and affects the expression of genes involved in neural differentiation.

    PubMed

    Rouhiainen, Ari; Zhao, Xiang; Vanttola, Päivi; Qian, Kui; Kulesskiy, Evgeny; Kuja-Panula, Juha; Gransalke, Kathleen; Grönholm, Mikaela; Unni, Emmanual; Meistrich, Marvin; Tian, Li; Auvinen, Petri; Rauvala, Heikki

    2016-01-01

    HMGB4 is a new member in the family of HMGB proteins that has been characterized in sperm cells, but little is known about its functions in somatic cells. Here we show that HMGB4 and the highly similar rat Transition Protein 4 (HMGB4L1) are expressed in neuronal cells. Both proteins had slow mobility in nucleus of living NIH-3T3 cells. They interacted with histones and their differential expression in transformed cells of the nervous system altered the post-translational modification statuses of histones in vitro. Overexpression of HMGB4 in HEK 293T cells made cells more susceptible to cell death induced by topoisomerase inhibitors in an oncology drug screening array and altered variant composition of histone H3. HMGB4 regulated over 800 genes in HEK 293T cells with a p-value ≤0.013 (n = 3) in a microarray analysis and displayed strongest association with adhesion and histone H2A -processes. In neuronal and transformed cells HMGB4 regulated the expression of an oligodendrocyte marker gene PPP1R14a and other neuronal differentiation marker genes. In conclusion, our data suggests that HMGB4 is a factor that regulates chromatin and expression of neuronal differentiation markers. PMID:27608812

  1. SCM-198 Ameliorates Cognitive Deficits, Promotes Neuronal Survival and Enhances CREB/BDNF/TrkB Signaling without Affecting Aβ Burden in AβPP/PS1 Mice

    PubMed Central

    Hong, Zhen-Yi; Yu, Shuang-Shuang; Wang, Zhi-Jun; Zhu, Yi-Zhun

    2015-01-01

    SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson’s disease and Alzheimer’s disease (AD). In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-β protein precursor and presenilin-1(AβPP/PS1) double-transgenic mice without affecting amyloid-β (Aβ) burden. In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future. PMID:26262618

  2. Beta-blocker migraine prophylaxis affects the excitability of the visual cortex as revealed by transcranial magnetic stimulation.

    PubMed

    Gerwig, Marcus; Niehaus, L; Stude, P; Katsarava, Z; Diener, H C

    2012-01-01

    The objective of this study is to assess effects of beta-blocker migraine prophylaxis on cortical excitability determined by transcranial magnetic stimulation (TMS). Phosphene and motor thresholds (PT, MT) were investigated in 29 patients with migraine, in 15 of them prior to and following preventive medication with metoprolol and in 14 patients without prophylaxis. Following prophylaxis headache frequency significantly decreased (p = 0.005) and mean PT were significantly increased (51.5 ± 7.5 vs. 63.6 ± 8.4%) compared to patients without preventive treatment (53.7 ± 5.3 vs. 52.3 ± 6.3%; p = 0.040). Mean MT did not significantly differ either between groups or due to treatment. In the group of all patients, a significant inverse correlation between headache frequency and the level of PT was found (R = -0.629; p < 0.01). There was, however, no significant correlation in the subgroups of patients. We conclude that (a) clinical efficacy of beta-blocker treatment in migraine could be (at least partly) linked to its ability to modulate the excitability of the visual cortex and (b) the PT determined by TMS appears suitable to assess the effects of prophylaxis on cortical excitability in the individual patient. This may be useful in clinical trials investigating migraine preventive drugs. PMID:22089539

  3. The excitability and rhythm of medullary respiratory neurons in the cat are altered by the serotonin receptor agonist 5-methoxy-N,N, dimethyltryptamine.

    PubMed

    Lalley, P M

    1994-06-13

    5-Methoxy-N,N-dimethyltryptamine (5-MeODMT) is an indolealkylamine which has agonist activity at 5HT receptors. In the present investigation, 5-MeODMT had two types of effects on medullary respiratory neurons of the cat. Iontophoretic administration or i.v. doses (43 +/- 8.9 micrograms/kg) of 5-MeODMT hyperpolarized respiratory neurons and severely reduced action potential discharges. Cinanserin, a 5HT-2/1 c receptor antagonist, when injected i.v. reduced the inhibition produced by i.v. injection of 5-MeODMT. Iontophoresis of cinanserin did not antagonize inhibition produced by iontophoresis of 5-MeODMT or 5-HT. The depression of respiratory discharge by i.v. injection of 5-MeODMT is attributed to presynaptic effects (network depression) and post-synaptic activation of 5HT-1A receptors on respiratory neurons. 5-MeODMT (27 +/- 2.78 micrograms/kg i.v.) also increased discharge frequency of inspiratory and expiratory neurons. Inspiratory neuron discharges were briefer and expiratory neuron discharges occurred earlier in relation to phrenic nerve activity. It is suggested that the effects of the smaller doses are due to binding of 5-MeODMT to 5HT-1A receptors on early inspiratory neurons of the medulla. PMID:7922531

  4. Chronic inflammation and estradiol interact through MAPK activation to affect TMJ nociceptive processing by trigeminal caudalis neurons.

    PubMed

    Tashiro, A; Okamoto, K; Bereiter, D A

    2009-12-29

    The mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway plays a key role in mediating estrogen actions in the brain and neuronal sensitization during inflammation. Estrogen status is a risk factor in chronic temporomandibular muscle/joint (TMJ) disorders; however, the basis for this relationship is not known. The present study tested the hypothesis that estrogen status acts through the MAPK/ERK signaling pathway to alter TMJ nociceptive processing. Single TMJ-responsive neurons were recorded in laminae I-II at the spinomedullary (Vc/C(1-2)) junction in naïve ovariectomized (OvX) female rats treated for 2 days with high-dose (20 microg/day; HE2) or low-dose estradiol (2 microg/day; LE2) and after chronic inflammation of the TMJ region by complete Freund's adjuvant for 12-14 days. Intra-TMJ injection of ATP (1 mM) was used to activate Vc/C(1-2) neurons. The MAPK/ERK inhibitor (PD98059, 0.01-1 mM) was applied topically to the dorsal Vc/C(1-2) surface at the site of recording 10 min prior to each ATP stimulus. In naïve HE2 rats, low-dose PD98059 caused a maximal inhibition of ATP-evoked activity, whereas even high doses had only minor effects on units in LE2 rats. By contrast, after chronic TMJ inflammation, PD98059 produced a marked and similar dose-related inhibition of ATP-evoked activity in HE2 and LE2 rats. These results suggested that E2 status and chronic inflammation acted, at least in part, through a common MAPK/ERK-dependent signaling pathway to enhance TMJ nociceptive processing by laminae I-II neurons at the spinomedullary junction region. PMID:19786077

  5. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.

    PubMed

    Huffaker, Stephen J; Chen, Jingshan; Nicodemus, Kristin K; Sambataro, Fabio; Yang, Feng; Mattay, Venkata; Lipska, Barbara K; Hyde, Thomas M; Song, Jian; Rujescu, Dan; Giegling, Ina; Mayilyan, Karine; Proust, Morgan J; Soghoyan, Armen; Caforio, Grazia; Callicott, Joseph H; Bertolino, Alessandro; Meyer-Lindenberg, Andreas; Chang, Jay; Ji, Yuanyuan; Egan, Michael F; Goldberg, Terry E; Kleinman, Joel E; Lu, Bai; Weinberger, Daniel R

    2009-05-01

    Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K(+) channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K(+) current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target. PMID:19412172

  6. Altered neuronal gene expression in brain regions differentially affected by Alzheimer’s disease: a reference data set

    PubMed Central

    Liang, Winnie S.; Dunckley, Travis; Beach, Thomas G.; Grover, Andrew; Mastroeni, Diego; Ramsey, Keri; Caselli, Richard J.; Kukull, Walter A.; McKeel, Daniel; Morris, John C.; Hulette, Christine M.; Schmechel, Donald; Reiman, Eric M.; Rogers, Joseph; Stephan, Dietrich A.

    2009-01-01

    Alzheimer’s Disease (AD) is the most widespread form of dementia during the later stages of life. If improved therapeutics are not developed, the prevalence of AD will drastically increase in the coming years as the world’s population ages. By identifying differences in neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand the molecular mechanisms that drive AD pathogenesis, including the formation of amyloid plaques and neurofibrillary tangles. In this study, we expression profiled histopathologically normal cortical neurons collected with laser capture microdissection (LCM) from six anatomically and functionally discrete postmortem brain regions in 34 AD-afflicted individuals, using Affymetrix Human Genome U133 Plus 2.0 microarrays. These regions include the entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus, and primary visual cortex. This study is predicated on previous parallel research on the postmortem brains of the same six regions in 14 healthy elderly individuals, for which LCM neurons were similarly processed for expression analysis. We identified significant regional differential expression in AD brains compared with control brains including expression changes of genes previously implicated in AD pathogenesis, particularly with regards to tangle and plaque formation. Pinpointing the expression of factors that may play a role in AD pathogenesis provides a foundation for future identification of new targets for improved AD therapeutics. We provide this carefully phenotyped, laser capture microdissected intraindividual brain region expression data set to the community as a public resource. PMID:18270320

  7. Inhibition of neuronal and inducible nitric oxide synthase does not affect the analgesic effects of NMDA antagonists in visceral inflammatory pain.

    PubMed

    Srebro, Dragana; Vučković, Sonja; Prostran, Milica

    2016-01-01

    Previously we described the antinociceptive effect of magnesium sulfate and dizocilpine (MK-801) in the visceral and somatic rat models of pain. In the somatic model of pain, we established the influence of selective inhibitors of neuronal and inducible nitric oxide synthase on the antihyperalgesic effects of magnesium sulfate and dizocilpine. Therefore, the objective of the present study was to determine in the rat model of visceral pain whether same mechanisms are involved in the antinociceptive action of magnesium sulfate and dizocilpine. Analgesic activity was assessed using the acetic acid-induced writhing test in rats. Subcutaneous injection of either magnesium sulfate (15 mg/kg) or dizocilpine (0.01 mg/kg) decreased the number of writhes by about 60 and 70%, respectively. The role of nitric oxide on the effects of magnesium sulfate and dizocilpine was evaluated using selective inhibitor of neuronal (N-ω-Propyl-L-arginine hydrochloride (L-NPA)) and inducible (S-methylisothiourea (SMT)) nitric oxide synthase, which per se did not affect the number of writhes. We observed that the antinociceptive effect of magnesium sulfate or dizocilpine did not change in the presence of L-NPA (2 and 10 mg/kg, i.p.) and SMT (0.015 and 10 mg/kg, i.p.). We conclude that, nitric oxide produced by neuronal and inducible nitric oxide synthase does not modulate the effects of magnesium sulfate and dizocilpine in the visceral inflammatory model of pain in the rat. PMID:27373948

  8. Arsenic affects expression and processing of amyloid precursor protein (APP) in primary neuronal cells overexpressing the Swedish mutation of human APP.

    PubMed

    Zarazúa, Sergio; Bürger, Susanne; Delgado, Juan M; Jiménez-Capdeville, Maria E; Schliebs, Reinhard

    2011-06-01

    Arsenic poisoning due to contaminated water and soil, mining waste, glass manufacture, select agrochemicals, as well as sea food, affects millions of people world wide. Recently, an involvement of arsenic in Alzheimer's disease (AD) has been hypothesized (Gong and O'Bryant, 2010). The present study stresses the hypothesis whether sodium arsenite, and its main metabolite, dimethylarsinic acid (DMA), may affect expression and processing of the amyloid precursor protein (APP), using the cholinergic cell line SN56.B5.G4 and primary neuronal cells overexpressing the Swedish mutation of APP, as experimental approaches. Exposure of cholinergic SN56.B5.G4 cells with either sodium arsenite or DMA decreased cell viability in a concentration- and exposure-time dependent manner, and affected the activities of the cholinergic enzymes acetylcholinesterase and choline acetyltransferase. Both sodium arsenite and DMA exposure of SN56.B5.G4 cells resulted in enhanced level of APP, and sAPP in the membrane and cytosolic fractions, respectively. To reveal any effect of arsenic on APP processing, the amounts of APP cleavage products, sAPPβ, and β-amyloid (Aβ) peptides, released into the culture medium of primary neuronal cells derived from transgenic Tg2576 mice, were assessed by ELISA. Following exposure of neuronal cells by sodium arsenite for 12h, the membrane-bound APP level was enhanced, the amount of sAPPβ released into the culture medium was slightly higher, while the levels of Aβ peptides in the culture medium were considerably lower as compared to that assayed in the absence of any drug. The sodium arsenite-induced reduction of Aβ formation suggests an inhibition of the APP γ-cleavage step by arsenite. In contrast, DMA exposure of neuronal cells considerably increased formation of Aβ and sAPPβ, accompanied by enhanced membrane APP level. The DMA-induced changes in APP processing may be the result of the enhanced APP expression. Alternatively, increased Aβ production

  9. Feedforward and Feedback inhibition in Neostriatal GABAergic Spiny Neurons

    PubMed Central

    Tepper, James M.; Wilson, Charles J.; Koós, Tibor

    2008-01-01

    There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of

  10. Amitriptyline and carbamazepine utilize voltage-gated ion channel suppression to impair excitability of sensory dorsal horn neurons in thin tissue slice: An in vitro study.

    PubMed

    Wolff, Matthias; Czorlich, Patrick; Nagaraj, Chandran; Schnöbel-Ehehalt, Rose; Li, Yingji; Kwapiszewska, Grazyna; Olschewski, Horst; Heschl, Stefan; Olschewski, Andrea

    2016-08-01

    Amitriptyline, carbamazepine and gabapentin are often used for the treatment of neuropathic pain. However, their analgesic action on central sensory neurons is still not fully understood. Moreover, the expression pattern of their target ion channels is poorly elucidated in the dorsal horn of the spinal cord. Thus, we performed patch-clamp investigations in visualized neurons of lamina I-III of the spinal cord. The expression of the different voltage-gated ion channels, as the targets of these drugs, was detected by RT-PCR and immunohistochemistry. Neurons of the lamina I-III express the TTX-sensitive voltage-gated Na(+) as well as voltage-gated K(+) subunits assembling the fast inactivating (A-type) currents and the delayed rectifier K(+) currents. Our pharmacological studies show that tonically-firing, adapting-firing and single spike neurons responded dose-dependently to amitriptyline and carbamazepine. The ion channel inhibition consecutively reduced the firing rate of tonically-firing and adapting-firing neurons. This study provides evidence for the distribution of voltage-gated Na(+) and K(+) subunits in lamina I-III of the spinal cord and for the action of drugs used for the treatment of neuropathic pain. Our work confirms that modulation of voltage-gated ion channels in the central nervous system contributes to the antinociceptive effects of these drugs. PMID:26945616

  11. Tityus bahiensis toxin IV-5b selectively affects Na channel inactivation in chick dorsal root ganglion neurons.

    PubMed

    Trequattrini, C; Zamudio, F Z; Petris, A; Prestipino, G; Possani, L D; Franciolini, F

    1995-09-01

    A novel toxin was isolated from the venom of the Brazilian scorpion Tityus (T.) bahiensis. The N-terminal amino acid sequence of this toxin was shown to be 80% identical to the corresponding segment of T. serrulatus toxin IV-5. The new toxin was thus named toxin IV-5b. Toxin IV-5b was found to markedly slow inactivation of Na channel in dorsal root ganglion neurons from chick embryo. By contrast, Na channel activation was only negligibly delayed, and deactivation completely unaffected. Similarly unaffected by the toxin were K and Ca currents. The slowing effect of the toxin starts to appear at concentrations of c. 80 nM, and shows a KD of 143 nM. With a toxin concentration of 2.4 microM, the Na channel inactivation time constant was increased c. 3-fold with respect to the control. The slowing of inactivation was voltage dependent, and increased with depolarization. PMID:7553331

  12. Local knockdown of the NaV1.6 sodium channel reduces pain behaviors, sensory neuron excitability, and sympathetic sprouting in rat models of neuropathic pain.

    PubMed

    Xie, W; Strong, J A; Zhang, J-M

    2015-04-16

    In the spinal nerve ligation (SNL) model of neuropathic pain, as in other pain models, abnormal spontaneous activity of myelinated sensory neurons occurs early and is essential for establishing pain behaviors and other pathologies. Sympathetic sprouting into the dorsal root ganglion (DRG) is observed after SNL, and sympathectomy reduces pain behavior. Sprouting and spontaneous activity may be mutually reinforcing: blocking neuronal activity reduces sympathetic sprouting, and sympathetic spouts functionally increase spontaneous activity in vitro. However, most studies in this field have used nonspecific methods to block spontaneous activity, methods that also block evoked and normal activity. In this study, we injected small inhibitory (si) RNA directed against the NaV1.6 sodium channel isoform into the DRG before SNL. This isoform can mediate high-frequency repetitive firing, like that seen in spontaneously active neurons. Local knockdown of NaV1.6 markedly reduced mechanical pain behaviors induced by SNL, reduced sympathetic sprouting into the ligated sensory ganglion, and blocked abnormal spontaneous activity and other measures of hyperexcitability in myelinated neurons in the ligated sensory ganglion. Immunohistochemical experiments showed that sympathetic sprouting preferentially targeted NaV1.6-positive neurons. Under these experimental conditions, NaV1.6 knockdown did not prevent or strongly alter single evoked action potentials, unlike previous less specific methods used to block spontaneous activity. NaV1.6 knockdown also reduced pain behaviors in another pain model, chronic constriction of the sciatic nerve, provided the model was modified so that the lesion site was relatively close to the siRNA-injected lumbar DRGs. The results highlight the relative importance of abnormal spontaneous activity in establishing both pain behaviors and sympathetic sprouting, and suggest that the NaV1.6 isoform may have value as a therapeutic target. PMID:25686526

  13. Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1

    PubMed Central

    Brew, Helen M; Hallows, Janice L; Tempel, Bruce L

    2003-01-01

    A low voltage-activated potassium current, IKL, is found in auditory neuron types that have low excitability and precisely preserve the temporal pattern of activity present in their presynaptic inputs. The gene Kcnal codes for Kv1.1 potassium channel subunits, which combine in expression systems to produce channel tetramers with properties similar to those of IKL, including sensitivity to dendrotoxin (DTX). Kv1.1 is strongly expressed in neurons with IKL, including auditory neurons of the medial nucleus of the trapezoid body (MNTB). We therefore decided to investigate how the absence of Kv1.1 affected channel properties and function in MNTB neurons from mice lacking Kcnal. We used the whole cell version of the patch clamp technique to record from MNTB neurons in brainstem slices from Kcnal-null (−/−) mice and their wild-type (+/+) and heterozygous (+/−) littermates. There was an IKL in voltage-clamped −/− MNTB neurons, but it was about half the amplitude of the IKL in +/+ neurons, with otherwise similar properties. Consistent with this, −/− MNTB neurons were more excitable than their +/+ counterparts; they fired more than twice as many action potentials (APs) during current steps, and the threshold current amplitude required to generate an AP was roughly halved. +/− MNTB neurons had excitability and IKL amplitudes identical to the +/+ neurons. The IKL remaining in −/− neurons was blocked by DTX, suggesting the underlying channels contained subunits Kv1.2 and/or Kv1.6 (also DTX-sensitive). DTX increased excitability further in the already hyperexcitable −/− MNTB neurons, suggesting that −/−IKL limited excitability despite its reduced amplitude in the absence of Kv1.1 subunits. PMID:12611922

  14. Serotonin type-1D receptor stimulation of A-type K(+) channel decreases membrane excitability through the protein kinase A- and B-Raf-dependent p38 MAPK pathways in mouse trigeminal ganglion neurons.

    PubMed

    Zhao, Xianyang; Zhang, Yuan; Qin, Wenjuan; Cao, Junping; Zhang, Yi; Ni, Jianqiang; Sun, Yangang; Jiang, Xinghong; Tao, Jin

    2016-08-01

    Although recent studies have implicated serotonin 5-HT1B/D receptors in the nociceptive sensitivity of primary afferent neurons, the underlying molecular and cellular mechanisms remain unclear. In this study, we identified a novel functional role of the 5-HT1D receptor subtype in regulating A-type potassium (K(+)) currents (IA) as well as membrane excitability in small trigeminal ganglion (TG) neurons. We found that the selective activation of 5-HT1D, rather than 5-HT1B, receptors reversibly increased IA, while the sustained delayed rectifier K(+) current was unaffected. The 5-HT1D-mediated IA increase was associated with a depolarizing shift in the voltage dependence of inactivation. Blocking G-protein signaling with pertussis toxin or by intracellular application of a selective antibody raised against Gαo or Gβ abolished the 5-HT1D effect on IA. Inhibition of protein kinase A (PKA), but not of phosphatidylinositol 3-kinase or protein kinase C, abolished the 5-HT1D-mediated IA increase. Analysis of phospho-p38 (p-p38) revealed that activation of 5-HT1D, but not 5-HT1B, receptors significantly activated p38, while p-ERK and p-JNK were unaffected. The p38 MAPK inhibitor SB203580, but not its inactive analogue SB202474, and inhibition of B-Raf blocked the 5-HT1D-mediated IA response. Functionally, we observed a significantly decreased action potential firing rate induced by the 5-HT1D receptors; pretreatment with 4-aminopyridine abolished this effect. Taken together, these results suggest that the activation of 5-HT1D receptors selectively enhanced IA via the Gβγ of the Go-protein, PKA, and the sequential B-Raf-dependent p38 MAPK signaling cascade. This 5-HT1D receptor effect may contribute to neuronal hypoexcitability in small TG neurons. PMID:27156838

  15. Acute Stress Facilitates Trace Eyeblink Conditioning in C57BL/6 Male Mice and Increases the Excitability of Their CA1 Pyramidal Neurons

    ERIC Educational Resources Information Center

    Weiss, Craig; Sametsky, Evgeny; Sasse, Astrid; Spiess, Joachim; Disterhoft, John F.

    2005-01-01

    The effects of stress (restraint plus tail shock) on hippocampus-dependent trace eyeblink conditioning and hippocampal excitability were examined in C57BL/6 male mice. The results indicate that the stressor significantly increased the concentration of circulating corticosterone, the amount and rate of learning relative to nonstressed conditioned…

  16. Lateral spike conduction velocity in the visual cortex affects spatial range of synchronization and receptive field size without visual experience: a learning model with spiking neurons.

    PubMed

    Saam, M; Eckhorn, R

    2000-07-01

    Classical receptive fields (cRF) increase in size from the retina to higher visual centers. The present work shows how temporal properties, in particular lateral spike velocity and spike input correlation, can affect cRF size and position without visual experience. We demonstrate how these properties are related to the spatial range of cortical synchronization if Hebbian learning dominates early development. For this, a largely reduced model of two successive levels of the visual cortex is developed (e.g., areas V1 and V2). It consists of retinotopic networks of spiking neurons with constant spike velocity in lateral connections. Feedforward connections between level 1 and 2 are additive and determine cRF size and shape, while lateral connections within level 1 are modulatory and affect the cortical range of synchronization. Input during development is mimicked by spike trains with spatially homogeneous properties and a confined temporal correlation width. During learning, the homogeneous lateral coupling shrinks to limited coupling structures defining synchronization and related association fields (AF). The size of level-1 synchronization fields determines the lateral coupling range of developing level-1-to-2 connections and, thus, the size of level-2 cRFs, even if the feedforward connections have distance-independent delays. AFs and cRFs increase with spike velocity in the lateral network and temporal correlation width of the input. Our results suggest that AF size of V1 and cRF size of V2 neurons are confined during learning by the temporal width of input correlations and the spike velocity in lateral connections without the need of visual experience. During learning from visual experience, a similar influence of AF size on the cRF size may be operative at successive levels of processing, including other parts of the visual system. PMID:10933233

  17. Alcohol Affects Neuronal Substrates of Response Inhibition but Not of Perceptual Processing of Stimuli Signalling a Stop Response

    PubMed Central

    Nikolaou, Kyriaki; Critchley, Hugo; Duka, Theodora

    2013-01-01

    Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits

  18. Lower motor neuron dysfunction in ALS.

    PubMed

    de Carvalho, Mamede; Swash, Michael

    2016-07-01

    In the motor system there is a complex interplay between cortical structures and spinal cord lower motor neurons (LMN). In this system both inhibitory and excitatory neurons have relevant roles. LMN loss is a marker of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Conventional needle electromyography (EMG) does not allow LMN loss to be quantified. Measurement of compound muscle action potential (CMAP) amplitude or area, and the neurophysiological index, provide a surrogate estimate of the number of functional motor units. Increased motor neuronal excitability is a neurophysiological marker of ALS in the context of a suspected clinical and electrophysiological diagnosis. In the LMN system, fasciculation potentials (FPs) are the earliest changes observed in affected muscles, a feature of LMN hyperexcitability. Reinnervation is best investigated by needle EMG although other methods can be explored. Moreover needle EMG give information about the temporal profile of the reinnervation process, important ancillary data. Quantitative motor unit potential analysis is a valuable method of evaluating reinnervation. The importance of FPs has been recognized in the Awaji criteria for the electrodiagnosis of ALS, criteria that are a sensitive adjunct to the revised El Escorial criteria. Finally, functionality of LMN's, and perhaps excitability studies in motor nerves, aids understanding of the disease process, allowing measurement of potential treatment effects in clinical trials. Other investigational techniques, such as electrical impedance myography, muscle and nerve ultrasound, and spinal cord imaging methods may prove useful in future. PMID:27117334

  19. White-light-exciting, layer-by-layer-assembled ZnCdHgSe quantum dots/polymerized ionic liquid hybrid film for highly sensitive photoelectrochemical immunosensing of neuron specific enolase.

    PubMed

    Yu, Xiangyang; Wang, Yanying; Chen, Xuemin; Wu, Kangbing; Chen, Danchao; Ma, Ming; Huang, Zhenjia; Wu, Wangze; Li, Chunya

    2015-04-21

    ZnCdHgSe quantum dots (QDs) functionalized with N-acetyl-l-cysteine were synthesized and characterized. Through layer-by-layer assembling, the ZnCdHgSe QDs was integrated with a polymerized 1-decyl-3-[3-pyrrole-1-yl-propyl]imidazolium tetrafluoroborate (PDPIT) ionic liquid film modified indium tin oxide (ITO) electrode to fabricated a photoelectrochemical interface for the immobilization of rabbit antihuman neuron specific enolase (anti-NSE). After being treated with glutaraldehyde vapor and bovine serum albumin successively, an anti-NSE/ZnCdHgSe QDs/PDPIT/ITO sensing platform was established. Simplely using a white-light LED as an excitation source, the immunoassay of neuron specific enolase (NSE) was achieved through monitoring the photocurrent variation. The polymerized ionic liquid film was demonstrated to be an important element to enhance the photocurrent response of ZnCdHgSe QDs. The anti-NSE/ZnCdHgSe QDs/PDPIT/ITO based immunosensor presents excellent performances in neuron specific enolase determination. The photocurrent variation before and after being interacted with NSE exhibits a good linear relationship with the logarithm of its concentration (log cNSE) in the range from 1.0 pg mL(-1) to 100 ng mL(-1). The limit of detection of this immunosensor is able to reach 0.2 pg mL(-1) (S/N = 3). The determination of NSE in clinical human sera was also demonstrated using anti-NSE/ZnCdHgSe QDs/PDPIT/ITO electrode. The results were found comparable with those obtained by using enzyme-linked immunosorbent assay method. PMID:25790014

  20. Excited Delirium

    PubMed Central

    Takeuchi, Asia; Ahern, Terence L.; Henderson, Sean O.

    2011-01-01

    Excited (or agitated) delirium is characterized by agitation, aggression, acute distress and sudden death, often in the pre-hospital care setting. It is typically associated with the use of drugs that alter dopamine processing, hyperthermia, and, most notably, sometimes with death of the affected person in the custody of law enforcement. Subjects typically die from cardiopulmonary arrest, although the cause is debated. Unfortunately an adequate treatment plan has yet to be established, in part due to the fact that most patients die before hospital arrival. While there is still much to be discovered about the pathophysiology and treatment, it is hoped that this extensive review will provide both police and medical personnel with the information necessary to recognize and respond appropriately to excited delirium. PMID:21691475

  1. The potential for utilizing the "mirror neurone system" to enhance recovery of the severely affected upper limb early after stroke: a review and hypothesis.

    PubMed

    Pomeroy, Valerie M; Clark, Christopher A; Miller, J Simon G; Baron, Jean-Claude; Markus, Hugh S; Tallis, Raymond C

    2005-03-01

    Recovery of upper limb movement control after stroke might be enhanced by repetitive goal-directed functional activities. Providing such activity is challenging in the presence of severe paresis. A possible new approach is based on the discovery of mirror neurons in the monkey cortical area F5, which are active both in observing and executing a movement. Indirect evidence for a comparable human "mirror neurone system" is provided by functional imaging. The primary motor cortex, the premotor cortex, other brain areas, and muscles appropriate for the action being observed are probably activated in healthy volunteers observing another's movement. These findings raise the hypothesis that observation of another's movement might train the movement execution system of stroke patients who have severe paresis to bring them to the point at which they could actively participate in rehabilitation consisting of goal-directed activities. The point of providing an observation therapy would be to facilitate the voluntary production of movement; therefore, the condition of interest would be observation with intent to imitate. However, there is as yet insufficient evidence to enable the testing of this hypothesis in stroke patients. Studies in normal subjects are needed to determine which brain sites are activated in response to observation with intent to imitate. Studies in stroke subjects are needed to determine how activation is affected after damage to different brain areas. The information from such studies should aid identification of those stroke patients who might be most likely to benefit from observation to imitate and therefore guide phase I clinical studies. PMID:15673838

  2. Ablation of CBP in forebrain principal neurons causes modest memory and transcriptional defects and a dramatic reduction of histone acetylation but does not affect cell viability.

    PubMed

    Valor, Luis M; Pulopulos, Matias M; Jimenez-Minchan, Maria; Olivares, Roman; Lutz, Beat; Barco, Angel

    2011-02-01

    Rubinstein-Taybi syndrome (RSTS) is an inheritable disease associated with mutations in the gene encoding the CREB (cAMP response element-binding protein)-binding protein (CBP) and characterized by growth impairment, learning disabilities, and distinctive facial and skeletal features. Studies in mouse models for RSTS first suggested a direct role for CBP and histone acetylation in cognition and memory. Here, we took advantage of the genetic tools for generating mice in which the CBP gene is specifically deleted in postmitotic principal neurons of the forebrain to investigate the consequences of the loss of CBP in the adult brain. In contrast to the conventional CBP knock-out mice, which exhibit very early embryonic lethality, postnatal forebrain-restricted CBP mutants were viable and displayed no overt abnormalities. We identified the dimer of histones H2A and H2B as the preferred substrate of the histone acetyltransferase domain of CBP. Surprisingly, the loss of CBP and subsequent histone hypoacetylation had a very modest impact in the expression of a number of immediate early genes and did not affect neuronal viability. In addition, the behavioral characterization of these mice dissociated embryonic and postnatal deficits caused by impaired CBP function, narrowed down the anatomical substrate of specific behavioral defects, and confirmed the special sensitivity of object recognition memory to CBP deficiency. Overall, our study provides novel insights into RSTS etiology and clarifies some of the standing questions concerning the role of CBP and histone acetylation in activity-driven gene expression, memory formation, and neurodegeneration. PMID:21289174

  3. What Gets a Cell Excited? Kinky Curves

    ERIC Educational Resources Information Center

    Kay, Alan R.

    2014-01-01

    Hodgkin and Huxley's (5) revealing the origins of cellular excitability is one of the great triumphs of physiology. In an extraordinarily deft series of papers, they were able to measure the essential electrical characteristics of neurons and synthesize them into a quantitative model that accounts for the excitability of neurons and other…

  4. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory.

    PubMed

    Zhang, Ying; Bertolino, Alessandro; Fazio, Leonardo; Blasi, Giuseppe; Rampino, Antonio; Romano, Raffaella; Lee, Mei-Ling T; Xiao, Tao; Papp, Audrey; Wang, Danxin; Sadée, Wolfgang

    2007-12-18

    Subcortical dopamine D2 receptor (DRD2) signaling is implicated in cognitive processes and brain disorders, but the effect of DRD2 variants remains ambiguous. We measured allelic mRNA expression in postmortem human striatum and prefrontal cortex and then performed single nucleotide polymorphism (SNP) scans of the DRD2 locus. A previously uncharacterized promoter SNP (rs12364283) located in a conserved suppressor region was associated with enhanced DRD2 expression, whereas previously studied DRD2 variants failed to affect expression. Moreover, two frequent intronic SNPs (rs2283265 and rs1076560) decreased expression of DRD2 short splice variant (expressed mainly presynaptically) relative to DRD2 long (postsynaptic), a finding reproduced in vitro by using minigene constructs. Being in strong linkage disequilibrium with each other, both intronic SNPs (but not rs12364283) were also associated with greater activity of striatum and prefrontal cortex measured with fMRI during working memory and with reduced performance in working memory and attentional control tasks in healthy humans. Our results identify regulatory DRD2 polymorphisms that modify mRNA expression and splicing and working memory pathways. PMID:18077373

  5. More sensitivity of cortical GABAergic neurons than glutamatergic neurons in response to acidosis.

    PubMed

    Liu, Hua; Li, Fang; Wang, Chunyan; Su, Zhiqiang

    2016-05-25

    Acidosis impairs brain functions. Neuron-specific mechanisms underlying acidosis-induced brain dysfunction remain elusive. We studied the sensitivity of cortical GABAergic neurons and glutamatergic neurons to acidosis by whole-cell recording in brain slices. The acidification to the neurons was induced by perfusing artificial cerebral spinal fluid with lower pH. This acidification impairs excitability and synaptic transmission in the glutamatergic and GABAergic neurons. Acidosis impairs spiking capacity in the GABAergic neurons more than in the glutamatergic neurons. Acidosis also strengthens glutamatergic synaptic transmission and attenuates GABAergic synaptic transmission on the GABAergic neurons more than the glutamatergic neurons, which results in the functional impairment of these GABAergic neurons. This acidosis-induced dysfunction predominantly in the cortical GABAergic neurons drives the homeostasis of neuronal networks toward overexcitation and exacerbates neuronal impairment. PMID:27116702

  6. Vestibular Neuronitis

    MedlinePlus

    ... Prevent Painful Swimmer's Ear Additional Content Medical News Vestibular Neuronitis By Lawrence R. Lustig, MD NOTE: This ... Drugs Herpes Zoster Oticus Meniere Disease Purulent Labyrinthitis Vestibular Neuronitis Vestibular neuronitis is a disorder characterized by ...

  7. Pharmacological Investigation of Fluoro-Gold Entry into Spinal Neurons

    PubMed Central

    Falgairolle, Melanie; O’Donovan, Michael J.

    2015-01-01

    The fluorescent tracer Fluoro-Gold has been widely used to label neurons retrogradely. Here we show that Fluoro-Gold can also enter neurons through AMPA receptor endocytosis. We found that a 30 minute application of Fluoro-Gold to the isolated spinal cord labeled neurons under control conditions and in the presence of glutamatergic agonists including NMDA and AMPA. The labeling was abolished or greatly reduced by glutamatergic antagonists and the endocytic inhibitors Dynasore and dynamin inhibitory peptide. Whole cell recordings from spinal neurons exposed to extracellular AMPA revealed large inward currents that spontaneously decayed in the presence of the agonist but were maintained when a dynamin inhibitory peptide was included in the electrode. These findings suggest that Fluoro-Gold enters spinal neurons through AMPA-mediated receptor internalization. Drugs used to induce locomotor-like activity in the spinal cord also increased and decreased Fluoro-Gold labeling in a drug and lamina specific manner, indicating that AMPAR endocytosis is altered in the presence of the locomotor cocktail. Our findings suggest that endocytosis of Fluoro-Gold could potentially complicate the interpretation of experiments in which the tracer is used to label neurons retrogradely. Moreover, they also demonstrate that many drugs, including the locomotor cocktail, can modulate the number and/or the composition of AMPA receptors on spinal neurons and thereby affect network excitability. PMID:26102354

  8. Exposure to GSM RF Fields Does Not Affect Calcium Homeostasis in Human Endothelial Cells, Rat Pheocromocytoma Cells or Rat Hippocampal Neurons

    PubMed Central

    O'Connor, Rodney P.; Madison, Steve D.; Leveque, Philippe; Roderick, H. Llewelyn; Bootman, Martin D.

    2010-01-01

    In the course of modern daily life, individuals are exposed to numerous sources of electromagnetic radiation that are not present in the natural environment. The strength of the electromagnetic fields from sources such as hairdryers, computer display units and other electrical devices is modest. However, in many home and office environments, individuals can experience perpetual exposure to an “electromagnetic smog”, with occasional peaks of relatively high electromagnetic field intensity. This has led to concerns that such radiation can affect health. In particular, emissions from mobile phones or mobile phone masts have been invoked as a potential source of pathological electromagnetic radiation. Previous reports have suggested that cellular calcium (Ca2+) homeostasis is affected by the types of radiofrequency fields emitted by mobile phones. In the present study, we used a high-throughput imaging platform to monitor putative changes in cellular Ca2+ during exposure of cells to 900 MHz GSM fields of differing power (specific absorption rate 0.012–2 W/Kg), thus mimicking the type of radiation emitted by current mobile phone handsets. Data from cells experiencing the 900 Mhz GSM fields were compared with data obtained from paired experiments using continuous wave fields or no field. We employed three cell types (human endothelial cells, PC-12 neuroblastoma and primary hippocampal neurons) that have previously been suggested to be sensitive to radiofrequency fields. Experiments were designed to examine putative effects of radiofrequency fields on resting Ca2+, in addition to Ca2+ signals evoked by an InsP3-generating agonist. Furthermore, we examined putative effects of radiofrequency field exposure on Ca2+ store emptying and store-operated Ca2+ entry following application of the Ca2+ATPase inhibitor thapsigargin. Multiple parameters (e.g., peak amplitude, integrated Ca2+ signal, recovery rates) were analysed to explore potential impact of radiofrequency field

  9. Exposure to GSM RF fields does not affect calcium homeostasis in human endothelial cells, rat pheocromocytoma cells or rat hippocampal neurons.

    PubMed

    O'Connor, Rodney P; Madison, Steve D; Leveque, Philippe; Roderick, H Llewelyn; Bootman, Martin D

    2010-01-01

    In the course of modern daily life, individuals are exposed to numerous sources of electromagnetic radiation that are not present in the natural environment. The strength of the electromagnetic fields from sources such as hairdryers, computer display units and other electrical devices is modest. However, in many home and office environments, individuals can experience perpetual exposure to an "electromagnetic smog", with occasional peaks of relatively high electromagnetic field intensity. This has led to concerns that such radiation can affect health. In particular, emissions from mobile phones or mobile phone masts have been invoked as a potential source of pathological electromagnetic radiation. Previous reports have suggested that cellular calcium (Ca2+) homeostasis is affected by the types of radiofrequency fields emitted by mobile phones. In the present study, we used a high-throughput imaging platform to monitor putative changes in cellular Ca2+ during exposure of cells to 900 MHz GSM fields of differing power (specific absorption rate 0.012-2 W/Kg), thus mimicking the type of radiation emitted by current mobile phone handsets. Data from cells experiencing the 900 Mhz GSM fields were compared with data obtained from paired experiments using continuous wave fields or no field. We employed three cell types (human endothelial cells, PC-12 neuroblastoma and primary hippocampal neurons) that have previously been suggested to be sensitive to radiofrequency fields. Experiments were designed to examine putative effects of radiofrequency fields on resting Ca2+, in addition to Ca2+ signals evoked by an InsP(3)-generating agonist. Furthermore, we examined putative effects of radiofrequency field exposure on Ca2+ store emptying and store-operated Ca2+ entry following application of the Ca2+ATPase inhibitor thapsigargin. Multiple parameters (e.g., peak amplitude, integrated Ca2+ signal, recovery rates) were analysed to explore potential impact of radiofrequency field

  10. Stress and Sucrose Intake Modulate Neuronal Activity in the Anterior Hypothalamic Area in Rats

    PubMed Central

    Mitra, Arojit; Guèvremont, Geneviève; Timofeeva, Elena

    2016-01-01

    The anterior hypothalamic area (AHA) is an important integrative relay structure for a variety of autonomic, endocrine, and behavioral responses including feeding behavior and response to stress. However, changes in the activity of the AHA neurons during stress and feeding in freely moving rats are not clear. The present study investigated the firing rate and burst activity of neurons in the central nucleus of the AHA (cAHA) during sucrose intake in non-stressful conditions and after acute stress in freely behaving rats. Rats were implanted with micro-electrodes into the cAHA, and extracellular multi-unit activity was recorded during 1-h access to 10% sucrose in non-stressful conditions or after acute foot shock stress. Acute stress significantly reduced sucrose intake, total sucrose lick number, and lick frequency in licking clusters, and increased inter-lick intervals. At the cluster start (CS) of sucrose licking, the cAHA neurons increased (CS-excited, 20% of the recorded neurons), decreased (CS-inhibited, 42% of the neurons) or did not change (CS-nonresponsive, 38% of the neurons) their firing rate. Stress resulted in a significant increase in the firing rate of the CS-inhibited neurons by decreasing inter-spike intervals within the burst firing of these neurons. This increase in the stress-induced firing rate of the CS-inhibited neurons was accompanied by a disruption of the correlation between the firing rate of CS-inhibited and CS-nonresponsive neurons that was observed in non-stressful conditions. Stress did not affect the firing rate of the CS-excited and CS-nonresponsive neurons. However, stress changed the pattern of burst firing of the CS-excited and CS-nonresponsive neurons by decreasing and increasing the burst number in the CS-excited and CS-nonresponsive neurons, respectively. These results suggest that the cAHA neurons integrate the signals related to stress and intake of palatable food and play a role in the stress- and eating-related circuitry

  11. Raptor ablation in skeletal muscle decreases Cav1.1 expression and affects the function of the excitation-contraction coupling supramolecular complex.

    PubMed

    Lopez, Rubén J; Mosca, Barbara; Treves, Susan; Maj, Marcin; Bergamelli, Leda; Calderon, Juan C; Bentzinger, C Florian; Romanino, Klaas; Hall, Michael N; Rüegg, Markus A; Delbono, Osvaldo; Caputo, Carlo; Zorzato, Francesco

    2015-02-15

    The protein mammalian target of rapamycin (mTOR) is a serine/threonine kinase regulating a number of biochemical pathways controlling cell growth. mTOR exists in two complexes termed mTORC1 and mTORC2. Regulatory associated protein of mTOR (raptor) is associated with mTORC1 and is essential for its function. Ablation of raptor in skeletal muscle results in several phenotypic changes including decreased life expectancy, increased glycogen deposits and alterations of the twitch kinetics of slow fibres. In the present paper, we show that in muscle-specific raptor knockout (RamKO), the bulk of glycogen phosphorylase (GP) is mainly associated in its cAMP-non-stimulated form with sarcoplasmic reticulum (SR) membranes. In addition, 3[H]-ryanodine and 3[H]-PN200-110 equilibrium binding show a ryanodine to dihydropyridine receptors (DHPRs) ratio of 0.79 and 1.35 for wild-type (WT) and raptor KO skeletal muscle membranes respectively. Peak amplitude and time to peak of the global calcium transients evoked by supramaximal field stimulation were not different between WT and raptor KO. However, the increase in the voltage sensor-uncoupled RyRs leads to an increase of both frequency and mass of elementary calcium release events (ECRE) induced by hyper-osmotic shock in flexor digitorum brevis (FDB) fibres from raptor KO. The present study shows that the protein composition and function of the molecular machinery involved in skeletal muscle excitation-contraction (E-C) coupling is affected by mTORC1 signalling. PMID:25431931

  12. Functional Network Overlap as Revealed by fMRI Using sICA and Its Potential Relationships with Functional Heterogeneity, Balanced Excitation and Inhibition, and Sparseness of Neuron Activity

    PubMed Central

    Xu, Jiansong; Calhoun, Vince D.; Worhunsky, Patrick D.; Xiang, Hui; Li, Jian; Wall, John T.; Pearlson, Godfrey D.; Potenza, Marc N.

    2015-01-01

    Functional magnetic resonance imaging (fMRI) studies traditionally use general linear model-based analysis (GLM-BA) and regularly report task-related activation, deactivation, or no change in activation in separate brain regions. However, several recent fMRI studies using spatial independent component analysis (sICA) find extensive overlap of functional networks (FNs), each exhibiting different task-related modulation (e.g., activation vs. deactivation), different from the dominant findings of GLM-BA. This study used sICA to assess overlap of FNs extracted from four datasets, each related to a different cognitive task. FNs extracted from each dataset overlapped with each other extensively across most or all brain regions and showed task-related concurrent increases, decreases, or no changes in activity. These findings indicate that neural substrates showing task-related concurrent but different modulations in activity intermix with each other and distribute across most of the brain. Furthermore, spatial correlation analyses found that most FNs were highly consistent in spatial patterns across different datasets. This finding indicates that these FNs probably reflect large-scale patterns of task-related brain activity. We hypothesize that FN overlaps as revealed by sICA might relate to functional heterogeneity, balanced excitation and inhibition, and population sparseness of neuron activity, three fundamental properties of the brain. These possibilities deserve further investigation. PMID:25714362

  13. Effects of sex and deletion of neuropeptide Y2 receptors from GABAergic neurons on affective and alcohol drinking behaviors in mice

    PubMed Central

    McCall, Nora M.; Sprow, Gretchen M.; Delpire, Eric; Thiele, Todd E.; Kash, Thomas L.; Pleil, Kristen E.

    2013-01-01

    A large literature has demonstrated that neuropeptide Y (NPY) regulates many emotional and reward-related behaviors via its primary receptors, Y1R and Y2R. Classically, NPY actions at postsynaptic Y1R decrease anxiety, depression, and alcohol drinking, while its actions at presynaptic Y2R produce the opposite behavioral phenotypes. However, emerging evidence suggests that activation of Y2R can also produce anxiolysis in a brain region and neurotransmitter system-dependent fashion. Further, numerous human and rodent studies have reported that females display higher levels of anxiety, depression, and alcohol drinking. In this study, we evaluated sex differences and the role of Y2R on GABAergic transmission in these behaviors using a novel transgenic mouse that lacks Y2R specifically in VGAT-expressing neurons (VGAT-Y2R knockout). First, we confirmed our genetic manipulation by demonstrating that Y2R protein expression was decreased and that a Y2R agonist could not alter GABAergic transmission in the extended amygdala, a limbic brain region critically implicated in the regulation of anxiety and alcohol drinking behaviors, using immunofluorescence and slice electrophysiology. Then, we tested male and female VGAT-Y2R knockout mice on a series of behavioral assays for anxiety, depression, fear, anhedonia, and alcohol drinking. We found that females displayed greater basal anxiety, higher levels of ethanol consumption, and faster fear conditioning than males, and that knockout mice exhibited enhanced depressive-like behavior in the forced swim test. Together, these results confirm previous studies that demonstrate higher expression of negative affective and alcohol drinking behaviors in females than males, and they highlight the importance of Y2R function in GABAergic systems in the expression of depressive-like behavior. PMID:24399943

  14. Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety.

    PubMed

    Wang, Guo-Qiang; Cen, Cheng; Li, Chong; Cao, Shuai; Wang, Ning; Zhou, Zheng; Liu, Xue-Mei; Xu, Yu; Tian, Na-Xi; Zhang, Ying; Wang, Jun; Wang, Li-Ping; Wang, Yun

    2015-01-01

    The medial prefrontal cortex (mPFC) is implicated in processing sensory-discriminative and affective pain. Nonetheless, the underlying mechanisms are poorly understood. Here we demonstrate a role for excitatory neurons in the prelimbic cortex (PL), a sub-region of mPFC, in the regulation of pain sensation and anxiety-like behaviours. Using a chronic inflammatory pain model, we show that lesion of the PL contralateral but not ipsilateral to the inflamed paw attenuates hyperalgesia and anxiety-like behaviours in rats. Optogenetic activation of contralateral PL excitatory neurons exerts analgesic and anxiolytic effects in mice subjected to chronic pain, whereas inhibition is anxiogenic in naive mice. The intrinsic excitability of contralateral PL excitatory neurons is decreased in chronic pain rats; knocking down cyclin-dependent kinase 5 reverses this deactivation and alleviates behavioural impairments. Together, our findings provide novel insights into the role of PL excitatory neurons in the regulation of sensory and affective pain. PMID:26179626

  15. Heat shock protein 60 affects behavioral improvement in a rat model of Parkinson's disease grafted with human umbilical cord mesenchymal stem cell-derived dopaminergic-like neurons.

    PubMed

    Zhao, Can; Li, Hui; Zhao, Xian-Jing; Liu, Zheng-Xia; Zhou, Ping; Liu, Ying; Feng, Mei-Jiang

    2016-06-01

    Parkinson's disease (PD) is a neurodegenerative disorder that is caused by a loss of dopaminergic (DAergic) neurons in mesencephalic substantia nigra (SN). Human umbilical cord mesenchymal stem cells (hUC-MSCs) are capable of self-renewal and differentiation into multiple cell lineages, including DAergic neurons. Thus, hUC-MSCs could be a promising alternative to compensate for the loss of DAergic neurons in PD. In the current study, hUC-MSCs and hUC-MSCs-derived DAergic-like neurons were transplanted into the striatum and SN of a rat model of PD that is induced by 6-hydroxydopamine (6-OHDA). We evaluated their therapeutic effects on improving rotation behavior in the rat and on modulating the level of heat shock protein 60 (Hsp60) expression in the brain. After transplantation, an amelioration of rotation behavior was observed in rats that underwent cell grafting, and hUC-MSCs-derived DAergic-like neurons were superior to hUC-MSCs at inducing behavioral improvement. Western blot and immunohistochemistry analysis indicated significantly elevated levels of Hsp60 in cell-grafted rats compared to 6-OHDA-lesioned (PD) rats. These results demonstrate that hUC-MSCs-based cell transplantation is potential therapeutic treatment for PD, and hUC-MSCs-derived DAergic-like neurons appear to be favorable candidates for cell replacement therapy in PD. Finally, Hsp60 could be involved in a mechanism of behavioral recovery. PMID:26758268

  16. Ocular dominance plasticity disrupts binocular inhibition-excitation matching in visual cortex

    PubMed Central

    Saiepour, M. Hadi; Rajendran, Rajeev; Omrani, Azar; Ma, Wen-pei; Tao, Huizhong W.; Heimel, J. Alexander; Levelt, Christiaan N.

    2015-01-01

    Background To ensure that neuronal networks function in a stable fashion, neurons receive balanced inhibitory and excitatory inputs. In various brain regions this balance has been found to change temporarily during plasticity. Whether changes in inhibition have an instructive or permissive role in plasticity remains unclear. Several studies have addressed this question using ocular dominance plasticity in the visual cortex as a model, but so far it remains controversial whether changes in inhibition drive this form of plasticity by directly affecting eye-specific responses or through increasing the plasticity potential of excitatory connections. Results We tested how three major classes of interneurons affect eye-specific responses in normally reared or monocularly deprived mice by optogenetically suppressing their activity. We find that in contrast to somatostatin or vasoactive intestinal polypeptide expressing interneurons, parvalbumin (PV)-expressing interneurons strongly inhibit visual responses. In individual neurons of normal mice, inhibition and excitation driven by either eye are balanced and suppressing PV interneurons does not alter ocular preference. Monocular deprivation disrupts the binocular balance of inhibition and excitation in individual neurons, causing suppression of PV interneurons to change their ocular preference. Importantly however, these changes do not consistently favor responses to one of the eyes at the population level. Conclusion Monocular deprivation disrupts the binocular balance of inhibition and excitation of individual cells. This disbalance does not affect the overall expression of ocular dominance. Our data therefore support a permissive rather than an instructive role of inhibition in ocular dominance plasticity. PMID:25754642

  17. Cryogenic exciter

    SciTech Connect

    Bray, James William; Garces, Luis Jose

    2012-03-13

    The disclosed technology is a cryogenic static exciter. The cryogenic static exciter is connected to a synchronous electric machine that has a field winding. The synchronous electric machine is cooled via a refrigerator or cryogen like liquid nitrogen. The static exciter is in communication with the field winding and is operating at ambient temperature. The static exciter receives cooling from a refrigerator or cryogen source, which may also service the synchronous machine, to selected areas of the static exciter and the cooling selectively reduces the operating temperature of the selected areas of the static exciter.

  18. TIMP-1 affects the spatial distribution of dendritic processes of second-order neurons in a rat model of Retinitis Pigmentosa.

    PubMed

    Shin, Jung-A; Eom, Yun Sung; Yu, Wan-Qing; Grzywacz, Norberto M; Craft, Cheryl Mae; Lee, Eun-Jin

    2015-11-01

    Retinitis Pigmentosa (RP) is an inherited disorder that may lead to blindness. In the rhodopsin S334ter-line-3 rat model of RP, the death of rods induces spatial rearrangement of cones into regular ring mosaics. Using this model, we discovered that the ring mosaics are restored to a homogeneous distribution upon application of tissue inhibitor of metalloproteinase-1 (TIMP-1). In this study, we further investigated the cone migration and spatial distribution of second-order neurons and their connections to cones in the presence or absence of TIMP-1 using immunohistochemistry to identify retinal neurons and their connections with cones. M-opsin cell bodies and their outer segments were evaluated to determine whether TIMP-1 delays the degeneration of outer segments of cones. We observed that during cone rearrangement into ring mosaics in RP retina, dendritic processes of second-order neurons undergo remodeling to maintain their synaptic connections with the cones in the rings. TIMP-1 treatment induced the cones to rearrange and dendritic processes of second-order neurons to return to a more homogeneous spatial distribution. In addition, TIMP-1 treatment protected the outer segments of cones at later stages of retinal degeneration. Our findings clearly demonstrate that despite their dramatic spatial rearrangement, cones and second-order neuron processes maintain their synaptic connections before and after TIMP-1 treatment. PMID:26277580

  19. Paired associative transspinal and transcortical stimulation produces plasticity in human cortical and spinal neuronal circuits.

    PubMed

    Dixon, Luke; Ibrahim, Mohamed M; Santora, Danielle; Knikou, Maria

    2016-08-01

    Anatomical, physiological, and functional connectivity exists between the neurons of the primary motor cortex (M1) and spinal cord. Paired associative stimulation (PAS) produces enduring changes in M1, based on the Hebbian principle of associative plasticity. The present study aimed to establish neurophysiological changes in human cortical and spinal neuronal circuits by pairing noninvasive transspinal stimulation with transcortical stimulation via transcranial magnetic stimulation (TMS). We delivered paired transspinal and transcortical stimulation for 40 min at precise interstimulus intervals, with TMS being delivered after (transspinal-transcortical PAS) or before (transcortical-transspinal PAS) transspinal stimulation. Transspinal-transcortical PAS markedly decreased intracortical inhibition, increased intracortical facilitation and M1 excitability with concomitant decreases of motor threshold, and reduced the soleus Hoffmann's reflex (H-reflex) low frequency-mediated homosynaptic depression. Transcortical-transspinal PAS did not affect intracortical circuits, decreased M1 excitability, and reduced the soleus H-reflex-paired stimulation pulses' mediated postactivation depression. Both protocols affected the excitation threshold of group Ia afferents and motor axons. These findings clearly indicate that the pairing of transspinal with transcortical stimulation produces cortical and spinal excitability changes based on the timing interval and functional network interactions between the two associated inputs. This new PAS paradigm may constitute a significant neuromodulation method with physiological impact, because it can be used to alter concomitantly excitability of intracortical circuits, corticospinal neurons, and spinal inhibition in humans. PMID:27281748

  20. An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons.

    PubMed

    Zhang, Shuang; Johnson, Christopher M; Cui, Ningren; Xing, Hao; Zhong, Weiwei; Wu, Yang; Jiang, Chun

    2016-10-01

    Rett syndrome (RTT) is a neurodevelopmental disorder affecting multiple functions, including the norepinephrine (NE) system. In the CNS, NE is produced mostly by neurons in the locus coeruleus (LC), where defects in intrinsic neuronal properties, NE biosynthetic enzymes, neuronal CO2 sensitivity, and synaptic currents have been reported in mouse models of RTT. LC neurons in methyl-CpG-binding protein 2 gene (Mecp2) null mice show a high rate of spontaneous firing, although whether such hyperexcitability might increase or decrease the NE release from synapses is unknown. To activate the NEergic axonal terminals selectively, we generated an optogenetic mouse model of RTT in which NEergic neuronal excitability can be manipulated with light. Using commercially available mouse breeders, we produced a new strain of double-transgenic mice with Mecp2 knockout and channelrhodopsin (ChR) knockin in catecholaminergic neurons. Several RTT-like phenotypes were found in the tyrosine hydroxylase (TH)-ChR-Mecp2(-/Y) mice, including hypoactivity, low body weight, hindlimb clasping, and breathing disorders. In brain slices, optostimulation produced depolarization and an increase in the firing rate of LC neurons from TH-ChR control mice. In TH-ChR control mice, optostimulation of presynaptic NEergic neurons augmented the firing rate of hypoglossal neurons (HNs), which was blocked by the α-adrenoceptor antagonist phentolamine. Such optostimulation of NEergic terminals had almost no effect on HNs from two or three TH-ChR-Mecp2(-/Y) mice, indicating that excessive excitation of presynaptic neurons does not benefit NEergic modulation in mice with Mecp2 disruption. These results also demonstrate the feasibility of generating double-transgenic mice for studies of RTT with commercially available mice, which are inexpensive, labor/time efficient, and promising for cell-specific stimulation. © 2016 Wiley Periodicals, Inc. PMID:27317352

  1. Effects of weak environmental magnetic fields on the spontaneous bioelectrical activity of snail neurons.

    PubMed

    Moghadam, Mehri Kaviani; Firoozabadi, Mohammad; Janahmadi, Mahyar

    2011-03-01

    We examined the effects of 50-Hz magnetic fields in the range of flux densities relevant to our current environmental exposures on action potential (AP), after-hyperpolarization potential (AHP) and neuronal excitability in neurons of land snails, Helix aspersa. It was shown that when the neurons were exposed to magnetic field at the various flux densities, marked changes in neuronal excitability, AP firing frequency and AHP amplitude were seen. These effects seemed to be related to the intensity, type (single and continuous or repeated and cumulative) and length of exposure (18 or 20 min). The extremely low-frequency (ELF) magnetic field exposures affect the excitability of F1 neuronal cells in a nonmonotonic manner, disrupting their normal characteristic and synchronized firing patterns by interfering with the cell membrane electrophysiological properties. Our results could explain one of the mechanisms and sites of action of ELF magnetic fields. A possible explanation of the inhibitory effects of magnetic fields could be a decrease in Ca(2+) influx through inhibition of voltage-gated Ca(2+) channels. The detailed mechanism of effect, however, needs to be further studied under voltage-clamp conditions. PMID:21249346

  2. CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice

    PubMed Central

    Vingtdeux, Valérie; Chang, Eric H.; Frattini, Stephen A.; Zhao, Haitian; Chandakkar, Pallavi; Adrien, Leslie; Strohl, Joshua J.; Gibson, Elizabeth L.; Ohmoto, Makoto; Matsumoto, Ichiro; Huerta, Patricio T.; Marambaud, Philippe

    2016-01-01

    CALHM1 is a cell surface calcium channel expressed in cerebral neurons. CALHM1 function in the brain remains unknown, but recent results showed that neuronal CALHM1 controls intracellular calcium signaling and cell excitability, two mechanisms required for synaptic function. Here, we describe the generation of Calhm1 knockout (Calhm1−/−) mice and investigate CALHM1 role in neuronal and cognitive functions. Structural analysis revealed that Calhm1−/− brains had normal regional and cellular architecture, and showed no evidence of neuronal or synaptic loss, indicating that CALHM1 deficiency does not affect brain development or brain integrity in adulthood. However, Calhm1−/− mice showed a severe impairment in memory flexibility, assessed in the Morris water maze, and a significant disruption of long-term potentiation without alteration of long-term depression, measured in ex vivo hippocampal slices. Importantly, in primary neurons and hippocampal slices, CALHM1 activation facilitated the phosphorylation of NMDA and AMPA receptors by protein kinase A. Furthermore, neuronal CALHM1 activation potentiated the effect of glutamate on the expression of c-Fos and C/EBPβ, two immediate-early gene markers of neuronal activity. Thus, CALHM1 controls synaptic activity in cerebral neurons and is required for the flexible processing of memory in mice. These results shed light on CALHM1 physiology in the mammalian brain. PMID:27066908

  3. IK1 channels do not contribute to the slow afterhyperpolarization in pyramidal neurons

    PubMed Central

    Wang, Kang; Mateos-Aparicio, Pedro; Hönigsperger, Christoph; Raghuram, Vijeta; Wu, Wendy W; Ridder, Margreet C; Sah, Pankaj; Maylie, Jim; Storm, Johan F; Adelman, John P

    2016-01-01

    In pyramidal neurons such as hippocampal area CA1 and basolateral amygdala, a slow afterhyperpolarization (sAHP) follows a burst of action potentials, which is a powerful regulator of neuronal excitability. The sAHP amplitude increases with aging and may underlie age related memory decline. The sAHP is due to a Ca2+-dependent, voltage-independent K+ conductance, the molecular identity of which has remained elusive until a recent report suggested the Ca2+-activated K+ channel, IK1 (KCNN4) as the sAHP channel in CA1 pyramidal neurons. The signature pharmacology of IK1, blockade by TRAM-34, was reported for the sAHP and underlying current. We have examined the sAHP and find no evidence that TRAM-34 affects either the current underling the sAHP or excitability of CA1 or basolateral amygdala pyramidal neurons. In addition, CA1 pyramidal neurons from IK1 null mice exhibit a characteristic sAHP current. Our results indicate that IK1 channels do not mediate the sAHP in pyramidal neurons. DOI: http://dx.doi.org/10.7554/eLife.11206.001 PMID:26765773

  4. NMDA-R inhibition affects cellular process formation in Tilapia melanocytes; a model for pigmented adrenergic neurons in process formation and retraction.

    PubMed

    Ogundele, Olalekan Michael; Okunnuga, Adetokunbo Adedotun; Fabiyi, Temitope Deborah; Olajide, Olayemi Joseph; Akinrinade, Ibukun Dorcas; Adeniyi, Philip Adeyemi; Ojo, Abiodun Ayodele

    2014-06-01

    Parkinson's disease has long been described to be a product of dopamine and (or) melanin loss in the substanstia nigra (SN). Although most studies have focused on dopaminergic neurons, it is important to consider the role of pigment cells in the etiology of the disease and to create an in vitro live cell model for studies involving pigmented adrenergic cells of the SN in Parkinsonism. The Melanocytes share specific features with the pigmented adrenergic neurons as both cells are pigmented, contain adrenergic receptors and have cellular processes. Although the melanocyte cellular processes are relatively short and observable only when stimulated appropriately by epinephrine and other factors or molecules. This study employs the manipulation of N-Methyl-D-Aspartate Receptor (NMDA-R), a major receptor in neuronal development, in the process formation pattern of the melanocyte in order to create a suitable model to depict cellular process elongation and shortening in pigmented adrenergic cells. NMDA-R is an important glutamate receptor implicated in neurogenesis, neuronal migration, maturation and cell death, thus we investigated the role of NMDA-R potentiation by glutamate/KCN and its inhibition by ketamine in the behavior of fish scale melanocytes in vitro. This is aimed at establishing the regulatory role of NMDA-R in this cell type (melanocytes isolated form Tilapia) in a similar manner to what is observable in the mammalian neurons. In vitro live cell culture was prepared in modified Ringer's solution following which the cells were treated as follows; Control, Glutamate, Ketamine, Glutamate + Ketamine, KCN + Ketamine and KCN. The culture was maintained for 10 min and the changes were captured in 3D-Time frame at 0, 5 and 10 min for the control and 5, 7 and 10 min for each of the treatment category. Glutamate treatment caused formation of short cellular processes localized directly on the cell body while ketamine treatment (inhibition of NMDA-R) facilitated

  5. Neuronal polarization.

    PubMed

    Takano, Tetsuya; Xu, Chundi; Funahashi, Yasuhiro; Namba, Takashi; Kaibuchi, Kozo

    2015-06-15

    Neurons are highly polarized cells with structurally and functionally distinct processes called axons and dendrites. This polarization underlies the directional flow of information in the central nervous system, so the establishment and maintenance of neuronal polarization is crucial for correct development and function. Great progress in our understanding of how neurons establish their polarity has been made through the use of cultured hippocampal neurons, while recent technological advances have enabled in vivo analysis of axon specification and elongation. This short review and accompanying poster highlight recent advances in this fascinating field, with an emphasis on the signaling mechanisms underlying axon and dendrite specification in vitro and in vivo. PMID:26081570

  6. A new work mechanism on neuronal activity.

    PubMed

    Wang, Rubin; Tsuda, Ichiro; Zhang, Zhikang

    2015-05-01

    By re-examining the neuronal activity energy model, we show the inadequacies in the current understanding of the energy consumption associated with neuron activity. Specifically, we show computationally that a neuron first absorbs and then consumes energy during firing action potential, and this result cannot be produced from any current neuron models or biological neural networks. Based on this finding, we provide an explanation for the observation that when neurons are excited in the brain, blood flow increases significantly while the incremental oxygen consumption is very small. We can also explain why external stimulation and perception emergence are synchronized. We also show that negative energy presence in neurons at the sub-threshold state is an essential reason that leads to blood flow incremental response time in the brain rather than neural excitation to delay. PMID:25640576

  7. Oxytocin activation of neurons in ventral tegmental area and interfascicular nucleus of mouse midbrain.

    PubMed

    Tang, Yamei; Chen, Zhiheng; Tao, Huai; Li, Cunyan; Zhang, Xianghui; Tang, Aiguo; Liu, Yong

    2014-02-01

    Oxytocin (OT) was reported to affect cognitive and emotional behavior by action in ventral tegmental area (VTA) and other brain areas. However, it is still unclear how OT activates VTA and related midline nucleus. Here, using patch-clamp recording, we studied the effects of OT on neuron activity in VTA and interfascicular nucleus (IF). OT dose-dependently and selectively excited small neurons located in medial VTA and the majority of IF neurons but not large neurons in lateral VTA. We found the hyperpolarization-activated current (I(h)) and the membrane capacitance of OT-sensitive neuron were significantly smaller than those of OT-insensitive neurons. The action potential width of OT-sensitive neurons was about half that of OT-insensitive neurons. The OT effect was blocked by the OT receptor antagonist atosiban and WAY-267464 but not by tetrodotoxin, suggesting a direct postsynaptic activation of OT receptors. In addition, the phospholipase C (PLC) inhibitor U73122 antagonized the depolarization by OT. Both the nonselective cation channel (NSCC) antagonist SKF96365 and the Na(+)-Ca(2+) exchanger (NCX) blocker SN-6 attenuated OT effects. These results suggested that the PLC signaling pathway coupling to NSCC and NCX contributes to the OT-mediated activation of neurons in medial VTA and IF. Taken together, our results indicate OT directly acted on medial VTA and especially IF neurons to activate NSCC and NCX via PLC. The direct activation by OT of midbrain neurons may be one mechanism underlying OT effects on social behavior. PMID:24148809

  8. Long-Term Treatment with Losartan Attenuates Seizure Activity and Neuronal Damage Without Affecting Behavioral Changes in a Model of Co-morbid Hypertension and Epilepsy.

    PubMed

    Tchekalarova, Jana D; Ivanova, Natasha; Atanasova, Dimitrina; Pechlivanova, Daniela M; Lazarov, Nikolai; Kortenska, Lidia; Mitreva, Rumiana; Lozanov, Valentin; Stoynev, Alexander

    2016-08-01

    Over the last 10 years, accumulated experimental and clinical evidence has supported the idea that AT1 receptor subtype is involved in epilepsy. Recently, we have shown that the selective AT1 receptor antagonist losartan attenuates epileptogenesis and exerts neuroprotection in the CA1 area of the hippocampus in epileptic Wistar rats. This study aimed to verify the efficacy of long-term treatment with losartan (10 mg/kg) after kainate-induced status epilepticus (SE) on seizure activity, behavioral and biochemical changes, and neuronal damage in a model of co-morbid hypertension and epilepsy. Spontaneous seizures were video- and EEG-monitored in spontaneously hypertensive rats (SHRs) for a 16-week period after SE. The behavior was analyzed by open field, elevated plus maze, sugar preference test, and forced swim test. The levels of serotonin in the hippocampus and neuronal loss were estimated by HPLC and hematoxylin and eosin staining, respectively. The AT1 receptor antagonism delayed the onset of seizures and alleviated their frequency and duration during and after discontinuation of treatment. Losartan showed neuroprotection mostly in the CA3 area of the hippocampus and the septo-temporal hilus of the dentate gyrus in SHRs. However, the AT1 receptor antagonist did not exert a substantial influence on concomitant with epilepsy behavioral changes and decreased 5-HT levels in the hippocampus. Our results suggest that the antihypertensive therapy with an AT1 receptor blocker might be effective against seizure activity and neuronal damage in a co-morbid hypertension and epilepsy. PMID:26464042

  9. Energy dissipation channels affecting photoluminescence from resonantly excited Er{sup 3+} ions doped in epitaxial ZnO host films

    SciTech Connect

    Akazawa, Housei; Shinojima, Hiroyuki

    2015-04-21

    We identified prerequisite conditions to obtain intense photoluminescence at 1.54 μm from Er{sup 3+} ions doped in ZnO host crystals. The epitaxial ZnO:Er films were grown on sapphire C-plane substrates by sputtering, and Er{sup 3+} ions were resonantly excited at a wavelength of 532 nm between energy levels of {sup 4}I{sub 15/2} and {sup 2}H{sub 11/2}. There is a threshold deposition temperature between 500 and 550 °C, above which epitaxial ZnO films become free of miss-oriented domains. In this case, Er{sup 3+} ions are outside ZnO crystallites, having the same c-axis lattice parameters as those of undoped ZnO crystals. The improved crystallinity was correlated with enhanced emissions peaking at 1538 nm. Further elevating the deposition temperature up to 650 °C generated cracks in ZnO crystals to relax the lattice mismatch strains, and the emission intensities from cracked regions were three times as large as those from smooth regions. These results can be consistently explained if we assume that emission-active Er{sup 3+} ions are those existing at grain boundaries and bonded to single-crystalline ZnO crystallites. In contrast, ZnO:Er films deposited on a ZnO buffer layer exhibited very weak emissions because of their degraded crystallinity when most Er{sup 3+} ions were accommodated into ZnO crystals. Optimizing the degree of oxidization of ZnO crystals is another important factor because reduced films suffer from non-radiative decay of excited states. The optimum Er content to obtain intense emissions was between 2 and 4 at. %. When 4 at. % was exceeded, the emission intensity was severely attenuated because of concentration quenching as well as the degradation in crystallinity. Precipitation of Er{sub 2}O{sub 3} crystals was clearly observed at 22 at. % for films deposited above 650 °C. Minimizing the number of defects and impurities in ZnO crystals prevents energy dissipation, thus exclusively utilizing the excitation energy to emissions from

  10. Cre recombinase expression or topical tamoxifen treatment do not affect retinal structure and function, neuronal vulnerability or glial reactivity in the mouse eye.

    PubMed

    Boneva, S K; Groß, T R; Schlecht, A; Schmitt, S I; Sippl, C; Jägle, H; Volz, C; Neueder, A; Tamm, E R; Braunger, B M

    2016-06-14

    Mice with a constitutive or tamoxifen-induced Cre recombinase (Cre) expression are frequently used research tools to allow the conditional deletion of target genes via the Cre-loxP system. Here we analyzed for the first time in a comprehensive and comparative way, whether retinal Cre expression or topical tamoxifen treatment itself would cause structural or functional changes, including changes in the expression profiles of molecular markers, glial reactivity and photoreceptor vulnerability. To this end, we characterized the transgenic α-Cre, Lmop-Cre and the tamoxifen-inducible CAGG-CreER™ mouse lines, all having robust Cre expression in the neuronal retina. In addition, we characterized the effects of topical tamoxifen treatment itself in wildtype mice. We performed morphometric analyses, immunohistochemical staining, in vivo ERG and angiography analyses and realtime RT-PCR analyses. Furthermore, the influence of Cre recombinase or topical tamoxifen exposure on neuronal vulnerability was studied by using light damage as a model for photoreceptor degeneration. Taken together, neither the expression of Cre, nor topical tamoxifen treatment caused detectable changes in retinal structure and function, the expression profiles of investigated molecular markers, glial reactivity and photoreceptor vulnerability. We conclude that the Cre-loxP system and its induction through tamoxifen is a safe and reliable method to delete desired target genes in the neural retina. PMID:27026593

  11. Subarachnoid Transplant of the Human Neuronal hNT2.19 Serotonergic Cell Line Attenuates Behavioral Hypersensitivity without Affecting Motor Dysfunction after Severe Contusive Spinal Cord Injury

    PubMed Central

    Eaton, Mary J.; Widerström-Noga, Eva; Wolfe, Stacey Quintero

    2011-01-01

    Transplant of cells which make biologic agents that can modulate the sensory and motor responses after spinal cord injury (SCI) would be useful to treat pain and paralysis. To address this need for clinically useful human cells, a unique neuronal cell line that synthesizes and secretes/releases the neurotransmitter serotonin (5HT) was isolated. Hind paw tactile allodynia and thermal hyperalgesia induced by severe contusive SCI were potently reversed after lumbar subarachnoid transplant of differentiated cells, but had no effect on open field motor scores, stride length, foot rotation, base of support, or gridwalk footfall errors associated with the SCI. The sensory effects appeared 1 week after transplant and did not diminish during the 8-week course of the experiment when grafts were placed 2 weeks after SCI. Many grafted cells were still present and synthesizing 5HT at the end of the study. These data suggest that the human neuronal serotonergic hNT2.19 cells can be used as a biologic minipump for receiving SCI-related neuropathic pain, but likely requires intraspinal grafts for motor recovery. PMID:21799949

  12. Dual depolarization responses generated within the same lateral septal neurons by TRPC4-containing channels

    PubMed Central

    Tian, Jinbin; Thakur, Dhananjay P.; Lu, Yun