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Sample records for a2 noradrenergic neurons

  1. Role of dorsal vagal complex A2 noradrenergic neurons in hindbrain glucoprivic inhibition of the luteinizing hormone surge in the steroid-primed ovariectomized female rat: effects of 5-thioglucose on A2 functional biomarker and AMPK activity.

    PubMed

    Ibrahim, B A; Briski, K P

    2014-06-06

    Neuro-glucostasis is required for normal expression of the steroid positive-feedback-induced preovulatory pituitary luteinizing hormone (LH) surge, a critical element of female reproduction. Glucoprivic signals from the caudal hindbrain restrain this surge, but the cellular source of this stimulus is unclear. Norepinephrine (NE) exerts well-defined stimulatory effects on the reproductive neuroendocrine axis. Our studies show that medullary A2 noradrenergic neurons are both estrogen- and glucoprivic-sensitive. Here, we investigated the premise that the LH surge is inhibited by A2 cell reactivity to hindbrain glucopenia and diminished preoptic NE neurotransmission. Estradiol- and progesterone-primed ovariectomized (OVX) female rats were injected into the caudal fourth ventricle (CV4) with the glucose anti-metabolite, 5-thioglucose (5TG) or saline (SAL) prior to onset of the LH surge. Pretreatment by intra-CV4 delivery of the selective catecholamine neurotoxin, 6-OHDA, attenuated LH output, but prevented inhibition by 5TG. 5TG modified patterns of steroid feedback-associated Fos staining of A2, but not other medullary catecholamine cell groups. Intra-preoptic administration of the alpha₁-adrenergic receptor agonist, methoxamine, elicited site-specific reversal of hindbrain glucoprivic suppression of gonadotropin-releasing hormone (GnRH) neuron Fos labeling and LH release. Western blotting of laser-microdissected A2 neurons revealed glucoprivic stimulation of Fos, but inhibition of the catecholamine synthetic enzyme, dopamine-β-hydroxylase; 5TG also diminished A2 estrogen receptor (ER)-α and progesterone receptor profiles, but augmented ER-β protein. Intriguingly, A2 AMPK activity was decreased in 5TG-treated rats, despite down-regulation of GLUT3 and no change in MCT2 protein expression. Rostral preoptic GnRH neurons also exhibited decreased AMPK activation simultaneous with apparent reduction of neuropeptide signaling to the pituitary. The present studies

  2. Cannabinoids modulate spontaneous neuronal activity and evoked inhibition of locus coeruleus noradrenergic neurons.

    PubMed

    Muntoni, Anna Lisa; Pillolla, Giuliano; Melis, Miriam; Perra, Simona; Gessa, Gian Luigi; Pistis, Marco

    2006-05-01

    The noradrenergic pathway arising from the locus coeruleus (LC) is involved in the regulation of attention, arousal, cognitive processes and sleep. These physiological activities are affected by Cannabis exposure - both in humans and laboratory animals. In addition, exogenous cannabinoids, as well as pharmacological and genetic manipulation of the endocannabinoid system, are known to influence emotional states (e.g. anxiety) for which a contributory role of the LC-noradrenergic system has long been postulated. However, whether cannabinoid administration would affect the LC neuronal activity in vivo is still unknown. To this end, single-unit extracellular recordings were performed from LC noradrenergic cells in anaesthetized rats. Intravenous injection of both the synthetic cannabinoid agonist, WIN55212-2, and the main psychoactive principle of Cannabis, Delta9-tetrahydrocannabinol, dose-dependently increased the firing rate of LC noradrenergic neurons, with WIN55212-2 being the most efficacious. Similar results were obtained by the administration of these drugs into a lateral ventricle. Cannabinoid-induced stimulation of LC noradrenergic neuronal activity was counteracted by SR141716A, a cannabinoid receptor antagonist/reverse agonist, which by itself slightly reduced LC discharge rate. Moreover, WIN55212-2 suppressed the inhibition of noradrenergic cells produced by stimulation of the major gamma-aminobutyric acid (GABA)ergic afferent to the LC, the nucleus prepositus hypoglossi. Altogether, these findings suggest the involvement of noradrenergic pathways in some consequences of Cannabis intake (e.g. cognitive and attention deficits, anxiety reactions), as well as a role for cannabinoid receptors in basic brain activities sustaining arousal and emotional states.

  3. Noradrenergic Neurons in the Locus Coeruleus Contribute to Neuropathic Pain

    PubMed Central

    Brightwell, Jennifer J.; Taylor, Bradley K.

    2009-01-01

    Current theories of neuropathic hypersensitivity include an imbalance of supraspinal inhibition and facilitation. Our overall hypothesis is that the locus coeruleus (LC), classically interpreted as a source of pain inhibition, may paradoxically result in facilitation after tibial and common peroneal nerve transection (spared sural nerve injury – SNI). We first tested the hypothesis that non-noxious tactile hindpaw stimulation of the spared sural innervation territory increases neuronal activity in the LC in male rats. We observed a bilateral increase in the stimulus-evoked expression of transcription factors Fos and phosphorylated CREB (pCREB) in LC after SNI but not sham surgery; these markers of neuronal activity correlated with the intensity of tactile allodynia. We next tested the hypothesis that noradrenergic neurons contribute to the development of neuropathic pain. To selectively destroy these neurons, we delivered anti-dopamine-β-hydroxylase saporin (anti-DβH-saporin) into the intracerebroventricular space two weeks before SNI. We found that anti-DβH-saporin, but not an IgG-saporin control, reduced behavioural signs of tactile allodynia, mechanical hyperalgesia, and cold allodynia from 3-28 d after SNI. Our final experiment tested the hypothesis that the LC contributes to the maintenance of neuropathic pain. We performed SNI, waited two weeks for maximal allodynia and hyperalgesia to develop, and then administered the local anaesthetic lidocaine (4%) directly into the LC parenchyma. Lidocaine reduced all behavioural signs of neuropathic pain in a reversible manner, suggesting that the LC contributes to pain facilitation. We conclude that, in addition to its well-known inhibition of acute and inflammatory pain, the LC facilitates the development and maintenance of neuropathic pain in the SNI model. Further studies are needed to determine the facilitatory pathways emanating from the LC. PMID:19223010

  4. Drugs of abuse specifically sensitize noradrenergic and serotonergic neurons via a non-dopaminergic mechanism.

    PubMed

    Lanteri, Christophe; Salomon, Lucas; Torrens, Yvette; Glowinski, Jacques; Tassin, Jean-Pol

    2008-06-01

    A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated d-amphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances. In all cases, this sensitization is prevented by alpha 1b-adrenergic and 5-HT2A receptors blockade, indicating the critical role of these receptors on long-term effects of drugs of abuse. However, repeated treatments with two non-addictive antidepressants, venlafaxine, and clorimipramine, which nevertheless inhibit noradrenergic and serotonergic reuptake, do not induce noradrenergic and serotonergic neurons sensitization. Similarly, this sensitization does not occur following repeated treatments with a specific inhibitor of dopamine (DA) reuptake, GBR12783. Moreover, we show that the effects of SCH23390, a D1 receptor antagonist known to inhibit development of d-amphetamine behavioral sensitization, are due to its 5-HT2C receptor agonist property. SCH23390 blocks amphetamine-induced release of norepinephrine and RS102221, a 5-HT2C antagonist, can reverse this inhibition as well as inhibition of noradrenergic sensitization and development of behavioral sensitization induced by repeated d-amphetamine. We propose that noradrenergic/serotonergic uncoupling is a common neurochemical consequence of repeated consumption of drugs of abuse, unrelated with DA release. Our data also suggest that compounds able to restore the link between noradrenergic and serotonergic modulatory systems could represent important therapeutic targets for investigation.

  5. Role of nucleus of the solitary tract noradrenergic neurons in post-stress cardiovascular and hormonal control in male rats

    PubMed Central

    Bundzikova-Osacka, Jana; Ghosal, Sriparna; Packard, Benjamin A.; Ulrich-Lai, Yvonne M.; Herman, James P.

    2015-01-01

    Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular dyshomeostasis. Noradrenergic neurons in the nucleus of the solitary tract (NTS) are considered to play a role in these changes. Here, we tested the hypothesis that NTS noradrenergic A2 neurons are required for cardiovascular and HPA axis responses to both acute and chronic stress. Adult male rats received bilateral microinjection into the NTS of 6-hydroxydopamine (6-OHDA) to lesion A2 neurons [cardiovascular study, n= 5; HPA study, n= 5], or vehicle [cardiovascular study, n= 6; HPA study, n= 4]. Rats were exposed to acute restraint stress followed by 14 days of chronic variable stress (CVS). On the last day of testing, rats were placed in a novel elevated plus maze (EPM) to test post-CVS stress responses. Lesions of NTS A2 neurons reduced the tachycardic response to acute restraint, confirming that A2 neurons promote sympathetic activation following acute stress. In addition, CVS increased the ratio of low frequency to high frequency power for heart rate variability, indicative of sympathovagal imbalance, and this effect was significantly attenuated by 6-OHDA lesion. Lesions of NTS A2 neurons reduced acute restraint-induced corticosterone secretion, but did not affect the corticosterone response to the EPM, indicating that A2 neurons promote acute HPA axis responses, but are not involved in CVS-mediated HPA axis sensitization. Collectively, these data indicate that A2 neurons promote both cardiovascular and HPA axis responses to acute stress. Moreover, A2 catecholaminergic neurons may contribute to the potentially deleterious enhancement of sympathetic drive following chronic stress. PMID:25765732

  6. Medullary noradrenergic neurons release norepinephrine in the medial amygdala in females in response to mating stimulation sufficient for pseudopregnancy.

    PubMed

    Cameron, Nicole M; Carey, Padraic; Erskine, Mary S

    2004-10-01

    In the female rat, stimuli from the uterine cervix and vagina are carried to the brain areas involved in the mating-induced pseudopregnancy (PSP) response via the ventral noradrenergic bundle. Noradrenergic neurons projecting through this tract synapse in many forebrain areas including the amygdala, and neurons in the posterodorsal medial amygdala (MePD) are activated following mating. The goal of this experiment was to investigate whether norepinephrine (NE) is released into the MePD after mating using microdialysis and to determine the origin of this release. Ovariectomized estrogen- and progesterone-treated rats were implanted unilaterally with guide cannulae aimed at the MePD. Females were placed with males until they received 15 intromissions (15I), 5 intromissions (5I) or 15 mounts-without-intromission (MO). Dialysate samples collected every 20 min for 2 h before to 3 h after mating were analyzed for NE using HPLC with electrochemical detection. A significant increase in mean NE release in the MePD was seen at 80 min after mating onset in females receiving 15I, and no increase was seen in animals receiving 5I or MO. The time of peak NE release varied in 15I animals from 60 to 160 min after mating. Mean baseline levels of NE did not differ between groups. The retrograde tracer FluoroGold (FG), administered through the probe after cessation of dialysis sampling, was observed within identified noradrenergic cells primarily within the A1 and A2 cell groups. Infusion of anti-dopamine-beta-hydroxylase-saporin (DBH-SAP) into the MePD lesioned noradrenergic neurons located in the A1 and A2 cell groups. Because high levels of NE release occurred in the MePD only after the females received a number of intromissions sufficient to induce PSP, these results suggest that NE release within the MePD may be important for the establishment of PSP.

  7. Molecular activation of noradrenergic neurons in the rabbit brainstem after coitus.

    PubMed

    Caba, M; Bao, J; Pau, K Y; Spies, H G

    2000-05-05

    Our previous studies indicate that coitus in female rabbits induces a gonadotropin-releasing hormone (GnRH) surge that is preceded by an increase in hypothalamic norepinephrine (NE) release. The additional findings of an enhanced tyrosine hydroxylase (TH) mRNA expression in the female brainstem after coitus, in addition to the appropriate topographic distribution of TH and dopamine-beta-hydroxylase (DBH), lead us to hypothesize that coital signals are relayed to hypothalamic GnRH-secreting neurons via brainstem NE-containing perikarya. Here we analyzed coitally activated areas in the brainstem by in situ hybridization of the oncogene c-fos, as well as the expression of TH mRNA at 0, 30 and 60 min postcoitus using specific 35S-labeled probes for c-fos and TH. To establish the identity of activated brainstem neurons, we immunocytochemically double-labeled cells with specific antibodies against Fos protein and DBH at 90 min postcoitus. Both c-fos and TH mRNAs were present at 0 min (control) in the A1, A2 and A6 brainstem-noradrenergic areas. At 30 min after coitus the expression of both genes significantly increased (P<0.01) in the A1 and A2 areas. By 60 min postcoitus the expression of c-fos mRNA decreased to control levels, while that of TH mRNA remained stimulated. Double-labeling of Fos and DBH indicated that the number of dual-labeled neurons increased (P<0.05) over control levels only in the A1 and A2 areas (not in A6) at 90 min postcoitus. These findings support the hypothesis that coitus activates transcriptional/translational events within brainstem NE neurons that culminate in the release of hypothalamic NE and hence a GnRH surge.

  8. Retrograde adenoviral vector targeting of nociresponsive pontospinal noradrenergic neurons in the rat in vivo

    PubMed Central

    Howorth, Patrick W; Teschemacher, Anja G; Pickering, Anthony E

    2009-01-01

    The spinal dorsal horn receives a dense innervation of noradrenaline-containing fibers that originate from pontine neurons in the A5, locus coeruleus (LC), and A7 cell groups. These pontospinal neurons are believed to constitute a component of the endogenous analgesic system. We used an adenoviral vector with a catecholaminergic-selective promoter (AVV-PRS) to retrogradely label the noradrenergic neurons projecting to the lumbar (L4–L5) dorsal horn with enhanced green fluorescent protein (EGFP) or monomeric red fluorescent protein (mRFP). Retrogradely labeled neurons (145 ± 12, n = 14) were found in A5-12%, LC-80% and A7-8% after injection of AVV-PRS-EGFP to the dorsal horn of L4–L5. These neurons were immunopositive for dopamine β-hydroxylase, indicating that they were catecholaminergic. Retrograde labeling was optimal 7 days after injection, persisted for over 4 weeks, and was dependent on viral vector titer. The spinal topography of the noradrenergic projection was examined using EGFP- and mRFP-expressing adenoviral vectors. Pontospinal neurons provide bilateral innervation of the cord and there was little overlap in the distribution of neurons projecting to the cervical and lumbar regions. The axonal arbor of the pontospinal neurons was visualized with GFP immunocytochemistry to show projections to the inferior olive, cerebellum, thalamus, and cortex but not to the hippocampus or caudate putamen. Formalin testing evoked c-fos expression in these pontospinal neurons, suggesting that they were nociresponsive (A5-21%, LC-16%, and A7-26%, n = 8). Thus, we have developed a viral vector-based strategy to selectively, retrogradely target the pontospinal noradrenergic neurons that are likely to be involved in the descending control of nociception. PMID:19003793

  9. Role of nucleus of the solitary tract noradrenergic neurons in post-stress cardiovascular and hormonal control in male rats.

    PubMed

    Bundzikova-Osacka, Jana; Ghosal, Sriparna; Packard, Benjamin A; Ulrich-Lai, Yvonne M; Herman, James P

    2015-01-01

    Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular dyshomeostasis. Noradrenergic (NA) neurons in the nucleus of the solitary tract (NTS) are considered to play a role in these changes. In this study, we tested the hypothesis that NTS NA A2 neurons are required for cardiovascular and HPA axis responses to both acute and chronic stress. Adult male rats received bilateral microinjection into the NTS of 6-hydroxydopamine (6-OHDA) to lesion A2 neurons [cardiovascular study, n = 5; HPA study, n = 5] or vehicle [cardiovascular study, n = 6; HPA study, n = 4]. Rats were exposed to acute restraint stress followed by 14 d of chronic variable stress (CVS). On the last day of testing, rats were placed in a novel elevated plus maze (EPM) to test post-CVS stress responses. Lesions of NTS A2 neurons reduced the tachycardic response to acute restraint, confirming that A2 neurons promote sympathetic activation following acute stress. In addition, CVS increased the ratio of low-frequency to high-frequency power for heart rate variability, indicative of sympathovagal imbalance, and this effect was significantly attenuated by 6-OHDA lesion. Lesions of NTS A2 neurons reduced acute restraint-induced corticosterone secretion, but did not affect the corticosterone response to the EPM, indicating that A2 neurons promote acute HPA axis responses, but are not involved in CVS-mediated HPA axis sensitization. Collectively, these data indicate that A2 neurons promote both cardiovascular and HPA axis responses to acute stress. Moreover, A2 catecholaminergic neurons may contribute to the potentially deleterious enhancement of sympathetic drive following chronic stress.

  10. Effect of cocaine on ion channels and glutamatergic EPSCs in noradrenergic locus coeruleus neurons.

    PubMed

    Liu, L N; Zhu, F P; Song, M Y; Kang, X J; Shang, S J; Zhang, X Y; Xu, H D; Teng, S S; Liu, B; Kuo, S T; Liu, W; Li, M L; Zhou, L; Jiao, R Y; Wang, C H; Wang, S R; Yang, H; Zhang, B; Zhou, Z; Xu, Z Q D

    2014-07-01

    The locus coeruleus (LC) is an important brainstem area involved in cocaine addiction. However, evidence to elucidate how cocaine modulates the activity of LC neurons remains incomplete. Here, we performed whole recordings in brain slices to evaluate the effects of cocaine on the sodium (Na(+)), potassium (K(+)), calcium (Ca(2+)) channels, and glutamatergic synaptic transmission in the locus coeruleus neurons. Local application of cocaine significantly and reversibly reduced the spontaneous firing rate but did not affect action potential amplitude, rising time, decay time, or half width of noradrenergic locus coeruleus neurons. Moreover, cocaine attenuated the sodium current but did not affect potassium and calcium currents. The N-methyl-D-aspartate receptor mediated excitatory postsynaptic currents were reduced by neuropeptide galanin but not cocaine. All those data demonstrate that cocaine has inhibitory effect on the spontaneous activities and sodium current in locus coeruleus neurons. Therefore, neuromodulation of sodium channel in locus coeruleus neurons may play an important role in drug addiction.

  11. Noradrenergic refinement of glutamatergic neuronal circuits in the lateral superior olivary nucleus before hearing onset.

    PubMed

    Hirao, Kenzo; Eto, Kei; Nakahata, Yoshihisa; Ishibashi, Hitoshi; Nagai, Taku; Nabekura, Junichi

    2015-09-01

    Neuronal circuit plasticity during development is fundamental for precise network formation. Pioneering studies of the developmental visual cortex indicated that noradrenaline (NA) is crucial for ocular dominance plasticity during the critical period in the visual cortex. Recent research demonstrated tonotopic map formation by NA during the critical period in the auditory system, indicating that NA also contributes to synaptic plasticity in this system. The lateral superior olive (LSO) in the auditory system receives glutamatergic input from the ventral cochlear nucleus (VCN) and undergoes circuit remodeling during postnatal development. LSO is innervated by noradrenergic afferents and is therefore a suitable model to study the function of NA in refinement of neuronal circuits. Chemical lesions of the noradrenergic system and chronic inhibition of α2-adrenoceptors in vivo during postnatal development in mice disrupted functional elimination and strengthening of VCN-LSO afferents. This was potentially mediated by activation of presynaptic α2-adrenoceptors and inhibition of glutamate release because NA presynaptically suppressed excitatory postsynaptic current (EPSC) through α2-adrenoceptors during the first two postnatal weeks in an in vitro study. Furthermore, NA and α2-adrenoceptor agonist induced long-term suppression of EPSCs and decreased glutamate release. These results suggest that NA has a critical role in synaptic refinement of the VCN-LSO glutamatergic pathway through failure of synaptic transmission. Because of the ubiquitous distribution of NA afferents and the extensive expression of α2-adrenoceptors throughout the immature brain, this phenomenon might be widespread in the developing central nervous system. Copyright © 2015 the American Physiological Society.

  12. Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma.

    PubMed

    Ikram, Fakhera; Ackermann, Sandra; Kahlert, Yvonne; Volland, Ruth; Roels, Frederik; Engesser, Anne; Hertwig, Falk; Kocak, Hayriye; Hero, Barbara; Dreidax, Daniel; Henrich, Kai-Oliver; Berthold, Frank; Nürnberg, Peter; Westermann, Frank; Fischer, Matthias

    2016-02-01

    Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic nervous system and shows a broad range of clinical behavior, ranging from fatal progression to differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid (RA) effectively induces neuronal differentiation, and RA treatment has been therefore integrated in current therapies. However, the molecular mechanisms underlying differentiation are still poorly understood. We here investigated the role of transcription factor activating protein 2 beta (TFAP2B), a key factor in sympathetic nervous system development, in neuroblastoma pathogenesis and differentiation. Microarray analyses of primary neuroblastomas (n = 649) demonstrated that low TFAP2B expression was significantly associated with unfavorable prognostic markers as well as adverse patient outcome. We also found that low TFAP2B expression was strongly associated with CpG methylation of the TFAP2B locus in primary neuroblastomas (n = 105) and demethylation with 5-aza-2'-deoxycytidine resulted in induction of TFAP2B expression in vitro, suggesting that TFAP2B is silenced by genomic methylation. Tetracycline inducible re-expression of TFAP2B in IMR-32 and SH-EP neuroblastoma cells significantly impaired proliferation and cell cycle progression. In IMR-32 cells, TFAP2B induced neuronal differentiation, which was accompanied by up-regulation of the catecholamine biosynthesizing enzyme genes DBH and TH, and down-regulation of MYCN and REST, a master repressor of neuronal genes. By contrast, knockdown of TFAP2B by lentiviral transduction of shRNAs abrogated RA-induced neuronal differentiation of SH-SY5Y and SK-N-BE(2)c neuroblastoma cells almost completely. Taken together, our results suggest that TFAP2B is playing a vital role in retaining RA responsiveness and mediating noradrenergic neuronal differentiation in neuroblastoma. Copyright © 2015 Federation of European Biochemical Societies

  13. Glutamate input to noradrenergic neurons plays an essential role in the development of morphine dependence and psychomotor sensitization.

    PubMed

    Parkitna, Jan Rodriguez; Solecki, Wojciech; Gołembiowska, Krystyna; Tokarski, Krzysztof; Kubik, Jakub; Gołda, Sławomir; Novak, Martin; Parlato, Rosanna; Hess, Grzegorz; Sprengel, Rolf; Przewłocki, Ryszard

    2012-11-01

    The brain's noradrenergic system is involved in the development of behaviours induced by drugs of abuse, e.g. dependence and withdrawal, and also reward or psychomotor effects. To investigate how noradrenergic system activity is controlled in the context associated with drug-induced behaviours, we generated a Cre/loxP mouse model in which the essential glutamate NMDA receptor subunit NR1 is ablated in cells expressing dopamine β-hydroxylase (Dbh). As a result, the noradrenergic cells in NR1DbhCre mice lack the NMDA receptor-dependent component of excitatory post-synaptic currents. The mutant mice displayed no obvious behavioural alterations, had unchanged noradrenaline content and mild increase in dopamine levels in the nucleus accumbens. Interestingly, NR1DbhCre animals did not develop morphine-induced psychomotor sensitization. However, when the morphine injections were preceded by treatment with RX821002, an antagonist of α2-adrenergic receptors, the development of sensitization was restored. Conversely, pretreatment with clonidine, an agonist of α2-adrenergic receptors, blocked development of sensitization in wild-type mice. We also found that while the development of tolerance to morphine was normal in mutant mice, withdrawal symptoms were attenuated. These data reveal that NMDA receptors on noradrenergic neurons regulate development of opiate dependence and psychomotor sensitization, by controlling drug-induced noradrenaline signalling.

  14. The inhibition of the dorsal paragigantocellular reticular nucleus induces waking and the activation of all adrenergic and noradrenergic neurons: a combined pharmacological and functional neuroanatomical study.

    PubMed

    Clément, Olivier; Valencia Garcia, Sara; Libourel, Paul-Antoine; Arthaud, Sébastien; Fort, Patrice; Luppi, Pierre-Hervé

    2014-01-01

    GABAergic neurons specifically active during paradoxical sleep (PS) localized in the dorsal paragigantocellular reticular nucleus (DPGi) are known to be responsible for the cessation of activity of the noradrenergic neurons of the locus coeruleus during PS. In the present study, we therefore sought to determine the role of the DPGi in PS onset and maintenance and in the inhibition of the LC noradrenergic neurons during this state. The effect of the inactivation of DPGi neurons on the sleep-waking cycle was examined in rats by microinjection of muscimol, a GABAA agonist, or clonidine, an alpha-2 adrenergic receptor agonist. Combining immunostaining of the different populations of wake-inducing neurons with that of c-FOS, we then determined whether muscimol inhibition of the DPGi specifically induces the activation of the noradrenergic neurons of the LC. Slow wave sleep and PS were abolished during 3 and 5 h after muscimol injection in the DPGi, respectively. The application of clonidine in the DPGi specifically induced a significant decrease in PS quantities and delayed PS appearance compared to NaCl. We further surprisingly found out that more than 75% of the noradrenergic and adrenergic neurons of all adrenergic and noradrenergic cell groups are activated after muscimol treatment in contrast to the other wake active systems significantly less activated. These results suggest that, in addition to its already know inhibition of LC noradrenergic neurons during PS, the DPGi might inhibit the activity of noradrenergic and adrenergic neurons from all groups during PS, but also to a minor extent during SWS and waking.

  15. Locomotor-activated neurons of the cat. II. Noradrenergic innervation and colocalization with NEα1a or NEα2b receptors in the thoraco-lumbar spinal cord

    PubMed Central

    Johnson, Dawn M. G.; Riesgo, Mirta I.; Pinzon, Alberto

    2011-01-01

    Norepinephrine (NE) is a strong modulator and/or activator of spinal locomotor networks. Thus noradrenergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the noradrenergic innervation of functionally related, locomotor-activated neurons within the thoraco-lumbar spinal cord. This was accomplished by immunohistochemical colocalization of noradrenergic fibers using dopamine-β-hydroxylase or NEα1A and NEα2B receptors with cells expressing the c-fos gene activity-dependent marker Fos. Experiments were performed on paralyzed, precollicular-postmamillary decerebrate cats, in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. The majority of Fos labeled neurons, especially abundant in laminae VII and VIII throughout the thoraco-lumbar (T13-L7) region of locomotor animals, showed close contacts with multiple noradrenergic boutons. A small percentage (10–40%) of Fos neurons in the T7-L7 segments showed colocalization with NEα1A receptors. In contrast, NEα2B receptor immunoreactivity was observed in 70–90% of Fos cells, with no obvious rostrocaudal gradient. In comparison with results obtained from our previous study on the same animals, a significantly smaller proportion of Fos labeled neurons were innervated by noradrenergic than serotonergic fibers, with significant differences observed for laminae VII and VIII in some segments. In lamina VII of the lumbar segments, the degree of monoaminergic receptor subtype/Fos colocalization examined statistically generally fell into the following order: NEα2B = 5-HT2A ≥ 5-HT7 = 5-HT1A > NEα1A. These results suggest that noradrenergic modulation of locomotion involves NEα1A/NEα2B receptors on noradrenergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments. Further study of the functional role of these receptors in locomotion is warranted. PMID:21307324

  16. Noradrenergic modulation of glutamate-induced excitatory responses in single neurons of the red nucleus: an electrophysiological study.

    PubMed

    Bronzi, D; Licata, F; Li Volsi, G

    2015-08-06

    The effect induced by noradrenaline (NA) on the spiking activity evoked by glutamate (Glu) on single neurons of the mesencephalic red nucleus (RN) of the rat was studied extracellularly. Long-lasting microiontophoretic applications of the amine induced a significant and reversible depression of the responsiveness of RN neurons to Glu. This effect was mediated by noradrenergic alpha2 receptors since it was mimicked by application of clonidine, an alpha2 adrenoceptor agonist, and blocked or at least reduced by application of yohimbine, an antagonist of NA for the same receptors. The effect appears homogeneously throughout the nucleus and is independent of the effect of NA on baseline firing rate. Application of isoproterenol, a beta adrenoceptor agonist, either enhanced or depressed neuronal responses to Glu in a high percentage (86%) of the tested neurons. Moreover, application of timolol, a beta adrenoceptor antagonist, was able to strengthen the depressive effects induced by NA application on neuronal responsiveness to Glu. Although these data suggest some involvement of beta adrenergic receptors in the modulation of neuronal responsiveness to Glu, the overall results indicate a short-term depressive action of NA, mediated by alpha2 receptors, on the responsiveness of RN neurons and suggest that stress initially leads to an attenuation of the relay function of the RN. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Transforming growth factor-beta in the brain enhances fat oxidation via noradrenergic neurons in the ventromedial and paraventricular hypothalamic nucleus.

    PubMed

    Fujikawa, Teppei; Matsumura, Shigenobu; Yamada, Hiroyuki; Inoue, Kazuo; Fushiki, Tohru

    2007-10-10

    We have previously reported that intracisternal administration of TGF-beta induces an increase in fat oxidation and that intracisternal administration of anti-TGF-beta antibody partially inhibits an increase in fat oxidation during treadmill running in rats. These results indicate a regulatory role of that TGF-beta in the brain on fat oxidation during exercise. However, it is not clear how TGF-beta in the brain enhance fat oxidation. We hypothesized that TGF-beta in the brain elicits its regulatory effects on fat oxidation via hypothalamic noradrenergic neurons, because some reports have demonstrated the important role of hypothalamic noradrenergic neurons in the regulation of fat oxidation during and after exercise. To examine this hypothesis, we measured the extracellular noradrenaline (NA) levels in the paraventricular hypothalamic nucleus (PVH), ventromedial hypothalamic nucleus (VMH) and lateral hypothalamic area, which are especially important in the regulation of energy metabolism, after intracisternal administration of TGF-beta by using an in vivo brain microdialysis. Microdialysis study revealed that intracisternal administration of TGF-beta3 caused increases in the NA levels in the PVH and VMH. Then, we investigated the impact of impairment of noradrenergic neurons in the PVH and VMH by neurotoxin 6-hydroxydopamine microinjection (NA-lesion) on the action of intracisternal administration of TGF-beta. The NA lesion completely abolished the regulatory effect of TGF-beta on fat oxidation. These results suggest that TGF-beta in the brain enhances fat oxidation via noradrenergic neurons in the PVH and VMH.

  18. Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats

    PubMed Central

    Lu, Jackie W; Fenik, Victor B; Branconi, Jennifer L; Mann, Graziella L; Rukhadze, Irma; Kubin, Leszek

    2007-01-01

    Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABAA receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABAA receptor antagonist, bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABAA receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABAA receptor-expressing PF neurones may cause narcolepsy/cataplexy. PMID:17495048

  19. Transgenic mice lacking CREB and CREM in noradrenergic and serotonergic neurons respond differently to common antidepressants on tail suspension test.

    PubMed

    Rafa-Zabłocka, Katarzyna; Kreiner, Grzegorz; Bagińska, Monika; Kuśmierczyk, Justyna; Parlato, Rosanna; Nalepa, Irena

    2017-10-18

    Evidence exists that chronic antidepressant therapy enhances CREB levels and activity. Nevertheless, the data are not conclusive, as previous analysis of transgenic mouse models has suggested that CREB inactivation in fact contributes to antidepressant-like behavior. The aim of this study was to evaluate the role of CREB in this context by exploiting novel transgenic mouse models, characterized by selective ablation of CREB restricted to noradrenergic (Creb1 DBHCre /Crem-/-) or serotonergic (Creb1 TPH2CreERT2 /Crem-/-) neurons in a CREM-deficient background to avoid possible compensatory effects of CREM. Selective and functional ablation of CREB affected antidepressant-like behavior in a tail suspension test (TST) after antidepressant treatment. Contrary to single Creb1 DBHCre mutants, Creb1 DBHCre /Crem-/- mice did not respond to acute desipramine administration (20 mg/kg) on the TST. On the other hand, single Creb1 TPH2CreERT2 mutants displayed reduced responses to fluoxetine (10 mg/kg) on the TST, while the effects in Creb1 TPH2CreERT2 /Crem-/- mice differed by gender. Our results provide further evidence for the important role of CREM as a compensatory factor. Additionally, the results indicate that new models based on the functional ablation of CREB in select neuronal populations may represent a valuable tool for investigating the role of CREB in the mechanism of antidepressant therapy.

  20. Yohimbine Anxiogenesis in the Elevated Plus Maze Requires Hindbrain Noradrenergic Neurons that Target the Anterior Ventrolateral Bed Nucleus of the Stria Terminalis

    PubMed Central

    Zheng, Huiyuan; Rinaman, Linda

    2013-01-01

    The α2 adrenergic receptor antagonist yohimbine (YO) increases transmitter release from noradrenergic (NA) terminals in cortical and subcortical brain regions, including the bed nucleus of the stria terminalis (BST). YO activates the HPA stress axis and is potently anxiogenic in rats and humans. We previously reported that hindbrain NA neurons within the caudal nucleus of the solitary tract (NST-A2/C2) and ventrolateral medulla (VLM-A1/C1) that innervate the anterior ventrolateral (vl)BST contribute to the ability of YO to activate the HPA stress axis in rats. To determine whether the same NA pathway also contributes to YO-induced anxiogenesis in the elevated plus maze (EPMZ), a selective saporin ribotoxin conjugate (DSAP) was microinjected bilaterally into the anterior vlBST to destroy its NA inputs. Sham-lesioned controls were microinjected with vehicle. Two experiments were conducted to determine DSAP lesion effects on EPMZ behavior. DSAP lesions did not alter maze behavior in rats after i.p. saline, and did not alter the significant effect of prior maze experience to reduce exploratory and open arm maze activities. However, in maze-naïve rats, DSAP lesions abolished YO anxiogenesis in the EPMZ. Postmortem immunocytochemical analyses confirmed that DSAP consistently ablated caudal NST-A2/C2 and VLM-A1/C1 neurons that innervate the anterior vlBST. DSAP lesions did not destroy non-NA inputs to the anterior vlBST, and produced inconsistent cell loss within the pontine locus coeruleus (A6 cell group) that was unrelated to YO anxiogenesis. Thus, the ability of YO to increase anxiety-like behavior in the EPMZ depends on hindbrain NA neurons that target the anterior vlBST. PMID:23368289

  1. Metformin normalizes the structural changes in glycogen preceding prediabetes in mice overexpressing neuropeptide Y in noradrenergic neurons.

    PubMed

    Ailanen, Liisa; Bezborodkina, Natalia N; Virtanen, Laura; Ruohonen, Suvi T; Malova, Anastasia V; Okovityi, Sergey V; Chistyakova, Elizaveta Y; Savontaus, Eriika

    2018-04-01

    Hepatic insulin resistance and increased gluconeogenesis are known therapeutic targets of metformin, but the role of hepatic glycogen in the pathogenesis of diabetes is less clear. Mouse model of neuropeptide Y (NPY) overexpression in noradrenergic neurons (OE-NPY D βH ) with a phenotype of late onset obesity, hepatosteatosis, and prediabetes was used to study early changes in glycogen structure and metabolism preceding prediabetes. Furthermore, the effect of the anti-hyperglycemic agent, metformin (300 mg/kg/day/4 weeks in drinking water), was assessed on changes in glycogen metabolism, body weight, fat mass, and glucose tolerance. Glycogen structure was characterized by cytofluorometric analysis in isolated hepatocytes and mRNA expression of key enzymes by qPCR. OE-NPY D βH mice displayed decreased labile glycogen fraction relative to stabile fraction (the intermediate form of glycogen) suggesting enhanced glycogen cycling. This was supported by decreased filling of glucose residues in the 10th outer tier of the glycogen molecule, which suggests accelerated glycogen phosphorylation. Metformin reduced fat mass gain in both genotypes, but glucose tolerance was improved mostly in wild-type mice. However, metformin inhibited glycogen accumulation and normalized the ratio between glycogen structures in OE-NPY D βH mice indicating decreased glycogen synthesis. Furthermore, the presence of glucose residues in the 11th tier together with decreased glycogen phosphorylase expression suggested inhibition of glycogen degradation. In conclusion, structural changes in glycogen of OE-NPY D βH mice point to increased glycogen metabolism, which may predispose them to prediabetes. Metformin treatment normalizes these changes and suppresses both glycogen synthesis and phosphorylation, which may contribute to its preventive effect on the onset of diabetes.

  2. Iontophoresis of lithium antagonizes noradrenergic action on prefrontal neurons of the rat.

    PubMed

    Kovács, Péter; Hernádi, István

    2002-08-23

    Various lithium (Li(+)) compounds have been proven to be effective in the therapy of bipolar affective disorder, but their mechanism of pharmacological action is not clearly defined. In our present in vivo electrophysiological study we tested the action of microiontophoretically applied Li(+) and NE on the maintained firing activity of prefrontal cortical neurons of the rat. Target cells were located in the prelimbic cortical projection region (PrL) of the ascending norepinephrinergic pathway. Our data, collected from single unit activity of 59 PrL neurons, demonstrate that lithium can (1) suppress maintained discharge activity, or (2) antagonize both the inhibitory and excitatory modulation of firing activity elicited by NE. These effects of Li(+) were not replicable with GABA-initiated inhibition or glutamate analogue-initiated excitation of discharge activity. Our findings suggest that the action of Li(+) mainly targets the NE-coupled receptor mechanisms and, therefore, it may play an important role in stabilizing the modulation of discharge activity in the PFC caused by different extracellular levels of NE.

  3. Repetitive treatment with diluted bee venom reduces neuropathic pain via potentiation of locus coeruleus noradrenergic neuronal activity and modulation of spinal NR1 phosphorylation in rats.

    PubMed

    Kang, Suk-Yun; Roh, Dae-Hyun; Yoon, Seo-Yeon; Moon, Ji-Young; Kim, Hyun-Woo; Lee, Hye-Jung; Beitz, Alvin J; Lee, Jang-Hern

    2012-02-01

    We previously demonstrated that a single injection of diluted bee venom (DBV) temporarily alleviates thermal hyperalgesia, but not mechanical allodynia, in neuropathic rats. The present study was designed to determine whether repetitive injection of DBV produces more potent analgesic effects on neuropathy-induced nociception and whether those effects are associated with increased neuronal activity in the locus coeruleus (LC) and with the suppression of spinal NMDA receptor NR1 subunit phosphorylation (pNR1). DBV (.25 mg/kg) was administered subcutaneously twice a day for 2 weeks beginning on day 15 post-chronic constrictive injury surgery. Pain responses were examined and potential changes in LC Fos expression and spinal pNR1 expression were determined. Repetitive DBV administration significantly reduced mechanical allodynia, as well as thermal hyperalgesia. The activity of LC noradrenergic neurons was increased and spinal pNR1 expression was significantly suppressed by repetitive DBV as compared with those of vehicle or single DBV injection. These suppressive effects of repetitive DBV on neuropathic pain and spinal pNR1 were prevented by intrathecal pretreatment of idazoxan, an alpha-2 adrenoceptor antagonist. These results indicate that repetitive DBV produces potent analgesic effects on neuropathic pain and this is associated with the activation of the LC noradrenergic system and with a reduction in spinal pNR1. The results of current study demonstrate that repetitive administration of DBV significantly suppresses neuropathic pain. Furthermore, this study provides mechanistic information that repetitive treatment of DBV can produce more potent analgesic effect than single DBV treatment, indicating a potential novel strategy for the management of chronic pain. Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.

  4. Opioid and noradrenergic contributions of tapentadol to the inhibition of locus coeruleus neurons in the streptozotocin rat model of polyneuropathic pain.

    PubMed

    Torres-Sanchez, Sonia; Borges, Gisela Da Silva; Mico, Juan A; Berrocoso, Esther

    2018-03-15

    Tapentadol is an analgesic that acts as an agonist of µ opioid receptors (MOR) and that inhibits noradrenaline reuptake. Data from healthy rats show that tapentadol inhibits neuronal activity in the locus coeruleus (LC), a nucleus regulated by both the noradrenergic and opioid systems. Thus, we set out to investigate the effect of tapentadol on LC activity in streptozotocin (STZ)-induced diabetic rats, a model of diabetic polyneuropathy, by analyzing single-unit extracellular recordings of LC neurons. Four weeks after inducing diabetes, tapentadol dose-response curves were obtained from animals pre-treated with RX821002 or naloxone (alpha2-adrenoceptors and opioid receptors antagonists, respectively). In STZ rats, the spontaneous activity of LC neurons (0.9 ± 0.1 Hz) was lower than in naïve animals (1.5 ± 0.1 Hz), and tapentadol's inhibitory effect was also weaker. Alpha2-adrenoceptors blockade by RX821002 (100 μg/kg i.v.) in STZ animals significantly increased the spontaneous activity (from 0.8 ± 0.1 to 1.4 ± 0.2 Hz) and it dampened the inhibition of LC neurons produced by tapentadol. However, opioid receptors blockade following naloxone pre-treatment (5 mg/kg i.v.) did not alter the spontaneous firing rate (0.9 ± 0.2 vs 0.9 ± 0.2 Hz) or the inhibitory effect of tapentadol on LC neurons in STZ animals. Thus, diabetic polyneuropathy appears to exert neuroplastic changes in LC neurotransmission, enhancing the sensitivity of alpha2-adrenoceptors and dampening opioid receptors expression. Tapentadol's activity seems to be predominantly mediated through its noradrenergic effects rather than its influence on opioid receptors in the STZ model of diabetic polyneuropathy. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. vglut2 and gad expression reveal distinct patterns of dual GABAergic versus glutamatergic cotransmitter phenotypes of dopaminergic and noradrenergic neurons in the zebrafish brain.

    PubMed

    Filippi, Alida; Mueller, Thomas; Driever, Wolfgang

    2014-06-15

    Throughout the vertebrate lineage, dopaminergic neurons form important neuromodulatory systems that influence motor behavior, mood, cognition, and physiology. Studies in mammals have established that dopaminergic neurons often use γ-aminobutyric acid (GABA) or glutamatergic cotransmission during development and physiological function. Here, we analyze vglut2, gad1b and gad2 expression in combination with tyrosine hydroxylase immunoreactivity in 4-day-old larval and 30-day-old juvenile zebrafish brains to determine which dopaminergic and noradrenergic groups may use GABA or glutamate as a second transmitter. Our results show that most dopaminergic neurons also express GABAergic markers, including the dopaminergic groups of the olfactory bulb (homologous to mammalian A16) and the subpallium, the hypothalamic groups (A12, A14), the prethalamic zona incerta group (A13), the preoptic groups (A15), and the pretectal group. Thus, the majority of catecholaminergic neurons are gad1b/2-positive and coexpress GABA. A very few gad1/2-negative dopaminergic groups, however, express vglut2 instead and use glutamate as a second transmitter. These glutamatergic dual transmitter phenotypes are the Orthopedia transcription factor-dependent, A11-type dopaminergic neurons of the posterior tuberculum. All together, our results demonstrate that all catecholaminergic groups in zebrafish are either GABAergic or glutamatergic. Thus, cotransmission of dopamine and noradrenaline with either GABA or glutamate appears to be a regular feature of zebrafish catecholaminergic systems. We compare our results with those that have been described for mammalian systems, discuss the phenomenon of transmitter dualism in the context of developmental specification of GABAergic and glutamatergic regions in the brain, and put this phenomenon in an evolutionary perspective. Copyright © 2013 Wiley Periodicals, Inc.

  6. vglut2 and gad expression reveal distinct patterns of dual GABAergic versus glutamatergic cotransmitter phenotypes of dopaminergic and noradrenergic neurons in the zebrafish brain

    PubMed Central

    Filippi, Alida; Mueller, Thomas; Driever, Wolfgang

    2014-01-01

    Throughout the vertebrate lineage, dopaminergic neurons form important neuromodulatory systems that influence motor behavior, mood, cognition, and physiology. Studies in mammals have established that dopaminergic neurons often use γ-aminobutyric acid (GABA) or glutamatergic cotransmission during development and physiological function. Here, we analyze vglut2, gad1b and gad2 expression in combination with tyrosine hydroxylase immunoreactivity in 4-day-old larval and 30-day-old juvenile zebrafish brains to determine which dopaminergic and noradrenergic groups may use GABA or glutamate as a second transmitter. Our results show that most dopaminergic neurons also express GABAergic markers, including the dopaminergic groups of the olfactory bulb (homologous to mammalian A16) and the subpallium, the hypothalamic groups (A12, A14), the prethalamic zona incerta group (A13), the preoptic groups (A15), and the pretectal group. Thus, the majority of catecholaminergic neurons are gad1b/2-positive and coexpress GABA. A very few gad1/2-negative dopaminergic groups, however, express vglut2 instead and use glutamate as a second transmitter. These glutamatergic dual transmitter phenotypes are the Orthopedia transcription factor–dependent, A11-type dopaminergic neurons of the posterior tuberculum. All together, our results demonstrate that all catecholaminergic groups in zebrafish are either GABAergic or glutamatergic. Thus, cotransmission of dopamine and noradrenaline with either GABA or glutamate appears to be a regular feature of zebrafish catecholaminergic systems. We compare our results with those that have been described for mammalian systems, discuss the phenomenon of transmitter dualism in the context of developmental specification of GABAergic and glutamatergic regions in the brain, and put this phenomenon in an evolutionary perspective. J. Comp. Neurol. 522:2019–2037, 2014. PMID:24374659

  7. Both serotonergic and noradrenergic systems modulate the development of tolerance to chronic stress in rats with lesions of the serotonergic neurons of the median raphe nucleus.

    PubMed

    Pereira, A C; Carvalho, M C; Padovan, C M

    2017-06-27

    Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2h) or chronic restraint (2h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10mg/kg) or saline was performed twice daily (12-12h interval), for 7 consecutive days. EPM test was conducted 24h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Interactions between Brainstem Noradrenergic Neurons and the Nucleus Accumbens Shell in Modulating Memory for Emotionally Arousing Events

    ERIC Educational Resources Information Center

    Kerfoot, Erin C.; Williams, Cedric L.

    2011-01-01

    The nucleus accumbens shell (NAC) receives axons containing dopamine-[beta]-hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these…

  9. Cannabinoid modulation of limbic forebrain noradrenergic circuitry

    PubMed Central

    Carvalho, Ana Franky; Mackie, Kenneth; Van Bockstaele, Elisabeth J.

    2012-01-01

    Both the endocannabinoid and noradrenergic systems have been implicated in neuropsychiatric disorders. Importantly, low levels of norepinephrine are seen in patients with depression and antagonism of the cannabinoid receptor type 1 (CB1R) is able to induce depressive symptoms in rodents and humans. Whether the interaction between the two systems is important for the regulation of these behaviors is not known. In the present study, adult male Sprague-Dawley rats were acutely or chronically administered the CB1R synthetic agonist, WIN 55,212-2, and α2A and β1 adrenergic receptors (AR) were quantified by western blot. These AR have been shown to be altered in a number of psychiatric disorders and following antidepressant treatment. CB1R agonist treatment induced a differential decrease of α2A- and β1-ARs in the nucleus accumbens (Acb). Moreover, to assess long lasting changes induced by CB1R activation, some of the chronically treated rats were euthanized seven days following the last injection. This revealed a persistent effect on α2A-AR levels. Furthermore, the localization of CB1R with respect to noradrenergic profiles was assessed in the Acb and in the nucleus of the solitary tract (NTS). Our results show a significant topographic distribution of CB1R and dopamine beta hydroxylase immunoreactivities in the Acb with higher co-localization observed in the NTS. In the Acb, CB1R-ir was found in terminals forming either symmetric or asymmetric synapses. These results suggest that cannabinoids may modulate noradrenergic signaling in the Acb by acting on noradrenergic neurons in the NTS or indirectly by modulating inhibitory and excitatory input in the Acb. PMID:20074224

  10. Plasma Dopamine-Beta-Hydroxylase as an Index of Peripheral Noradrenergic Activity

    DTIC Science & Technology

    1981-08-17

    acinar ducts of salivary and sublingual glands and in peripheral noradrenergic neurons. 17 The plasma contains DBH but the cellular elements do not...subl in- gual glands . Noradrenergic neurons are not totally responsible for the saliva DBH because th i r t y days after these glands are denervated...a substantial amount remains (29, 275). DBH’s presence in the ducts suggests that it is transported by the salivary gland from the circulation into

  11. The role of central noradrenergic dysregulation in anxiety disorders: evidence from clinical studies.

    PubMed

    Kalk, N J; Nutt, D J; Lingford-Hughes, A R

    2011-01-01

    The nature of the noradrenergic dysregulation in clinical anxiety disorders remains unclear. In panic disorder, the predominant view has been that central noradrenergic neuronal networks and/or the sympathetic nervous system was normal in patients at rest, but hyper-reactive to specific stimuli, for example carbon dioxide. These ideas have been extended to other anxiety disorders, which share with panic disorder characteristic subjective anxiety and physiological symptoms of excess sympathetic activity. For example, Generalized Anxiety Disorder is characterized by chronic free-floating anxiety, muscle tension, palpitation and insomnia. It has been proposed that there is chronic central hypersecretion of noradrenaline in Generalized Anxiety Disorder, with consequent hyporesponsiveness of central post-synaptic receptors. With regards to other disorders, it has been suggested that there is noradrenergic involvement or derangement, but a more specific hypothesis has not been enunciated. This paper reviews the evidence for noradrenergic dysfunction in anxiety disorders, derived from indirect measures of noradrenergic function in clinical populations.

  12. Noradrenergic Nuclei that Receive Sensory Input During Mating and Project to the Ventromedial Hypothalamus Play a Role in Mating-Induced Pseudopregnancy in the Female Rat

    PubMed Central

    Northrop, L. E.; Polston, E. K.; Erskine, M. S.

    2011-01-01

    In female rats, vaginal-cervical stimulation (VCS) received during mating induces bicircadian prolactin surges that are required for the maintenance of pregnancy or pseudopregnancy (PSP). The neural circuits that transmit VCS inputs to the brain have not been fully described, although mating stimulation is known to activate medullary noradrenergic cell groups that project to the forebrain. In response to VCS, these neurones release noradrenaline within the ventrolateral division of the ventromedial hypothalamus (VMHvl) and the posterodorsal medial amygdala (MePD), two forebrain sites that are implicated in the initiation of PSP. Noradrenaline receptor activation within the VMHvl is both necessary and sufficient for PSP induction, suggesting that noradrenaline acting within the VMHvl is particularly important in mediating the effects of VCS towards the establishment of PSP. We therefore investigated whether or not endogenous, VCS-induced noradrenaline release within the VMHvl is involved in PSP induction in the rat. Before the receipt of sufficient mating stimulation to induce PSP, a retrograde neurotoxin, dopamine-β-hydroxylase-saporin (DBH-SAP), was infused bilaterally into the either the VMHvl or the MePD to selectively destroy afferent noradrenergic nuclei in the brainstem. DBH-SAP infusions into the VMHvl lesioned mating-responsive noradrenergic neurones in A1 and A2 medullary nuclei and reduced the incidence of PSP by 50%. Infusions of DBH-SAP into the MePD had no effect on the subsequent induction of PSP. These results suggest that VCS is conveyed to mating-responsive forebrain areas by brainstem noradrenergic neurones, and that the activity of noradrenergic cells projecting to the VMHvl is involved in the induction of PSP. PMID:20673300

  13. Noradrenergic nuclei that receive sensory input during mating and project to the ventromedial hypothalamus play a role in mating-induced pseudopregnancy in the female rat.

    PubMed

    Northrop, L E; Polston, E K; Erskine, M S

    2010-10-01

    In female rats, vaginal-cervical stimulation (VCS) received during mating induces bicircadian prolactin surges that are required for the maintenance of pregnancy or pseudopregnancy (PSP). The neural circuits that transmit VCS inputs to the brain have not been fully described, although mating stimulation is known to activate medullary noradrenergic cell groups that project to the forebrain. In response to VCS, these neurones release noradrenaline within the ventrolateral division of the ventromedial hypothalamus (VMHvl) and the posterodorsal medial amygdala (MePD), two forebrain sites that are implicated in the initiation of PSP. Noradrenaline receptor activation within the VMHvl is both necessary and sufficient for PSP induction, suggesting that noradrenaline acting within the VMHvl is particularly important in mediating the effects of VCS towards the establishment of PSP. We therefore investigated whether or not endogenous, VCS-induced noradrenaline release within the VMHvl is involved in PSP induction in the rat. Before the receipt of sufficient mating stimulation to induce PSP, a retrograde neurotoxin, dopamine-β-hydroxylase-saporin (DBH-SAP), was infused bilaterally into the either the VMHvl or the MePD to selectively destroy afferent noradrenergic nuclei in the brainstem. DBH-SAP infusions into the VMHvl lesioned mating-responsive noradrenergic neurones in A1 and A2 medullary nuclei and reduced the incidence of PSP by 50%. Infusions of DBH-SAP into the MePD had no effect on the subsequent induction of PSP. These results suggest that VCS is conveyed to mating-responsive forebrain areas by brainstem noradrenergic neurones, and that the activity of noradrenergic cells projecting to the VMHvl is involved in the induction of PSP. © 2010 The Authors. Journal of Neuroendocrinology © 2010 Blackwell Publishing Ltd.

  14. Striatal adenosine A2A receptor neurons control active-period sleep via parvalbumin neurons in external globus pallidus

    PubMed Central

    Qu, Wei-Min; Yang, Su-Rong; Cherasse, Yoan; Lazarus, Michael; Schiffmann, Serge N; d'Exaerde, Alban de Kerchove

    2017-01-01

    Dysfunction of the striatum is frequently associated with sleep disturbances. However, its role in sleep-wake regulation has been paid little attention even though the striatum densely expresses adenosine A2A receptors (A2ARs), which are essential for adenosine-induced sleep. Here we showed that chemogenetic activation of A2AR neurons in specific subregions of the striatum induced a remarkable increase in non-rapid eye movement (NREM) sleep. Anatomical mapping and immunoelectron microscopy revealed that striatal A2AR neurons innervated the external globus pallidus (GPe) in a topographically organized manner and preferentially formed inhibitory synapses with GPe parvalbumin (PV) neurons. Moreover, lesions of GPe PV neurons abolished the sleep-promoting effect of striatal A2AR neurons. In addition, chemogenetic inhibition of striatal A2AR neurons led to a significant decrease of NREM sleep at active period, but not inactive period of mice. These findings reveal a prominent contribution of striatal A2AR neuron/GPe PV neuron circuit in sleep control. PMID:29022877

  15. Norepinephrine transport-mediated gene expression in noradrenergic neurogenesis.

    PubMed

    Hu, Yao Fei; Caron, Marc G; Sieber-Blum, Maya

    2009-04-08

    We have identified a differential gene expression profile in neural crest stem cells that is due to deletion of the norepinephrine transporter (NET) gene. NET is the target of psychotropic substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET mutations have been implicated in depression, anxiety, orthostatic intolerance and attention deficit hyperactivity disorder (ADHD). NET function in adult noradrenergic neurons of the peripheral and central nervous systems is to internalize norepinephrine from the synaptic cleft. By contrast, during embryogenesis norepinephrine (NE) transport promotes differentiation of neural crest stem cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors block noradrenergic differentiation. While the structure of NET und the regulation of NET function are well described, little is known about downstream target genes of norepinephrine (NE) transport. We have prepared gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) mouse neural crest cells using long serial analysis of gene expression (LongSAGE). Comparison analyses have identified a number of important differentially expressed genes, including genes relevant to neural crest formation, noradrenergic neuron differentiation and the phenotype of NETKO mice. Examples of differentially expressed genes that affect noradrenergic cell differentiation include genes in the bone morphogenetic protein (BMP) signaling pathway, the Phox2b binding partner Tlx2, the ubiquitin ligase Praja2, and the inhibitor of Notch signaling, Numbl. Differentially expressed genes that are likely to contribute to the NETKO phenotype include dopamine-beta-hydroxylase (Dbh), tyrosine hydroxylase (Th), the peptide transmitter 'cocaine and amphetamine regulated transcript' (Cart), and the serotonin receptor subunit Htr3a. Real-time PCR confirmed differential expression of key genes not only in neural

  16. Noradrenergic modulation of retinogeniculate transmission in the cat.

    PubMed Central

    Funke, K; Pape, H C; Eysel, U T

    1993-01-01

    1. Relay neurones were extracellularly recorded from the A-layers of the dorsal lateral geniculate nucleus (dLGN) of the anaesthetized cat. The noradrenergic influence on retinogeniculate transmission was investigated through microiontopheretic techniques in a total of 140 dLGN relay cells using three experimental approaches: (i) the effects of agonists for alpha 1-, alpha 2- and beta-adrenoceptors were separately analysed; (ii) the noradrenergic influence was related to the global state of activity of the relay neurones, which was associated with discrete patterns of the electroencephalogram (EEG); (iii) distinct phases of visual responses evoked from the area of the retinal receptive field, and of binocular and lateral inhibitory responses, were evaluated before, during and after the action of noradrenergic agonists. 2. The spontaneous generation of high-frequency bursts of spikes in dLGN relay neurones, associated with periods of highly synchronized, delta-like patterns of the EEG, was selectively suppressed by the beta-adrenoceptor agonist isoprenaline or the alpha 1- adrenoceptor agonist phenylephrine. Single action potentials, occurring at a low frequency between bursts, were significantly less affected. Depending upon the ejection level of the adrenoceptor agonists, burst activity was suppressed by 23-73%, compared with a reduction in single spike firing in the range 7-24%. The suppression of burst firing occurred in all functional types of dLGN relay neurones (X, Y; on, off), enhanced burst activity was observed in less than 1% of the cells. 3. On-going tonic sequences of action potentials (around 15 Hz), occurring during periods of EEG activity characterized by lower amplitudes and higher frequencies, were separately affected by adrenoceptor agonists. Isoprenaline had no significant effect, phenylephrine induced a global reduction of spike firing with no obvious relation to the ejection level, and the alpha 2-adrenoceptor agonist clonidine inhibited action

  17. Noradrenergic inputs from locus coeruleus to posterior ventral tegmental area are essential to support ethanol reinforcement.

    PubMed

    Shelkar, Gajanan P; Kumar, Santosh; Singru, Praful S; Subhedar, Nishikant K; Kokare, Dadasaheb M

    2017-03-01

    Although dysregulation of the dopaminergic mesolimbic system is generally considered central to addiction, the involvement of other circuits is increasingly being appreciated. An interaction between locus coeruleus (LC) noradrenergic neurons and the posterior ventral tegmental area (pVTA) dopaminergic system, in the processing of drug-triggered reward, has been suggested, but not demonstrated in behaving animals. Herein, we try to tease out the precise role of noradrenergic neurons in the LC-VTA circuit in mediating reward and reinforcement behavior associated with ethanol. In the standard two-lever (active/inactive) operant paradigm, the rats were trained to self-administer ethanol in pVTA and subjected to pharmacological intervention. Intra-pVTA administration of phenylephrine (alpha-1 adrenoceptor agonist) increased ethanol self-administration, while prazosin and disulfiram (agents that reduce noradrenergic tone) produced opposite effects. While degeneration [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, DSP-4, intraperitoneal route] or silencing (lidocaine or muscimol, both via intra-LC route) of the LC noradrenergic neurons decreased, phenylephrine via the intra-LC route reinstated ethanol self-administration. Furthermore, lidocaine reduced ethanol self-administration, but the effect was fully attenuated by noradrenaline given directly in the pVTA. This suggests that the feedback signals from LC to pVTA are necessary to sustain the ethanol self-infusion activity. Ethanol self-administration significantly increased tyrosine hydroxylase immunoreactivity in pVTA and LC; the response was blocked by DSP-4 pre-treatment. While dopamine D 1 , but not D 2 , receptors were localized on noradrenergic LC neurons, pre-treatment with SCH-23390 (intra-LC) dampened the lever press activity. We suggest that two-way communications between VTA and LC regions is essential for ethanol-triggered reinforcement behavior. © 2015 Society for the Study of Addiction.

  18. Noradrenergic lesioning with an anti-dopamine beta-hydroxylase immunotoxin

    NASA Technical Reports Server (NTRS)

    Picklo, M. J.; Wiley, R. G.; Lappi, D. A.; Robertson, D.

    1994-01-01

    Sympathectomy has been achieved by a variety of methods but each has its limitations. These include lack of tissue specificity, incomplete lesioning, and the age range of susceptibility to the lesioning. To circumvent these drawbacks, an immunotoxin was constructed using a monoclonal antibody against the noradrenergic specific enzyme dopamine beta-hydroxylase (D beta H) coupled via a disulfide bond to saporin, a ribosomal inactivating protein. Three days after intravenous injection of the anti-D beta H immunotoxin (50 micrograms) into adult Sprague-Dawley rats, 66% of neurons in the superior cervical ganglia were chromatolytic. Superior cervical ganglia neurons were poisoned in 1 day old and 1 week old (86% of neurons) neonatal rats following subcutaneous injection of 3.75 and 15 micrograms, respectively. The anti-D beta H immunotoxin will be a useful tool in the study of the peripheral noradrenergic system in adult and neonatal animals.

  19. Genetic dissection of dopaminergic and noradrenergic contributions to catecholaminergic tracts in early larval zebrafish.

    PubMed

    Kastenhuber, Edda; Kratochwil, Claudius F; Ryu, Soojin; Schweitzer, Jörn; Driever, Wolfgang

    2010-02-15

    The catecholamines dopamine and noradrenaline provide some of the major neuromodulatory systems with far-ranging projections in the brain and spinal cord of vertebrates. However, development of these complex systems is only partially understood. Zebrafish provide an excellent model for genetic analysis of neuronal specification and axonal projections in vertebrates. Here, we analyze the ontogeny of the catecholaminergic projections in zebrafish embryos and larvae up to the fifth day of development and establish the basic scaffold of catecholaminergic connectivity. The earliest dopaminergic diencephalospinal projections do not navigate along the zebrafish primary neuron axonal scaffold but establish their own tracts at defined ventrolateral positions. By using genetic tools, we study quantitative and qualitative contributions of noradrenergic and defined dopaminergic groups to the catecholaminergic scaffold. Suppression of Tfap2a activity allows us to eliminate noradrenergic contributions, and depletion of Otp activity deletes mammalian A11-like Otp-dependent ventral diencephalic dopaminergic groups. This analysis reveals a predominant contribution of Otp-dependent dopaminergic neurons to diencephalospinal as well as hypothalamic catecholaminergic tracts. In contrast, noradrenergic projections make only a minor contribution to hindbrain and spinal catecholaminergic tracts. Furthermore, we can demonstrate that, in zebrafish larvae, ascending catecholaminergic projections to the telencephalon are generated exclusively by Otp-dependent diencephalic dopaminergic neurons as well as by hindbrain noradrenergic groups. Our data reveal the Otp-dependent A11-type dopaminergic neurons as the by far most prominent dopaminergic system in larval zebrafish. These findings are consistent with a hypothesis that Otp-dependent dopaminergic neurons establish the major modulatory system for somatomotor and somatosensory circuits in larval fish. 2009 Wiley-Liss, Inc.

  20. Stress Response, Brain Noradrenergic System and Cognition.

    PubMed

    Winklewski, Pawel J; Radkowski, Marek; Wszedybyl-Winklewska, Magdalena; Demkow, Urszula

    2017-01-01

    Locus coeruleus is a critical component of the brain noradrenergic system. The brain noradrenergic system provides the neural substrate for the architecture supporting the interaction with, and navigation through, an external world complexity. Changes in locus coeruleus tonic and phasic activity and the interplay between norepinephrine and α 1 - and α 2 -adrenoceptors in the prefrontal cortex are the key elements of this sophisticated architecture. In this narrative review we discuss how the brain noradrenergic system is affected by increased exposure to corticotropin-releasing hormone triggered by stress response. In particular, we present the mechanisms responsible for thinking inflexibility often observed under highly stressful conditions. Finally, the main directions for future research are highlighted.

  1. A Noradrenergic Lesion Exacerbates Neurodegeneration in a Down Syndrome Mouse Model

    PubMed Central

    Lockrow, Jason; Boger, Heather; Gerhardt, Greg; Aston-Jones, Gary; Bachman, David; Granholm, Ann-Charlotte

    2012-01-01

    Individuals with Down syndrome (DS) acquire Alzheimer’s-like dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However, biological mechanisms have not been discovered and there is currently limited therapy for either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits, neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies. PMID:21098982

  2. Noradrenergic modulation of emotional memory in aging.

    PubMed

    Mammarella, Nicola; Di Domenico, Alberto; Palumbo, Rocco; Fairfield, Beth

    2016-05-01

    Interest in the role of the noradrenergic system in the modulation of emotional memories has recently increased. This study briefly reviews this timely line of research with a specific focus on aging. After having identified surprisingly few studies that investigated emotional memory in older adults from a neurobiological perspective, we found a significant interaction between noradrenergic activity and emotional memory enhancement in older adults. This pattern of data are explained both in terms of a top-down modulation of behavioral processes (e.g., changes in priority and individual goals) and in terms of greater activity of noradrenergic system during aging. Altogether, both behavioral and genetic variations studies (e.g., Alpha 2 B Adrenoceptor genotype) have shown that healthy older adults are able to circumvent or minimize the experience of negative emotions and stabilize or even enhance positive emotional experiences. Future studies are highly warranted to better clarify the relationship between noradrenaline and emotional memories in the aging brain. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Noradrenergic mechanisms in the prefrontal cortex.

    PubMed

    Nutt, D J; Lalies, M D; Lione, L A; Hudson, A L

    1997-01-01

    There is growing evidence that noradrenergic inputs to the prefrontal cortex (PFC) play an important role in regulating its function. This paper reviews the pharmacological control of noradrenaline (NA) release in this region, with particular reference to our studies using brain microdialysis, and also describes how NA levels are modulated by antidepressant and antipsychotic drugs. The suggestion that atypical antipsychotics such as clozapine and risperidone may produce clinical benefits by their ability to increase NA release is discussed. Finally, a new class of drugs, which show selectivity for imidazoline receptors is described. These compounds are shown to similarly increase extracellular NA in the PFC. Their potential utility as clinical treatments is discussed.

  4. Immunohistochemical and functional evidence for a noradrenergic regulation in the horse penile deep dorsal vein.

    PubMed

    Recio, P; Prieto, D; Martínez, M P; García, P; Rivera, L; Benedito, S; Martínez, A C; Sacristán, A G; Orensanz, L M; Hernández, M

    2004-12-01

    Our aim was to study the presence of noradrenergic nerves and to characterize the alpha-adrenergic receptors involved in the contractions to electrical field stimulation and to alpha-adrenergic agonists of the horse penile deep dorsal vein. Noradrenergic fibres were visualized by immunohistochemistry using an antibody against dopamine-beta-hydroxylase (DBH). For functional studies, the responses of the venous rings to electrical field stimulation and to alpha-adrenergic agonists (noradrenaline, phenylephrine and BHT 920) were studied in the absence and the presence of noradrenergic transmission- and neuronal sodium channel-blockers (guanethidine and tetrodotoxin, respectively) and of alpha1- and alpha2-adrenergic antagonists (prazosin and rauwolscine, respectively). DBH-immunoreactive fibres were present in the adventitia and in the media layer of the venous rings. Electrical field stimulation (0.5-32 Hz) caused frequency-dependent contractions that were abolished by guanethidine (10(-6) M) and tetrodotoxin (10(-6) M) and reduced by prazosin (10(-9)-10(-7) M) and rauwolscine (3 x 10(-8)-3 x 10(-7) M). Noradrenaline, phenylephrine and BHT 920 induced equipotent contractions of the rings. Prazosin and rauwolscine competitively antagonized the contractions to phenylephrine and BHT 920, respectively. In conclusion, DBH-immunoreactive nerve fibres are present in the horse penile dorsal vein. Both transmural nerve stimulation and alpha-adrenergic agonists induce contraction of the venous rings through a heterogeneous population of alpha1- and alpha2-adrenoceptors.

  5. Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system.

    PubMed

    Ijiro, Tomoyuki; Nakamura, Kayo; Ogata, Masanori; Inada, Hiroyuki; Kiguchi, Sumiyoshi; Maruyama, Kazuyasu; Nabekura, Junichi; Kobayashi, Mamoru; Ishibashi, Hitoshi

    2015-08-15

    Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Reduced Noradrenergic Signaling in the Spleen Capsule in the Absence of CB1and CB2Cannabinoid Receptors.

    PubMed

    Simkins, Tyrell J; Fried, David; Parikh, Kevin; Galligan, James J; Goudreau, John L; Lookingland, Keith J; Kaplan, Barbara L F

    2016-12-01

    The spleen is a visceral organ that contracts during hypoxia to expel erythrocytes and immune cells into the circulation. Spleen contraction is under the control of noradrenergic sympathetic innervation. The activity of noradrenergic neurons terminating in the spleen capsule is regulated by α2-adrenergic receptors (AR). Interactions between endogenous cannabinoid signaling and noradrenergic signaling in other organ systems suggest endocannabinoids might also regulate spleen contraction. Spleens from mice congenitally lacking both CB 1 and CB 2 cannabinoid receptors (Cnr1 -/- /Cnr2 -/- mice) were used to explore the role of endocannabinoids in spleen contraction. Spleen contraction in response to exogenous norepinephrine (NE) was found to be significantly lower in Cnr1 -/- /Cnr2 -/- mouse spleens, likely due to decreased expression of capsular α1AR. The majority of splenic Cnr1 mRNA expression is by cells of the spleen capsule, suggestive of post-synaptic CB 1 receptor signaling. Thus, these studies demonstrate a role for CB 1 and/or CB 2 in noradrenergic splenic contraction.

  7. Disrupting spinal noradrenergic activation delays recovery of acute incision induced hypersensitivity and increases spinal glial activation in the rat

    PubMed Central

    Arora, Vipin; Morado-Urbina, Carlos Eduardo; Aschenbrenner, Carol A.; Hayashida, Ken-ichiro; Wang, FuZhou; Martin, Thomas J.; Eisenach, James C.; Peters, Christopher M.

    2016-01-01

    Clinical studies suggest that descending inhibitory controls from the brainstem are important for speeding recovery from pain following surgery. We examined the effects of destroying spinally projecting noradrenergic neurons via intrathecally administered antibody to dopamine β-hydroxylase conjugated to saporin (DβH-saporin) on recovery in an acute incisional pain model. Mechanical and thermal paw withdrawal thresholds and non-evoked spontaneous guarding scores were tested for several weeks postoperatively and analyzed using mixed effects growth curve modeling. DβH-saporin treatment resulted in a significant prolongation in the duration of mechanical and to a lesser degree thermal hypersensitivity in the ipsilateral paw of incised rats but did not increase the duration of spontaneous guarding. DβH-saporin treatment was also associated with increased microglial and astrocyte activation in the ipsilateral spinal cord 21 days post-incision compared to IgG-saporin treated controls. Chronic intrathecal administration of the α2 adrenergic receptor antagonist atipamezole (50-200 μg/day) produced similar effects. These data suggest that spinally projecting noradrenergic pathways and spinal α2 adrenergic receptor activation are important for speeding recovery from hypersensitivity following surgical incision possibly by reducing spinal glial activation. Interventions that augment the noradrenergic system may be important to speed recovery from pain after surgery. Perspective Endogenous descending spinal noradrenergic activation promotes resolution of incision induced hypersensitivity and inhibits spinal microglial and astrocyte activation in part through α2 adrenergic receptors. PMID:26545342

  8. Discrete forebrain neuronal networks supporting noradrenergic regulation of sensorimotor gating.

    PubMed

    Alsene, Karen M; Rajbhandari, Abha K; Ramaker, Marcia J; Bakshi, Vaishali P

    2011-04-01

    Prepulse inhibition (PPI) refers to the reduction in the startle response when a startling stimulus is preceded by a weak prestimulus, and is an endophenotype of deficient sensorimotor gating in several neuropsychiatric disorders. Emerging evidence suggests that norepinephrine (NE) regulates PPI, however, the circuitry involved is unknown. We found recently that stimulation of the locus coeruleus (LC), the primary source of NE to the forebrain, induces a PPI deficit that is a result of downstream NE release. Hence, this study sought to identify LC-innervated forebrain regions that mediate this effect. Separate groups of male Sprague-Dawley rats received a cocktail solution of the α1-NE receptor agonist phenylephrine plus the β-receptor agonist isoproterenol (equal parts of each; 0, 3, 10, and 30 μg) into subregions of the medial prefrontal cortex (mPFC), nucleus accumbens (NAcc), extended amygdala, mediodorsal thalamus (MD-thalamus), or the dorsal hippocampus (DH) before PPI testing. NE agonist infusion into the posterior mPFC, NAcc shell, bed nucleus of the stria terminalis, basolateral amygdala, and the MD-thalamus disrupted PPI, with particularly strong effects in MD-thalamus. Sites in which NE receptor stimulation did not disrupt PPI (anterior mPFC, NAcc core, central amygdala, and DH) did support PPI disruptions with the dopamine D2 receptor agonist quinpirole (0, 10 μg). This pattern reveals new pathways in the regulation of PPI, and suggests that NE transmission within distinct thalamocortical and ventral forebrain networks may subserve the sensorimotor gating deficits that are seen in disorders such as schizophrenia, Tourette syndrome, and post-traumatic stress disorder.

  9. Pharmacological Modulation of Noradrenergic Arousal Circuitry Disrupts Functional Connectivity of the Locus Ceruleus in Humans

    PubMed Central

    Song, Andrew H.

    2017-01-01

    State-dependent activity of locus ceruleus (LC) neurons has long suggested a role for noradrenergic modulation of arousal. However, in vivo insights into noradrenergic arousal circuitry have been constrained by the fundamental inaccessibility of the human brain for invasive studies. Functional magnetic resonance imaging (fMRI) studies performed during site-specific pharmacological manipulations of arousal levels may be used to study brain arousal circuitry. Dexmedetomidine is an anesthetic that alters the level of arousal by selectively targeting α2 adrenergic receptors on LC neurons, resulting in reduced firing rate and norepinephrine release. Thus, we hypothesized that dexmedetomidine-induced altered arousal would manifest with reduced functional connectivity between the LC and key brain regions involved in the regulation of arousal. To test this hypothesis, we acquired resting-state fMRI data in right-handed healthy volunteers 18–36 years of age (n = 15, 6 males) at baseline, during dexmedetomidine-induced altered arousal, and recovery states. As previously reported, seed-based resting-state fMRI analyses revealed that the LC was functionally connected to a broad network of regions including the reticular formation, basal ganglia, thalamus, posterior cingulate cortex (PCC), precuneus, and cerebellum. Functional connectivity of the LC to only a subset of these regions (PCC, thalamus, and caudate nucleus) covaried with the level of arousal. Functional connectivity of the PCC to the ventral tegmental area/pontine reticular formation and thalamus, in addition to the LC, also covaried with the level of arousal. We propose a framework in which the LC, PCC, thalamus, and basal ganglia comprise a functional arousal circuitry. SIGNIFICANCE STATEMENT Electrophysiological studies of locus ceruleus (LC) neurons have long suggested a role for noradrenergic mechanisms in mediating arousal. However, the fundamental inaccessibility of the human brain for invasive studies has

  10. Localization of endogenous amyloid-β to the coeruleo-cortical pathway: consequences of noradrenergic depletion.

    PubMed

    Ross, Jennifer A; Reyes, Beverly A S; Thomas, Steven A; Van Bockstaele, Elisabeth J

    2018-01-01

    The locus coeruleus (LC)-norepinephrine (NE) system is an understudied circuit in the context of Alzheimer's disease (AD), and is thought to play an important role in neurodegenerative and neuropsychiatric diseases involving catecholamine neurotransmitters. Understanding the expression and distribution of the amyloid beta (Aβ) peptide, a primary component of AD, under basal conditions and under conditions of NE perturbation within the coeruleo-cortical pathway may be important for understanding its putative role in pathological states. Thus, the goal of this study is to define expression levels and the subcellular distribution of endogenous Aβ with respect to noradrenergic profiles in the rodent LC and medial prefrontal cortex (mPFC) and, further, to determine the functional relevance of NE in modulating endogenous Aβ 42 levels. We report that endogenous Aβ 42 is localized to tyrosine hydroxylase (TH) immunoreactive somatodendritic profiles of the LC and dopamine-β-hydroxylase (DβH) immunoreactive axon terminals of the infralimbic mPFC (ILmPFC). Male and female naïve rats have similar levels of amyloid precursor protein (APP) cleavage products demonstrated by western blot, as well as similar levels of endogenous Aβ 42 as determined by enzyme-linked immunosorbent assay. Two models of NE depletion, DSP-4 lesion and DβH knockout (KO) mice, were used to assess the functional relevance of NE on endogenous Aβ 42 levels. DSP-4 lesioned rats and DβH-KO mice show significantly lower levels of endogenous Aβ 42 . Noradrenergic depletion did not change APP-cleavage products resulting from β-secretase processing. Thus, resultant decreases in endogenous Aβ 42 may be due to decreased neuronal activity of noradrenergic neurons, or, by decreased stimulation of adrenergic receptors which are known to contribute to Aβ 42 production by enhancing γ-secretase processing under normal physiological conditions.

  11. The Influence of Resiniferatoxin (RTX) and Tetrodotoxin (TTX) on the Distribution, Relative Frequency, and Chemical Coding of Noradrenergic and Cholinergic Nerve Fibers Supplying the Porcine Urinary Bladder Wall

    PubMed Central

    Lepiarczyk, Ewa; Bossowska, Agnieszka; Kaleczyc, Jerzy; Skowrońska, Agnieszka; Majewski, Michal

    2017-01-01

    The present study investigated the influence of intravesically instilled resiniferatoxin (RTX) or tetrodotoxin (TTX) on the distribution, number, and chemical coding of noradrenergic and cholinergic nerve fibers (NF) supplying the urinary bladder in female pigs. Samples from the bladder wall were processed for double-labelling immunofluorescence with antibodies against cholinergic and noradrenergic markers and some other neurotransmitter substances. Both RTX and TTX caused a significant decrease in the number of cholinergic NF in the urinary bladder wall (in the muscle coat, submucosa, and beneath the urothelium). RTX instillation resulted in a decrease in the number of noradrenergic NF in the submucosa and urothelium, while TTX treatment caused a significant increase in the number of these axons in all the layers. The most remarkable changes in the chemical coding of the NF comprised a distinct decrease in the number of the cholinergic NF immunoreactive to CGRP (calcitonin gene-related peptide), nNOS (neuronal nitric oxide synthase), SOM (somatostatin) or VIP (vasoactive intestinal polypeptide), and an increase in the number of noradrenergic NF immunopositive to GAL (galanin) or nNOS, both after RTX or TTX instillation. The present study is the first to suggest that both RTX and TTX can modify the number of noradrenergic and cholinergic NF supplying the porcine urinary bladder. PMID:28972567

  12. Noradrenergic antagonists mitigate amphetamine-induced recovery.

    PubMed

    Hylin, M J; Brenneman, M M; Corwin, J V

    2017-09-15

    Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that shown limited amounts of success in improving functional outcome. The use of stimulants such as amphetamine have shown some success in improving outcome following brain injury. While the pharmacological mechanisms for amphetamine are known; the specific processes responsible for improving behavioral outcome following injury remain unknown. Understanding these mechanisms can help to refine the use of amphetamine as a potential treatment or lead to the use of other methods that share the same pharmacological properties. One proposed mechanism is amphetamine's impact upon noradrenaline (NA). In the current, study noradrenergic antagonists were administered prior to amphetamine to pharmacologically block α- and β-adrenergic receptors. The results demonstrated that the blockade of these receptors disrupted amphetamines ability to induce recovery from hemispatial neglect using an established aspiration lesion model. This suggests that amphetamine's ability to ameliorate neglect deficits may be due in part to noradrenaline. These results further support the role of noradrenaline in functional recovery. Finally, the development of polytherapies and combined therapeutics, while promising, may need to consider the possibility that drug interactions can negate the effectiveness of treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Glial cell line-derived neurotrophic factormediated enhancement of noradrenergic descending inhibition in the locus coeruleus exerts prolonged analgesia in neuropathic pain

    PubMed Central

    Kimura, M; Sakai, A; Sakamoto, A; Suzuki, H

    2015-01-01

    Background and Purpose The locus coeruleus (LC) is the principal nucleus containing the noradrenergic neurons and is a major endogenous source of pain modulation in the brain. Glial cell line-derived neurotrophic factor (GDNF), a well-established neurotrophic factor for noradrenergic neurons, is a major pain modulator in the spinal cord and primary sensory neurons. However, it is unknown whether GDNF is involved in pain modulation in the LC. Experimental Approach Rats with chronic constriction injury (CCI) of the left sciatic nerve were used as a model of neuropathic pain. GDNF was injected into the left LC of rats with CCI for 3 consecutive days and changes in mechanical allodynia and thermal hyperalgesia were assessed. The α2-adrenoceptor antagonist yohimbine was injected intrathecally to assess the involvement of descending inhibition in GDNF-mediated analgesia. The MEK inhibitor U0126 was used to investigate whether the ERK signalling pathway plays a role in the analgesic effects of GDNF. Key Results Both mechanical allodynia and thermal hyperalgesia were attenuated 24 h after the first GDNF injection. GDNF increased the noradrenaline content in the dorsal spinal cord. The analgesic effects continued for at least 3 days after the last injection. Yohimbine abolished these effects of GDNF. The analgesic effects of GDNF were partly, but significantly, inhibited by prior injection of U0126 into the LC. Conclusions and Implications GDNF injection into the LC exerts prolonged analgesic effects on neuropathic pain in rats by enhancing descending noradrenergic inhibition. PMID:25572945

  14. AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons.

    PubMed

    Rathje, Mette; Fang, Huaqiang; Bachman, Julia L; Anggono, Victor; Gether, Ulrik; Huganir, Richard L; Madsen, Kenneth L

    2013-08-27

    NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling. Here, we demonstrate that in somatic and dendritic regions of hippocampal neurons a large fraction of the fluorescent signal originates from intracellular pH-GluA2, and that the decline in fluorescence in response to NMDA and AMPA primarily describes an intracellular acidification, which quenches the pHluorin signal from intracellular receptor pools. Neurons expressing an endoplasmic reticulum-retained mutant of GluA2 (pH-GluA2 ΔC49) displayed a larger response to NMDA than neurons expressing wild-type pH-GluA2. A similar NMDA-elicited decline in pHluorin signal was observed by expressing cytosolic pHluorin alone without fusion to GluA2 (cyto-pHluorin). Intracellular acidification in response to NMDA was further confirmed by using the ratiometric pH indicator carboxy-SNARF-1. The NMDA-induced decline was followed by rapid recovery of the fluorescent signal from both cyto-pHluorin and pH-GluA2. The recovery was sodium-dependent and sensitive to Na(+)/H(+)-exchanger (NHE) inhibitors. Moreover, recovery was more rapid after shRNA-mediated knockdown of the GluA2 binding PDZ domain-containing protein interacting with C kinase 1 (PICK1). Interestingly, the accelerating effect of PICK1 knockdown on the fluorescence recovery was eliminated in the presence of the NHE1 inhibitor zoniporide. Our results indicate that the pH-GluA2 recycling assay is an unreliable assay for studying AMPA receptor trafficking and also suggest a role for PICK1 in regulating intracellular pH via modulation of NHE activity.

  15. AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons

    PubMed Central

    Rathje, Mette; Fang, Huaqiang; Bachman, Julia L.; Anggono, Victor; Gether, Ulrik; Huganir, Richard L.; Madsen, Kenneth L.

    2013-01-01

    NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling. Here, we demonstrate that in somatic and dendritic regions of hippocampal neurons a large fraction of the fluorescent signal originates from intracellular pH-GluA2, and that the decline in fluorescence in response to NMDA and AMPA primarily describes an intracellular acidification, which quenches the pHluorin signal from intracellular receptor pools. Neurons expressing an endoplasmic reticulum-retained mutant of GluA2 (pH-GluA2 ΔC49) displayed a larger response to NMDA than neurons expressing wild-type pH-GluA2. A similar NMDA-elicited decline in pHluorin signal was observed by expressing cytosolic pHluorin alone without fusion to GluA2 (cyto-pHluorin). Intracellular acidification in response to NMDA was further confirmed by using the ratiometric pH indicator carboxy-SNARF-1. The NMDA-induced decline was followed by rapid recovery of the fluorescent signal from both cyto-pHluorin and pH-GluA2. The recovery was sodium-dependent and sensitive to Na+/H+-exchanger (NHE) inhibitors. Moreover, recovery was more rapid after shRNA-mediated knockdown of the GluA2 binding PDZ domain-containing protein interacting with C kinase 1 (PICK1). Interestingly, the accelerating effect of PICK1 knockdown on the fluorescence recovery was eliminated in the presence of the NHE1 inhibitor zoniporide. Our results indicate that the pH-GluA2 recycling assay is an unreliable assay for studying AMPA receptor trafficking and also suggest a role for PICK1 in regulating intracellular pH via modulation of NHE activity. PMID:23940334

  16. Chaos and Complexity in Abnormal Oscillations of Two Excitable Neurons and a 2d Network Model Coupled via Gap Junctions

    NASA Astrophysics Data System (ADS)

    Ge, Manling; Guo, Hongyong; Sun, Mingui; Gusphyl, Justin; Dong, Guoya; Zhao, Tongjun; Yan, Weili

    Many electrophysiological experiments have shown that epileptic seizures often originate from the synchronous activities of abnormally excitable neurons. The dynamic process of epilepsy is very complex, and characterized by a seemingly rapid and dramatic birth of new oscillations, essentially leading to a propagation and amplification of the original aberrant activity. It is very difficult to thoroughly understand the mechanism from a theoretical standpoint, however some special work can prove helpful. Here we present a theoretical framework to investigate chaos and complexity in the synchrony of excitable neurons in an effort to study the collective oscillations within a neural network. As endogenous rhythms, oscillations arise because most cellular processes contain feedback. The Chay model of excitable neurons is chosen because the model describes the abnormal process, where spiking can be transformed into bursting via bifurcation. In our study, the Chay model is regarded as an abnormal oscillator and coupled via a resistor representing the effect of gap junctions (electrical synapses). In this paper, we present some models developed from the original Chay model, for the synchrony of two cells and a 2D neural network. Lyapunov exponent and phase portrait are utilized to evaluate the chaotic dynamics. Finally, approximate entropy is utilized to measure its complexity. Our results show that the synchrony of abnormal oscillations can occur when the coupling strength of the gap junction is sufficiently large. It is also found that the concentration of Ca2+ ions does not synchronize. In the 2D network, approximate entropies of different oscillations with strong coupling strength are greater than those with weak coupling strength. It is indicated that synchronous neurons have greater ability to produce new oscillations than asynchronous ones. This work shows that nonlinear analytical methods may prove useful in elucidating the mechanisms of pathologic conditions

  17. Tonic noradrenergic activity modulates explorative behavior and attentional set shifting: Evidence from pupillometry and gaze pattern analysis.

    PubMed

    Pajkossy, Péter; Szőllősi, Ágnes; Demeter, Gyula; Racsmány, Mihály

    2017-12-01

    A constant task for every living organism is to decide whether to exploit rewards associated with current behavior or to explore the environment for more rewarding options. Current empirical evidence indicates that exploitation is related to phasic whereas exploration is related to tonic firing mode of noradrenergic neurons in the locus coeruleus. In humans, this exploration-exploitation trade-off is subserved by the ability to flexibly switch attention between task-related and task-irrelevant information. Here, we investigated whether this function, called attentional set shifting, is related to exploration and tonic noradrenergic discharge. We measured pretrial baseline pupil dilation, proved to be strongly correlated with the activity of the locus coeruleus, while human participants took part in well-known tasks of attentional set shifting. Study 1 used the Wisconsin Card Sorting Task, whereas in Study 2, the Intra/Extradimensional Set Shifting Task was used. Both tasks require participants to choose between different compound stimuli based on feedback provided for their previous decisions. During the task, stimulus-reward contingencies change periodically, thus participants are repeatedly required to reassess which stimulus features are relevant (i.e., they shift their attentional set). Our results showed that baseline pupil diameter steadily decreased when the stimulus-reward contingencies were stable, whereas they suddenly increased when these contingencies changed. Analysis of looking patterns also confirmed the presence of exploratory behavior during attentional set shifting. Thus, our results suggest that tonic firing mode of noradrenergic neurons in the locus coeruleus is implicated in attentional set shifting, as it regulates the amount of exploration. © 2017 Society for Psychophysiological Research.

  18. CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety.

    PubMed

    McCall, Jordan G; Al-Hasani, Ream; Siuda, Edward R; Hong, Daniel Y; Norris, Aaron J; Ford, Christopher P; Bruchas, Michael R

    2015-08-05

    The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of in vivo chemogenetics, optogenetics, and retrograde tracing, we determine that increased tonic activity of the LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin-releasing hormone(+) (CRH(+)) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety

    PubMed Central

    McCall, Jordan G.; Al-Hasani, Ream; Siuda, Edward R.; Hong, Daniel Y.; Norris, Aaron J.; Ford, Christopher P.; Bruchas, Michael R.

    2015-01-01

    Summary The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of in vivo chemogenetics, optogenetics, and retrograde tracing we determine that increased tonic activity of the LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin releasing hormone+ (CRH+) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders. PMID:26212712

  20. Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress

    PubMed Central

    Kaster, Manuella P.; Machado, Nuno J.; Silva, Henrique B.; Nunes, Ana; Ardais, Ana Paula; Santana, Magda; Baqi, Younis; Müller, Christa E.; Rodrigues, Ana Lúcia S.; Porciúncula, Lisiane O.; Chen, Jiang Fan; Tomé, Ângelo R.; Agostinho, Paula; Canas, Paula M.; Cunha, Rodrigo A.

    2015-01-01

    The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function. PMID:26056314

  1. Developmental changes in central O2 chemoreflex in Rana catesbeiana: the role of noradrenergic modulation.

    PubMed

    Fournier, Stéphanie; Allard, Mathieu; Roussin, Stéphanie; Kinkead, Richard

    2007-09-01

    The in vitro brainstem preparation from Rana catesbeiana shows a functional central O(2) chemoreflex. Acute brainstem exposure to hypoxic superfusate elicits lung burst frequency responses that change over the course of development. Based on studies suggesting that brainstem noradrenergic neurons are involved in this reflex, we tested the following two hypotheses in vitro: (1) activation of adrenoceptors is necessary for the expression of the fictive lung ventilation response to hypoxia, and (2) changes in fast, Cl(-)-dependent neurotransmission (GABA/glycine) contribute to developmental changes in noradrenergic modulation. Experiments were performed on preparations from pre-metamorphics tadpoles (TK stages V-XIII) and adult bullfrogs. Acute exposure to hypoxic superfusate (98% N(2), 2% CO(2)) increased fictive lung ventilation frequency in the pre-metamorphic group, whereas a decrease was observed in adults. Buccal burst frequency was unchanged by hypoxia. Noradrenaline (NA; 5 micromol l(-1)) bath application mimicked both fictive breathing responses and application of the alpha(1)-antagonist prazosine (0.5 micromol l(-1)) blocked the lung burst response to hypoxia in both groups. Blocking GABA(A)/glycine receptors with a bicuculine/strychnine mixture (1.25 micromol l(-1)/1.5 micromol l(-1), respectively) or activation of GABA(B) pre-synaptic autoreceptors with baclofen (0.5 micromol l(-1)) prevented the lung burst response to hypoxia and to the alpha(1)-agonist phenylephrine (25 micromol l(-1)) in both stage groups. We conclude that NA modulation contributes to the central O(2) chemoreflex in bullfrog, which acts via GABA/glycine pathways. These data suggest that maturation of GABA/glycine neurotransmission contributes to the developmental changes in this chemoreflex.

  2. Ligand-dependent oligomerization of dopamine D(2) and adenosine A(2A) receptors in living neuronal cells.

    PubMed

    Vidi, Pierre-Alexandre; Chemel, Benjamin R; Hu, Chang-Deng; Watts, Val J

    2008-09-01

    Adenosine A(2A) and dopamine D(2) receptors (A(2A) and D(2)) associate in homo- and heteromeric complexes in the striatum, providing a structural basis for their mutual antagonism. At the cellular level, the portion of receptors engaging in homo- and heteromers, as well as the effect of persistent receptor activation or antagonism on the cell oligomer repertoire, are largely unknown. We have used bimolecular fluorescence complementation (BiFC) to visualize A(2A) and D(2) oligomerization in the Cath.a differentiated neuronal cell model. Receptor fusions to BiFC fluorescent protein fragments retained their function when expressed alone or in A(2A)/A(2A), D(2)/D(2), and A(2A)/D(2) BiFC pairs. Robust fluorescence complementation reflecting A(2A)/D(2) heteromers was detected at the cell membrane as well as in endosomes. In contrast, weaker BiFC signals, largely confined to intracellular domains, were detected with A(2A)/dopamine D(1) BiFC pairs. Multicolor BiFC was used to simultaneously visualize A(2A) and D(2) homo- and heteromers in living cells and to examine drug-induced changes in receptor oligomers. Prolonged D(2) stimulation with quinpirole lead to the internalization of D(2)/D(2) and A(2A)/D(2) oligomers and resulted in decreased A(2A)/D(2) relative to A(2A)/A(2A) oligomer formation. Opposing effects were observed in cells treated with D(2) antagonists or with the A(2A) agonist 5'-N-methylcarboxamidoadenosine (MECA). Subsequent radioreceptor binding analysis indicated that the drug-induced changes in oligomer formation were not readily explained by alterations in receptor density. These observations support the hypothesis that long-term drug exposure differentially alters A(2A)/D(2) receptor oligomerization and provide the first demonstration for the use of BiFC to monitor drug-modulated GPCR oligomerization.

  3. Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior.

    PubMed

    McCall, Jordan G; Siuda, Edward R; Bhatti, Dionnet L; Lawson, Lamley A; McElligott, Zoe A; Stuber, Garret D; Bruchas, Michael R

    2017-07-14

    Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and aversive behavior. While some information is known about the afferent circuitry that endogenously drives this neural activity and behavior, the downstream receptors and anatomical projections that mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions aversion, and increases anxiety-like behavior. Additionally, we report that β-adrenergic receptors mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through distinct receptor and projection-selective mechanisms.

  4. Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats

    PubMed Central

    Bruinstroop, Eveline; Cano, Georgina; VanderHorst, Veronique G.J.M.; Cavalcante, Judney C.; Wirth, Jena; Sena-Esteves, Miguel; Saper, Clifford B.

    2012-01-01

    The pontine noradrenergic cell groups, A5, A6 (locus coeruleus), and A7, provide the only noradrenergic innervation of the spinal cord, but the individual contribution of each of these populations to the regional innervation of the spinal cord remains controversial. We have used an adeno-associated viral (AAV) vector encoding green fluorescent protein under an artificial dopamine beta-hydroxylase (PRSx8) promoter, to trace the spinal projections from the A5, A6, and A7 groups. Projections from all three groups travel through the spinal cord in both the lateral and ventral funiculi and in the dorsal surface of the dorsal horn, but A6 axons take predominantly the dorsal and ventral routes whereas A5 and A7 axons take a predominantly lateral route. The A6 group provides the densest innervation at all levels, and includes all parts of the spinal gray matter, but it is particularly dense in the dorsal horn. The A7 group provides the next most dense innervation, again including all parts of the spinal cord, but is it denser in the ventral horn. The A5 group supplies only sparse innervation to the dorsal and ventral horns and to the cervical and lumbosacral levels, but provides the densest innervation to the thoracic intermediolateral cell column, and in particular to the sympathetic preganglionic neurons. Thus, the pontine noradrenergic cell groups project in a roughly topographic and complementary fashion onto the spinal cord. The pattern of spinal projections observed suggests that the locus coeruleus might have the greatest effect on somatosensory transmission, the A7 group on motor function, and the A5 group on sympathetic function. PMID:22173709

  5. Noradrenergic Modulation of Fear Conditioning and Extinction

    PubMed Central

    Giustino, Thomas F.; Maren, Stephen

    2018-01-01

    The locus coeruleus norepinephrine (LC-NE) system plays a broad role in learning and memory. Here we begin with an overview of the LC-NE system. We then consider how both direct and indirect manipulations of the LC-NE system affect cued and contextual aversive learning and memory. We propose that NE dynamically modulates Pavlovian conditioning and extinction, either promoting or impairing learning aversive processes under different levels of behavioral arousal. We suggest that under high levels of stress (e.g., during/soon after fear conditioning) the locus coeruleus (LC) promotes cued fear learning by enhancing amygdala function while simultaneously blunting prefrontal function. Under low levels of arousal, the LC promotes PFC function to promote downstream inhibition of the amygdala and foster the extinction of cued fear. Thus, LC-NE action on the medial prefrontal cortex (mPFC) might be described by an inverted-U function such that it can either enhance or hinder learning depending on arousal states. In addition, LC-NE seems to be particularly important for the acquisition, consolidation and extinction of contextual fear memories. This may be due to dense adrenoceptor expression in the hippocampus (HPC) which encodes contextual information, and the ability of NE to regulate long-term potentiation (LTP). Moreover, recent work reveals that the diversity of LC-NE functions in aversive learning and memory are mediated by functionally heterogeneous populations of LC neurons that are defined by their projection targets. Hence, LC-NE function in learning and memory is determined by projection-specific neuromodulation that accompanies various states of behavioral arousal. PMID:29593511

  6. Noradrenergic Modulation of Fear Conditioning and Extinction.

    PubMed

    Giustino, Thomas F; Maren, Stephen

    2018-01-01

    The locus coeruleus norepinephrine (LC-NE) system plays a broad role in learning and memory. Here we begin with an overview of the LC-NE system. We then consider how both direct and indirect manipulations of the LC-NE system affect cued and contextual aversive learning and memory. We propose that NE dynamically modulates Pavlovian conditioning and extinction, either promoting or impairing learning aversive processes under different levels of behavioral arousal. We suggest that under high levels of stress (e.g., during/soon after fear conditioning) the locus coeruleus (LC) promotes cued fear learning by enhancing amygdala function while simultaneously blunting prefrontal function. Under low levels of arousal, the LC promotes PFC function to promote downstream inhibition of the amygdala and foster the extinction of cued fear. Thus, LC-NE action on the medial prefrontal cortex (mPFC) might be described by an inverted-U function such that it can either enhance or hinder learning depending on arousal states. In addition, LC-NE seems to be particularly important for the acquisition, consolidation and extinction of contextual fear memories. This may be due to dense adrenoceptor expression in the hippocampus (HPC) which encodes contextual information, and the ability of NE to regulate long-term potentiation (LTP). Moreover, recent work reveals that the diversity of LC-NE functions in aversive learning and memory are mediated by functionally heterogeneous populations of LC neurons that are defined by their projection targets. Hence, LC-NE function in learning and memory is determined by projection-specific neuromodulation that accompanies various states of behavioral arousal.

  7. A quantitative evaluation of a 2.5-kb rat tyrosine hydroxylase promoter to target expression in ventral mesencephalic dopamine neurons in vivo.

    PubMed

    Rolland, Anne-Sophie; Kareva, Tatyana; Kholodilov, Nikolai; Burke, Robert E

    2017-03-27

    Adeno-associated viruses (AAVs) have become powerful tools in neuroscience for both basic research and potential therapeutic use. They have become especially important tools for optogenetic experiments based on their ability to achieve transgene expression in postmitotic neurons with regional selectivity. With the use of appropriate promoter elements they can achieve cellular specificity as well. One population of neurons that plays a central role in human neurodegenerative and psychiatric diseases are the dopamine neurons of the midbrain. To study these neurons in vivo with advanced techniques it would be highly advantageous to characterize an appropriate specific promoter. To this end we have characterized a 2.5-kb sequence of the rat tyrosine hydroxylase (TH) promoter. The rTHp(2.5) promoter induced expression of the fluorescent reporter protein mCherry in SN dopamine neurons. Although it showed excellent specificity in cortex and striatum, where no reporter expression was observed, in the SN region many neurons expressed reporter but not TH. We show that some of the TH negativity is due to the suppression of its expression by the transgene. We conclude that rTHp(2.5) does preferentially label dopamine neurons but its specificity is not complete within the substantia nigra and caution must be used. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. The selective neurotoxin DSP-4 impairs the noradrenergic projections from the locus coeruleus to the inferior colliculus in rats

    PubMed Central

    Hormigo, Sebastián; Horta Júnior, José de Anchieta de Castro e; Gómez-Nieto, Ricardo; López, Dolores E.

    2012-01-01

    The inferior colliculus (IC) and the locus coeruleus (LC) are two midbrain nuclei that integrate multimodal information and play a major role in novelty detection to elicit an orienting response. Despite the reciprocal connections between these two structures, the projection pattern and target areas of the LC within the subdivisions of the rat IC are still unknown. Here, we used tract-tracing approaches combined with immunohistochemistry, densitometry, and confocal microscopy (CM) analysis to describe a projection from the LC to the IC. Biotinylated dextran amine (BDA) injections into the LC showed that the LC-IC projection is mainly ipsilateral (90%) and reaches, to a major extent, the dorsal and lateral part of the IC and the intercollicular commissure. Additionally, some LC fibers extend into the central nucleus of the IC. The neurochemical nature of this projection is noradrenergic, given that tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) colocalize with the BDA-labeled fibers from the LC. To determine the total field of the LC innervations in the IC, we destroyed the LC neurons and fibers using a highly selective neurotoxin, DSP-4, and then studied the distribution and density of TH- and DBH-immunolabeled axons in the IC. In the DSP-4 treated animals, the number of axonal fibers immunolabeled for TH and DBH were deeply decreased throughout the entire rostrocaudal extent of the IC and its subdivisions compared to controls. Our densitometry results showed that the IC receives up to 97% of its noradrenergic innervations from the LC neurons and only 3% from non-coeruleus neurons. Our results also indicate that TH immunoreactivity in the IC was less impaired than the immunoreactivity for DBH after DSP-4 administration. This is consistent with the existence of an important dopaminergic projection from the substantia nigra to the IC. In conclusion, our study demonstrates and quantifies the noradrenergic projection from the LC to the IC and its

  9. Endogenous analgesic action of the pontospinal noradrenergic system spatially restricts and temporally delays the progression of neuropathic pain following tibial nerve injury

    PubMed Central

    Hughes, S.W.; Hickey, L.; Hulse, R.P.; Lumb, B.M.; Pickering, A.E.

    2013-01-01

    Pontospinal noradrenergic neurons form part of an endogenous analgesic system that suppresses acute pain, but there is conflicting evidence about its role in neuropathic pain. We investigated the chronology of descending noradrenergic control during the development of a neuropathic pain phenotype in rats following tibial nerve transection (TNT). A lumbar intrathecal cannula was implanted at the time of nerve injury allowing administration of selective α-adrenoceptor (α-AR) antagonists to sequentially assay their effects upon the expression of allodynia and hyperalgesia. Following TNT animals progressively developed mechanical and cold allodynia (by day 10) and subsequently heat hypersensitivity (day 17). Blockade of α2-AR with intrathecal yohimbine (30 μg) revealed earlier ipsilateral sensitization of all modalities while prazosin (30 μg, α1-AR) was without effect. Established allodynia (by day 21) was partly reversed by the re-uptake inhibitor reboxetine (5 μg, i.t.) but yohimbine no longer had any sensitising effect. This loss of effect coincided with a reduction in the descending noradrenergic innervation of the ipsilateral lumbar dorsal horn. Yohimbine reversibly unmasked contralateral hindlimb allodynia and hyperalgesia of all modalities and increased dorsal horn c-fos expression to an innocuous brush stimulus. Contralateral thermal hyperalgesia was also reversibly uncovered by yohimbine administration in a contact heat ramp paradigm in anaesthetised TNT rats. Following TNT there is an engagement of inhibitory α2-AR-mediated noradrenergic tone which completely masks contralateral and transiently suppresses the development of ipsilateral sensitization. This endogenous analgesic system plays a key role in shaping the spatial and temporal expression of the neuropathic pain phenotype after nerve injury. PMID:23707289

  10. Evidence that noradrenergic transmitter release is regulated by presynaptic receptors.

    PubMed

    Westfall, T C

    1984-04-01

    A review is provided of the evidence in support of the existence of prejunctional alpha adrenoceptors on noradrenergic nerve terminals as well as the evidence for their physiological importance. The use of alpha-adrenoceptor agonists and antagonists has provided convincing data in support of the presynaptic receptor hypothesis. Moreover, there is ample evidence for the location of alpha adrenoceptors on nerve terminals. This evidence has often been forgotten in arguments opposing the presynaptic alpha-adrenoceptor hypothesis. The precise physiological role of presynaptic alpha adrenoceptors is still an open question, but there is support from a wide range of experiments in favor of a physiological role. Although it is not known which of these functions is most important, presynaptic alpha adrenoceptors may: regulate the pulse-to-pulse regulation of norepinephrine release during nerve stimulation, prevent noise, and protect the neuroeffector cell from excessive activation by transmitter during periods of rest or as physiological antagonists to the facilitation of transmitter release. In summary, evidence reviewed here strongly supports the existence of presynaptic alpha adrenoceptors. These receptors are clearly important pharmacologically and may play a physiological role in noradrenergic transmission. The exact physiological function must await further experimentation.

  11. Combined Effects of Glucocorticoid and Noradrenergic Activity on Loss Aversion.

    PubMed

    Margittai, Zsofia; Nave, Gideon; Van Wingerden, Marijn; Schnitzler, Alfons; Schwabe, Lars; Kalenscher, Tobias

    2018-01-01

    Loss aversion is a well-known behavioral regularity in financial decision making, describing humans' tendency to overweigh losses compared to gains of the same amount. Recent research indicates that stress and associated hormonal changes affect loss aversion, yet the underlying neuroendocrine mechanisms are still poorly understood. Here, we investigated the causal influence of two major stress neuromodulators, cortisol and noradrenaline, on loss aversion during financial decision making. In a double-blind, placebo-controlled between-subject design, we orally administered either the α2-adrenergic antagonist yohimbine (increasing noradrenergic stimulation), hydrocortisone, both substances, or a placebo to healthy young men. We tested the treatments' influence on a financial decision-making task measuring loss aversion and risk attitude. We found that both drugs combined, relative to either drug by itself, reduced loss aversion in the absence of an effect on risk attitude or choice consistency. Our data suggest that concurrent glucocorticoid and noradrenergic activity prompts an alignment of reward- with loss-sensitivity, and thus diminishes loss aversion. Our results have implications for the understanding of the susceptibility to biases in decision making.

  12. Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of remote memory.

    PubMed

    Atucha, Erika; Vukojevic, Vanja; Fornari, Raquel V; Ronzoni, Giacomo; Demougin, Philippe; Peter, Fabian; Atsak, Piray; Coolen, Marcel W; Papassotiropoulos, Andreas; McGaugh, James L; de Quervain, Dominique J-F; Roozendaal, Benno

    2017-08-22

    Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkm ζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.

  13. Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of remote memory

    PubMed Central

    Atucha, Erika; Vukojevic, Vanja; Fornari, Raquel V.; Ronzoni, Giacomo; Demougin, Philippe; Peter, Fabian; Atsak, Piray; Coolen, Marcel W.; Papassotiropoulos, Andreas; McGaugh, James L.; de Quervain, Dominique J.-F.; Roozendaal, Benno

    2017-01-01

    Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock–context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory. PMID:28790188

  14. Activation of β-noradrenergic receptors enhances rhythmic bursting in mouse olfactory bulb external tufted cells.

    PubMed

    Zhou, Fu-Wen; Dong, Hong-Wei; Ennis, Matthew

    2016-12-01

    The main olfactory bulb (MOB) receives a rich noradrenergic innervation from the nucleus locus coeruleus. Despite the well-documented role of norepinephrine and β-adrenergic receptors in neonatal odor preference learning, identified cellular physiological actions of β-receptors in the MOB have remained elusive. β-Receptors are expressed at relatively high levels in the MOB glomeruli, the location of external tufted (ET) cells that exert an excitatory drive on mitral and other cell types. The present study investigated the effects of β-receptor activation on the excitability of ET cells with patch-clamp electrophysiology in mature mouse MOB slices. Isoproterenol and selective β 2 -, but not β 1 -, receptor agonists were found to enhance two key intrinsic currents involved in ET burst initiation: persistent sodium (I NaP ) and hyperpolarization-activated inward (I h ) currents. Together, the positive modulation of these currents increased the frequency and strength of ET cell rhythmic bursting. Rodent sniff frequency and locus coeruleus neuronal firing increase in response to novel stimuli or environments. The increase in ET excitability by β-receptor activation may better enable ET cell rhythmic bursting, and hence glomerular network activity, to pace faster sniff rates during heightened norepinephrine release associated with arousal. Copyright © 2016 the American Physiological Society.

  15. Differential activation of chemically identified neurons in the caudal nucleus of the solitary tract in non-entrained rats after intake of satiating vs. non-satiating meals.

    PubMed

    Kreisler, Alison D; Davis, Elizabeth A; Rinaman, Linda

    2014-09-01

    Satiety signals arising from the gastrointestinal (GI) tract and related digestive organs during food ingestion and digestion are conveyed by vagal sensory afferents to the hindbrain nucleus of the solitary tract (NST). Two intermingled but chemically distinct NST neuronal populations have been implicated in meal size control: noradrenergic (NA) neurons that comprise the A2 cell group, and glucagon-like peptide-1 (GLP-1)-positive neurons. Previous results indicate that A2 neurons are activated in a meal size-dependent manner in rats that have been acclimated/entrained to a feeding schedule in order to increase meal size, whereas feeding under the same conditions does not activate GLP-1 neurons. The present study was designed to test the hypothesis that both A2 and GLP-1 neuronal populations are recruited in non-entrained rats after voluntary first-time intake of an unrestricted, satiating volume of liquid Ensure. DBH-positive A2 neurons within the caudal visceral NST were progressively recruited to express cFos in rats that consumed progressively larger volumes of Ensure. Among these DBH-positive neurons, the prolactin-releasing peptide (PrRP)-positive subset was more sensitive to feeding-induced activation than the PrRP-negative subset. Notably, significant activation of GLP-1-positive neurons occurred only in rats that consumed the largest volumes of Ensure, corresponding to nearly 5% of their BW. We interpret these results as evidence that progressive recruitment of NA neurons within the caudal NST, especially the most caudally-situated PrRP-positive subset, effectively "tracks" the magnitude of GI satiety signals and other meal-related sensory feedback. Conversely, GLP-1 neurons may only be recruited in response to the homeostatic challenge of consuming a very large, unanticipated meal. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity

    PubMed Central

    Counts, Scott E.; Mufson, Elliott J.

    2010-01-01

    Degeneration of locus coeruleus (LC) noradrenergic forebrain projection neurons is an early feature of Alzheimer’s disease (AD). The physiological consequences of this phenomenon are unclear, but observations correlating LC neuron loss with increased AD pathology in LC projection sites suggest that noradrenaline (NA) is neuroprotective. To investigate this hypothesis, we determined that NA protected both hNT human neuronal cultures and rat primary hippocampal neurons from amyloid-β (Aβ1–42 and Aβ25–35) toxicity. The noradrenergic co-transmitter galanin was also effective at preventing Aβ-induced cell death. NA inhibited Aβ25–35-mediated increases in intracellular reactive oxygen species, mitochondrial membrane depolarization, and caspase activation in hNT neurons. NA exerted its neuroprotective effects in these cells by stimulating canonical β1 and β2 adrenergic receptor signaling pathways involving the activation of cAMP response element binding protein (CREB) and the induction of endogenous nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Treatment with functional blocking antibodies for either NGF or BDNF blocked NA’s protective actions against Aβ1–42 and Aβ25–35 toxicity in primary hippocampal and hNT neurons, respectively. Taken together, these data suggest that the neuroprotective effects of noradrenergic LC afferents result from stimulating neurotrophic NGF and BDNF autocrine or paracrine loops via β adrenoceptor activation of the CREB pathway. PMID:20132474

  17. The neuronal Ca(2+) -binding protein 2 (NECAB2) interacts with the adenosine A(2A) receptor and modulates the cell surface expression and function of the receptor.

    PubMed

    Canela, Laia; Luján, Rafael; Lluís, Carme; Burgueño, Javier; Mallol, Josefa; Canela, Enric I; Franco, Rafael; Ciruela, Francisco

    2007-09-01

    Heptaspanning membrane also known as G protein-coupled receptors (GPCR) do interact with a variety of intracellular proteins whose function is regulate receptor traffic and/or signaling. Using a yeast two-hybrid screen, NECAB2, a neuronal calcium binding protein, was identified as a binding partner for the adenosine A(2A) receptor (A(2A)R) interacting with its C-terminal domain. Co-localization, co-immunoprecipitation and pull-down experiments showed a close and specific interaction between A(2A)R and NECAB2 in both transfected HEK-293 cells and also in rat striatum. Immunoelectron microscopy detection of NECAB2 and A(2A)R in the rat striatopallidal structures indicated that both proteins are co-distributed in the same glutamatergic nerve terminals. The interaction of NECAB2 with A(2A)R modulated the cell surface expression, the ligand-dependent internalization and the receptor-mediated activation of the MAPK pathway. Overall, these results show that A(2A)R interacts with NECAB2 in striatal neurones co-expressing the two proteins and that the interaction is relevant for A(2A)R function.

  18. Noradrenergic innervation of the ventromedial hypothalamus is involved in mating-induced pseudopregnancy in the female rat.

    PubMed

    Northrop, L E; Shadrach, J L; Erskine, M S

    2006-08-01

    The ventromedial hypothalamus (VMH) is an oestrogen-responsive area known to facilitate female sexual behaviour in the rat. The VMH is innervated by noradrenergic neurones projecting from the brain stem, and it has been demonstrated that noradrenaline receptor activation in the VMH plays a role in the expression of the lordosis reflex. Noradrenaline has been shown to be released within the VMH after a female receives vaginocervical stimulation (VCS) from the male during mating. VCS also is required to induce twice-daily surges of prolactin (PRL) characteristic of early pregnancy or pseudopregnancy (PSP). To determine whether noradrenaline within the ventrolateral ventromedial hypothalamus (VMHvl) plays a facilitatory role in initiation of PSP, we administered the alpha(1)-noradrenergic receptor agonist, phenylephrine, and the alpha(2)-autoreceptor antagonist, yohimbine, unilaterally into the VMHvl. Phenylephrine stimulated PSP in 85.7% of females given an amount of VCS known to be subthreshold for the induction of PSP, whereas saline infusion (0%) or cannula misplacement (7.7%) were ineffective. Yohimbine had a similar effect, inducing PSP in 85.7% of females, whereas 7.6% of both control groups together showed PSP. Finally, bilateral blockade of alpha(1)-receptors using prazosin blocked PSP in 100% of females given sufficient VCS to induce PSP, whereas saline infusion or misplaced intracerebral cannulae failed to prevent PSP in any animal. In all experiments, vaginal dioestrous was indicative of PSP, in that animals showed a mean number of days between oestrus of 12.8 +/- 0.9. The results of the study demonstrate an important role for the VMHvl in initiation of PSP and suggest that the release of noradrenaline in the VMHvl at the time of mating contributes to neuroendocrine mechanisms responsible for establishing PSP in the female rat.

  19. α-Synuclein-Induced Synapse Damage in Cultured Neurons Is Mediated by Cholesterol-Sensitive Activation of Cytoplasmic Phospholipase A2

    PubMed Central

    Bate, Clive; Williams, Alun

    2015-01-01

    The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson’s disease (PD) and Dementia with Lewy Bodies. The loss of synapses is an important event in the pathogenesis of these diseases. Here we show that aggregated recombinant human αSN, but not βSN, triggered synapse damage in cultured neurons as measured by the loss of synaptic proteins. Pre-treatment with the selective cytoplasmic phospholipase A2 (cPLA2) inhibitors AACOCF3 and MAFP protected neurons against αSN-induced synapse damage. Synapse damage was associated with the αSN-induced activation of synaptic cPLA2 and the production of prostaglandin E2. The activation of cPLA2 is the first step in the generation of platelet-activating factor (PAF) and PAF receptor antagonists (ginkgolide B or Hexa-PAF) also protect neurons against αSN-induced synapse damage. αSN-induced synapse damage was also reduced in neurons pre-treated with the cholesterol synthesis inhibitor (squalestatin). These results are consistent with the hypothesis that αSN triggered synapse damage via hyperactivation of cPLA2. They also indicate that αSN-induced activation of cPLA2 is influenced by the cholesterol content of membranes. Inhibitors of this pathway that can cross the blood brain barrier may protect against the synapse damage seen during PD. PMID:25761116

  20. α-Synuclein-induced synapse damage in cultured neurons is mediated by cholesterol-sensitive activation of cytoplasmic phospholipase A2.

    PubMed

    Bate, Clive; Williams, Alun

    2015-03-09

    The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson's disease (PD) and Dementia with Lewy Bodies. The loss of synapses is an important event in the pathogenesis of these diseases. Here we show that aggregated recombinant human αSN, but not βSN, triggered synapse damage in cultured neurons as measured by the loss of synaptic proteins. Pre-treatment with the selective cytoplasmic phospholipase A2 (cPLA2) inhibitors AACOCF3 and MAFP protected neurons against αSN-induced synapse damage. Synapse damage was associated with the αSN-induced activation of synaptic cPLA2 and the production of prostaglandin E2. The activation of cPLA2 is the first step in the generation of platelet-activating factor (PAF) and PAF receptor antagonists (ginkgolide B or Hexa-PAF) also protect neurons against αSN-induced synapse damage. αSN-induced synapse damage was also reduced in neurons pre-treated with the cholesterol synthesis inhibitor (squalestatin). These results are consistent with the hypothesis that αSN triggered synapse damage via hyperactivation of cPLA2. They also indicate that αSN-induced activation of cPLA2 is influenced by the cholesterol content of membranes. Inhibitors of this pathway that can cross the blood brain barrier may protect against the synapse damage seen during PD.

  1. L-type voltage-dependent calcium channel is involved in the snake venom group IA secretory phospholipase A2-induced neuronal apoptosis.

    PubMed

    Yagami, Tatsurou; Yamamoto, Yasuhiro; Kohma, Hiromi; Nakamura, Tsutomu; Takasu, Nobuo; Okamura, Noboru

    2013-03-01

    Snake venom group IA secretory phospholipase A2 (sPLA2-IA) is known as a neurotoxin. Snake venom sPLA2s are neurotoxic in vivo and in vitro, causing synergistic neurotoxicity to cortical cultures when applied with toxic concentrations of glutamate. However, it has not yet been cleared sufficiently how sPLA2-IA exerts neurotoxicity. Here, we found sPLA2-IA induced neuronal cell death in a concentration-dependent manner. This death was a delayed response requiring a latent time for 6h. sPLA2-IA-induced neuronal cell death was accompanied with apoptotic blebbing, condensed chromatin, and fragmented DNA, exhibiting apoptotic features. NMDA receptor blockers suppressed the neurotoxicity of sPLA2-IA, but an AMPA receptor blocker did not. Interestingly, L-type voltage-dependent Ca(2+) channel (L-VDCC) blocker significantly protected neurons from the sPLA2-IA-induced apoptosis. On the other hand, neither N-VDCC blockers nor P/Q-VDCC blocker did. In conclusion, we demonstrated that sPLA2-IA induced neuronal cell death via apoptosis. Furthermore, the present study suggests that not only NMDA receptor but also L-VDCC contributed to the neurotoxicity of snake venom sPLA2-IA. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Aldehyde Dehydrogenases 1A2 Expression and Distribution are Potentially Associated with Neuron Death in Spinal Cord of Tg(SOD1*G93A)1Gur Mice.

    PubMed

    Liang, Huiting; Wu, Chengsi; Deng, Youqing; Zhu, Lei; Zhang, Jie; Gan, Weiming; Tang, Chunyan; Xu, Renshi

    2017-01-01

    The pathogenesis of amyotrophic lateral sclerosis (ALS) has not been unclear yet, it might be associated with the abnormal expression and distribution of certain proteins. Aldehyde dehydrogenases 1A2 (ALDH1A2) was thought to be one of potential candidates. Therefore, in this study we observed and analyzed the alteration of the expression and distribution of ALDH1A2 in the spinal cord of wild-type (WT) and Tg(SOD1*G93A)1Gur mice. We compared the expression and distribution of ALDH1A2 in the different segments, anatomic regions and neural cells of spinal cord at the different stages of WT and Tg(SOD1*G93A)1Gur mice applied the methods of fluorescent immunohistochemistry and western blot. Results revealed that ALDH1A2 extensively expressed and distributed in the spinal cord of adult WT and Tg(SOD1*G93A)1Gur mice. The expression and distribution of ALDH1A2 in the white matter including the anterior, posterior and lateral funiculus were more than that in the gray matter including the central canal, the anterior and dorsal horn. ALDH1A2 majorly expressed and distributed in the astrocyte, microglial, oligodendrocyte and neuron cells. The ALDH1A2 expression significantly decreased and redistributed in some anatomic regions of spinal cord at the onset and progression stages of Tg(SOD1*G93A)1Gur mice. The expression decrease of ALDH1A2 followed with the increase of neuron cells death. This study suggested that the alteration of expression and distribution of ALDH1A2 was potentially associated with the pathogenesis of ALS.

  3. Dissociable roles of glucocorticoid and noradrenergic activation on social discounting.

    PubMed

    Margittai, Zsofia; van Wingerden, Marijn; Schnitzler, Alfons; Joëls, Marian; Kalenscher, Tobias

    2018-04-01

    People often exhibit prosocial tendencies towards close kin and friends, but generosity decreases as a function of increasing social distance between donor and recipient, a phenomenon called social discounting. Evidence suggests that acute stress affects prosocial behaviour in general and social discounting in particular. We tested the causal role of the important stress neuromodulators cortisol (CORT) and noradrenaline (NA) in this effect by considering two competing hypotheses. On the one hand, it is possible that CORT and NA act in concert to increase generosity towards socially close others by reducing the aversiveness of the cost component in costly altruism and enhancing the emotional salience of vicarious reward. Alternatively, it is equally plausible that CORT and NA exert dissociable, opposing effects on prosocial behaviour based on prior findings implicating CORT in social affiliation, and NA in aggressive and antagonistic tendencies. We pharmacologically manipulated CORT and NA levels in a sample of men (N = 150) and found that isolated hydrocortisone administration promoted prosocial tendencies towards close others, reflected in an altered social discount function, but this effect was offset by concurrent noradrenergic activation brought about by simultaneous yohimbine administration. These results provide inceptive evidence for causal, opposing roles of these two important stress neuromodulators on prosocial behaviour, and give rise to the possibility that, depending on the neuroendocrine response profile, stress neuromodulator action can foster both tend-and-befriend and fight-or-flight tendencies at the same time. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Intrinsic neural circuits between dorsal midbrain neurons that control fear-induced responses and seizure activity and nuclei of the pain inhibitory system elaborating postictal antinociceptive processes: a functional neuroanatomical and neuropharmacological study.

    PubMed

    Freitas, Renato L; Ferreira, Célio M R; Ribeiro, Sandro J; Carvalho, Andressa D; Elias-Filho, Daoud H; Garcia-Cairasco, Norberto; Coimbra, Norberto Cysne

    2005-02-01

    The blockade of GABA-mediated Cl(-) influx with pentylenetetrazol (PTZ) was used in the present work to induce seizures in Rattus norvegicus. The aim of this work was to study the involvement of monoamines in the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the postictal period. Peripheral administration of methysergide (0.5, 1, 2, and 3 mg/kg) caused a significant decrease in the TFL in seizing animals, as compared to controls, in all postictal periods studied. These findings were corroborated by the pretreatment with ketanserin, a 5-HT(2A/2C)-serotonergic/alpha(1)-noradrenergic receptors antagonist, at the same doses. Peripheral administration of yohimbine (0.5, 1, 2, and 3 mg/kg), alpha(2)-noradrenergic antagonist, also decreased the postictal analgesia either at initial or more terminal periods of the postictal analgesia. These data were corroborated with peripheral administrations of propranolol, a beta-noradrenergic receptor blocker that caused a decrease in the postictal analgesia consistently in later stages (after the first 20-min post-tonic-clonic convulsive reactions) of the post-seizure analgesia, except for the highest dose. These results indicate that monoamines may be involved in the postictal analgesia. The blockade of 5-HT(2A/2C)-serotoninergic, alpha(1)-noradrenergic, or alpha(2)-noradrenergic receptors before tonic clonic seizure-induced analgesia antagonized the increase in the nociceptive threshold caused by seizures in initial steps of the temporal antinociceptive curve, as compared to the blockade of beta-noradrenergic ones. These findings suggest that the recruitment of alpha-noradrenergic receptor and serotonergic receptors was made immediately after convulsions and in other

  5. Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys

    PubMed Central

    Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland

    2017-01-01

    There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the sub-thalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson’s disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30–40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DβH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral mid-brain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50–70%) decrease in NE innervation. At the electron microscopic level, some DβH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD. PMID:28042095

  6. Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys.

    PubMed

    Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland

    2017-04-01

    There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30-40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DβH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50-70%) decrease in NE innervation. At the electron microscopic level, some DβH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Impact of bounded noise on the formation and instability of spiral wave in a 2D Lattice of neurons

    NASA Astrophysics Data System (ADS)

    Yao, Yuangen; Deng, Haiyou; Yi, Ming; Ma, Jun

    2017-02-01

    Spiral waves in the neocortex may provide a spatial framework to organize cortical oscillations, thus help signal communication. However, noise influences spiral wave. Many previous theoretical studies about noise mainly focus on unbounded Gaussian noise, which contradicts that a real physical quantity is always bounded. Furthermore, non-Gaussian noise is also important for dynamical behaviors of excitable media. Nevertheless, there are no results concerning the effect of bounded noise on spiral wave till now. Based on Hodgkin-Huxley neuron model subjected to bounded noise with the form of Asin[ωt + σW(t)], the influences of bounded noise on the formation and instability of spiral wave in a two-dimensional (2D) square lattice of neurons are investigated in detail by separately adjusting the intensity σ, amplitude A, and frequency f of bounded noise. It is found that the increased intensity σ can facilitate the formation of spiral wave while the increased amplitude A tends to destroy spiral wave. Furthermore, frequency of bounded noise has the effect of facilitation or inhibition on pattern synchronization. Interestingly, for the appropriate intensity, amplitude and frequency can separately induce resonance-like phenomenon.

  8. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways

    PubMed Central

    Hasegawa, Emi; Yanagisawa, Masashi; Sakurai, Takeshi; Mieda, Michihiro

    2014-01-01

    The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron–dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy. PMID:24382351

  9. [Developmental changes of neurotransmitter properties in sympathetic neurons].

    PubMed

    Masliukov, P M; Emanuilov, A I; Nozdrachev, A D

    2016-01-01

    Sympathetic ganglia consist of neurochemically and functionally distinct populations of neurons, characterized by a specific projection pattern and a set of neutransmitters including classical mediators (catecholamines and acetylcholine), neuropeptides and small molecules such as NO, H2S, CO. The majority of the principal ganglionic sympathetic neurons is noradrenergic and expresses tyrosine hydroxylase (TH), i.e., a key enzyme in catecholamine synthesis. In mammals, two third of catecholaminergic neurons also co-localizes neuropeptide Y. A small number of ganglionic sympathetic neurons contains enzyme of acetylcholine synthesis and some neuropeptides, such as somatostatin, vasoactive intestinal (poly)peptide (VIP), calcitonin gene-related peptide (CGRP). Acetylcholine-containing sympathetic neurons in most cases colocalize VIP and/or CGRP. Phenotype of autonomic neurons is regulated by both target-independent and target-dependent mechanisms. The most of transmitters are expressed during embryogenesis. TH appears during embryonic development and the percentage of TH-positive neurons remains virtually identical during ontogenesis. After birth, cholinergic neurons exhibit a noradrenergic phenotype. Expression of different neuropeptides changes in pre- and postnatal development. Neurotransmitter expression in sympathetic neurons is influenced by growth factor signaling via innervated target tissues. Multiple growth factors including bone morphogenetic proteins, neurotrophins, glial cell line-derived neurotrophic factor family ligands and neuropoietic cytokines play instructive role at different stages of neurotransmitter development.

  10. BR-16A DOES NOT INTERFERE WITH ALPHA - 2 NORADRENERGIC AND DOPAMINE POSTSYNAPTIC RECEPTOR FUNCTIONING

    PubMed Central

    Andrade, Chittaranjan; George, Jenniffer; Joseph, Thangam

    1993-01-01

    SUMMARY BR-16A is a herbal preparation with several putative psychotropic effects. Recent work has suggested that it facilities certain aspects of cognition and that it ameliorates ECT-induced amnesia in animal models. The present study sought to assess whether it affects noradrenergic and dopaminergic functioning in the central nervous system. Adult male Sprague-Dawley rats received BR-16A (200mg/kg) or vehicle for one month. The animals were subsequently challenged with clonidine (100 mg/kg I.P.), apomorphine (2mg/kg I.P.), or saline in a factorial design, and motility of the animals was immediately thereafter assessed using a small open field. BR-16A neither attenuated clonidine induced alpha-2 noradrenergic receptor-mediated hypomotility nor accentuated apomorphine-induced dopamine postsynaptic receptor-mediated hypermotility, suggesting that it does not interfere with alpha-2 noradrenergic and dopamine postsynaptic receptor functioning. PMID:21743635

  11. A noradrenergic mechanism functions to couple motor behavior with arousal state.

    PubMed

    Burgess, Christian R; Peever, John H

    2013-09-23

    Appropriate levels of skeletal muscle tone are needed to support routine motor behaviors. But, the brain mechanisms that function to couple muscle tone with waking behaviors are unknown. We addressed this question by studying mice with cataplexy--a condition caused by a decoupling of motor and arousal behaviors. Cataplexy is characterized by involuntary loss of muscle tone during wakefulness, which results in postural collapse during otherwise normal consciousness. Cataplexy is caused by loss of hypocretin (orexin) cells, but it is unknown how this loss triggers motor inactivity during cataplexy. Here, we used hypocretin knockout mice to identify the neurochemical cause of cataplexy and to determine the biochemical mechanisms that normally function to couple arousal and motor systems. Using genetic, behavioral, electrophysiological, and pharmacological approaches, we show that the noradrenergic system acts to synchronize motor and arousal systems. Specifically, we show that an excitatory noradrenergic drive maintains postural muscle tone during wakefulness by activating α1 receptors on skeletal motoneurons. Loss of this normal excitatory drive triggers motor inactivity during cataplexy by reducing motoneuron excitation. However, loss of this drive does not affect arousal since mice remain awake during cataplexy, suggesting the noradrenergic system is not required for maintaining wakefulness. Artificial restoration of noradrenergic drive to motoneurons prevents motor inactivity and rescues cataplexy. We conclude that hypocretin deficiency causes cataplexy by short-circuiting the noradrenergic drive to skeletal motoneurons. We suggest that the noradrenergic system functions to couple the brain systems that control postural muscle tone and behavioral arousal state. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. NORADRENERGIC INNERVATION OF THE RAT SPINAL CORD CAUDAL TO A COMPLETE SPINAL CORD TRANSECTION: EFFECTS OF OLFACTORY ENSHEATHING GLIA

    PubMed Central

    Takeoka, Aya; Kubasak, Marc D.; Zhong, Hui; Kaplan, Jennifer; Roy, Roland R.; Phelps, Patricia E.

    2010-01-01

    Transplantation of olfactory bulb-derived olfactory ensheathing glia (OEG) combined with step training improves hindlimb locomotion in adult rats with a complete spinal cord transection. Spinal cord injury studies use the presence of noradrenergic (NA) axons caudal to the injury site as evidence of axonal regeneration and we previously found more NA axons just caudal to the transection in OEG- than media-injected spinal rats. We therefore hypothesized that OEG transplantation promotes descending coeruleospinal regeneration that contributes to the recovery of hindlimb locomotion. Now we report that NA axons are present throughout the caudal stump of both media- and OEG-injected spinal rats and they enter the spinal cord from the periphery via dorsal and ventral roots and along large penetrating blood vessels. These results indicate that the presence of NA fibers in the caudal spinal cord is not a reliable indicator of coeruleospinal regeneration. We then asked if NA axons appose cholinergic neurons associated with motor functions, i.e., central canal cluster and partition cells (active during fictive locomotion) and somatic motor neurons (SMNs). We found more NA varicosities adjacent to central canal cluster cells, partition cells, and SMNs in the lumbar enlargement of OEG- than media-injected rats. As non-synaptic release of NA is common in the spinal cord, more associations between NA varicosities and motor-associated cholinergic neurons in the lumbar spinal cord may contribute to the improved treadmill stepping observed in OEG-injected spinal rats. This effect could be mediated through direct association with SMNs and/or indirectly via cholinergic interneurons. PMID:20025875

  13. Relationship between the local structure of orientation map and the strength of orientation tuning of neurons in monkey V1: a 2-photon calcium imaging study.

    PubMed

    Ikezoe, Koji; Mori, Yoshiya; Kitamura, Kazuo; Tamura, Hiroshi; Fujita, Ichiro

    2013-10-16

    A majority of neurons in the monkey primary visual cortex (V1) are tuned to stimulus orientations. Preferred orientations and tuning strengths vary among V1 neurons. The preferred orientation of neurons gradually changes across the cortex with occasional failures of this organization. How V1 neurons are arranged by the strength of orientation tuning and whether neuronal arrangement for tuning strength relates to orientation preference maps remains controversial. In this study, we performed in vivo two-photon calcium imaging in macaque V1 to examine the local spatial organization of orientation tuning at the level of single cells. We recorded fluorescence signals from individual neurons loaded with a calcium-sensitive dye in layer 2 and the uppermost tier of layer 3. The strength of orientation tuning was shared by nearby neurons, and changed across the cortex. The neurons with similar tuning strength were distributed across at least the entire thickness of layer 2. The tuning strength was weaker in regions where neurons exhibited heterogeneous preferred orientations, as compared with regions where neurons shared similar orientation preferences. Nearby direction-selective neurons often shared their preferred directions, although only a few neurons were direction selective in the layers examined. Thus, the orientation tuning strength of V1 neurons is partially predictable from the local structure of orientation map. The weaker orientation tuning we found in regions with heterogeneous orientation preferences suggests that orientation-independent interactions among local populations of V1 neurons play a critical role in determining their orientation tuning.

  14. Noradrenergic Action in Prefrontal Cortex in the Late Stage of Memory Consolidation

    ERIC Educational Resources Information Center

    Tronel, Sophie; Feenstra, Matthijs G. P.; Sara, Susan J.

    2004-01-01

    These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory…

  15. Noradrenergic Control of Odor Recognition in a Nonassociative Olfactory Learning Task in the Mouse

    ERIC Educational Resources Information Center

    Veyrac, Alexandra; Nguyen, Veronique; Marien, Marc; Didier, Anne; Jourdan, Francois

    2007-01-01

    The present study examined the influence of pharmacological modulations of the locus coeruleus noradrenergic system on odor recognition in the mouse. Mice exposed to a nonrewarded olfactory stimulation (training) were able to memorize this odor and to discriminate it from a new odor in a recall test performed 15 min later. At longer delays (30 or…

  16. Orphanin FQ/Nociceptin Interacts with the Basolateral Amygdala Noradrenergic System in Memory Consolidation

    ERIC Educational Resources Information Center

    Roozendaal, Benno; Lengvilas, Ray; McGaugh, James L.; Civelli, Olivier; Reinscheid, Rainer K.

    2007-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) mediates hormonal and neurotransmitter effects on the consolidation of emotionally influenced memory and that such modulatory influences involve noradrenergic activation of the BLA. As the BLA also expresses a high density of receptors for orphanin FQ/nociceptin…

  17. Facilitation of Learning by Social-Emotional Feedback in Humans Is Beta-Noradrenergic-Dependent

    ERIC Educational Resources Information Center

    Mihov, Yoan; Mayer, Simon; Musshoff, Frank; Maier, Wolfgang; Kendrick, Keith M.; Hurlemann, Rene

    2010-01-01

    Adaptive behavior in dynamic environments critically depends on the ability to learn rapidly and flexibly from the outcomes of prior choices. In social environments, facial expressions of emotion often serve as performance feedback and thereby guide declarative learning. Abundant evidence implicates beta-noradrenergic signaling in the modulatory…

  18. The Memory Function of Noradrenergic Activity in Non-REM Sleep

    ERIC Educational Resources Information Center

    Gais, Steffen; Rasch, Bjorn; Dahmen, Johannes C.; Sara, Susan; Born, Jan

    2011-01-01

    There is a long-standing assumption that low noradrenergic activity during sleep reflects mainly the low arousal during this brain state. Nevertheless, recent research has demonstrated that the locus coeruleus, which is the main source of cortical noradrenaline, displays discrete periods of intense firing during non-REM sleep, without any signs of…

  19. Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

    PubMed

    Skelly, M J; Ariwodola, O J; Weiner, J L

    2017-02-01

    Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline

  20. The noradrenergic paradox: implications in the management of depression and anxiety

    PubMed Central

    Montoya, Alonso; Bruins, Robert; Katzman, Martin A; Blier, Pierre

    2016-01-01

    Both major depressive disorder and the anxiety disorders are major causes of disability and markedly contribute to a significant global burden of the disease worldwide. In part because of the significant socioeconomic burden associated with these disorders, theories have been developed to specifically build clinical treatment approaches. One such theory, the monoaminergic hypothesis, has led to the development of several generations of selective and nonselective inhibitors of transporters of serotonin and norepinephrine, with the goal of augmenting monoaminergic transmission. These efforts have led to considerable success in the development of antidepressant therapeutics. However, there is a strong correlation between enhanced noradrenergic activity and fear and anxiety. Consequently, some physicians have expressed concerns that the same enhanced noradrenergic activity that alleviates depression could also promote anxiety. The fact that the serotonergic and noradrenergic reuptake inhibitors are successfully used in the treatment of anxiety and panic disorders seems paradoxical. This review was undertaken to determine if any clinical evidence exists to show that serotonergic and noradrenergic reuptake inhibitors can cause anxiety. The PubMed, EMBASE, and Cochrane Library databases were searched, and the results limited to randomized, double-blind, placebo-controlled studies performed in nongeriatric adults and with clear outcome measures were reported. Based on these criteria, a total of 52 studies were examined. Patients in these studies suffered from depression or anxiety disorders (generalized and social anxiety disorders, panic disorder, and posttraumatic stress disorder). The large majority of these studies employed venlafaxine or duloxetine, and the remainder used tri-cyclic antidepressants, atomoxetine, or reboxetine. All the studies reported clinically significant alleviation of depressive and/or anxious symptoms by these therapeutics. In none of these

  1. Fear Conditioning Selectively Disrupts Noradrenergic Facilitation of GABAergic Inhibition in the Basolateral Amygdala

    PubMed Central

    Skelly, M. J.; Ariwodola, O. J.; Weiner, J. L.

    2016-01-01

    Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1- and β3-AR agonists (1μM A61603 and 10μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. PMID

  2. The locus coeruleus and noradrenergic modulation of cognition.

    PubMed

    Sara, Susan J

    2009-03-01

    Mood, attention and motivation co-vary with activity in the neuromodulatory systems of the brain to influence behaviour. These psychological states, mediated by neuromodulators, have a profound influence on the cognitive processes of attention, perception and, particularly, our ability to retrieve memories from the past and make new ones. Moreover, many psychiatric and neurodegenerative disorders are related to dysfunction of these neuromodulatory systems. Neurons of the brainstem nucleus locus coeruleus are the sole source of noradrenaline, a neuromodulator that has a key role in all of these forebrain activities. Elucidating the factors that control the activity of these neurons and the effect of noradrenaline in target regions is key to understanding how the brain allocates attention and apprehends the environment to select, store and retrieve information for generating adaptive behaviour.

  3. Noradrenergic and cholinergic innervation of the bone marrow.

    PubMed

    Artico, Marco; Bosco, Sandro; Cavallotti, Carlo; Agostinelli, Enzo; Giuliani-Piccari, Gabriella; Sciorio, Salvatore; Cocco, Lucio; Vitale, Marco

    2002-07-01

    Bone marrow is supplied by sensory and autonomic innervation. Although it is well established that hematopoiesis is regulated by cytokines and cell-to-cell contacts, the role played by neuromediators on the proliferation, differentiation and release of hematopoietic cells is still controversial. We studied the innervation of rat femur bone marrow by means of fluorescence histochemistry and immunohistochemistry. Glyoxylic acid-induced fluorescence was used to demonstrate catecholaminergic nerve fibers. The immunoperoxidase method with nickel amplification was applied to detect the distribution of nerve fibers using antibodies against the general neuronal marker PGP 9.5 (neuron-specific cytoplasmic protein), while the cholinacetyltransferase immunoreactivity was studied by immunohistochemistry. Our results show the presence of an extensive network of innervation in the rat bone marrow, providing a morphological basis for the neural modulation of hemopoiesis.

  4. Estrogen regulates energy metabolic pathway and upstream adenosine 5'-monophosphate-activated protein kinase and phosphatase enzyme expression in dorsal vagal complex metabolosensory neurons during glucostasis and hypoglycemia.

    PubMed

    Tamrakar, Pratistha; Ibrahim, Baher A; Gujar, Amit D; Briski, Karen P

    2015-02-01

    The ability of estrogen to shield the brain from the bioenergetic insult hypoglycemia is unclear. Estradiol (E) prevents hypoglycemic activation of the energy deficit sensor adenosine 5'-monophosphate-activated protein kinase (AMPK) in hindbrain metabolosensory A2 noradrenergic neurons. This study investigates the hypothesis that estrogen regulates A2 AMPK through control of fuel metabolism and/or upstream protein kinase/phosphatase enzyme expression. A2 cells were harvested by laser microdissection after insulin or vehicle (V) injection of E- or oil (O)-implanted ovariectomized female rats. Cell lysates were evaluated by immunoblot for glycolytic, tricarboxylic acid cycle, respiratory chain, and acetyl-CoA-malonyl-CoA pathway enzymes. A2 phosphofructokinase (PFKL), isocitrate dehydrogenase, pyruvate dehydrogenase, and ATP synthase subunit profiles were elevated in E/V vs. O/V; hypoglycemia augmented PFKL and α-ketoglutarate dehydrogenase expression in E only. Hypoglycemia increased A2 Ca(2+) /calmodulin-dependent protein kinase-β in O and reduced protein phosphatase in both groups. A2 phospho-AMPK levels were equivalent in O/V vs. E/V but elevated during hypoglycemia in O only. These results implicate E in compensatory upregulation of substrate catabolism and corresponding maintenance of energy stability of A2 metabolosensory neurons during hypoglycemia, outcomes that support the potential viability of molecular substrates for hormone action as targets for therapies alleviating hypoglycemic brain injury. © 2014 Wiley Periodicals, Inc.

  5. Anxious and depressive disorders and their comorbidity: effect on central nervous system noradrenergic function.

    PubMed

    Cameron, Oliver G; Abelson, James L; Young, Elizabeth A

    2004-12-01

    Although comorbidity of anxiety with depression is common, investigations of physiologic abnormalities related specifically to comorbidity are rare. This study examined relationships of DSM-IV-defined depression, anxiety, and their comorbidity to noradrenergic function measured by blunting of the growth hormone (GH) response to the alpha2 adrenoreceptor agonist (and imidazoline receptor agent) clonidine and by blood pressure and symptom responses. Fifteen subjects with pure social anxiety or panic disorder, 15 with pure major depression, and 18 with both depression and anxiety were compared with healthy control subjects matched for age and gender. Other factors known to affect GH (weight, menstrual status, prior antidepressant, or other drug exposure) were controlled. Anxiety produced GH blunting, but depression was associated with normal GH responses. The comorbid state did not affect results beyond the impact of anxiety. Preclonidine stress-related GH elevations were observed, to the greatest degree in anxious subjects. Relevant symptom, but not blood pressure, changes were significantly associated with blunting. With use of pure depression and anxiety groups and careful control of other factors known to affect GH, these results demonstrate central nervous system noradrenergic dysfunction in anxiety disorders. In contrast to less rigorously controlled studies, noradrenergic function in depression was normal.

  6. The Maudsley rat strains as a probe to investigate noradrenergic-cholinergic interaction in cognitive function.

    PubMed

    Sara, S J; Devauges, V; Biegon, A; Blizard, D A

    1994-01-01

    Central noradrenergic function in relation to cognitive performance was studied in the Maudsley rat strains. Neurochemical studies revealed a higher response to acute stress in the locus coeruleus (LC) in the Maudsley reactives (MR) than in the Maudsley non-reactives (MNRA). Autoradiographic studies showed that MNRAs had greater 125I clonidine binding to alpha 2 receptors in LC, which was accompanied by a higher behavioral sensitivity to clonidine. MRs had a deficit in working memory, but were superior to MNRAs in two reference memory tasks. MRs displayed a stronger preference for novel objects, with no strain differences in general exploratory activity. The behavioral profile of the MRs is similar to rats treated with drugs which enhance noradrenergic function. Furthermore, MNRA rats had greater availability of muscarinic receptors, which correlated with behavioral performance in the spatial working memory task. The differences in noradrenergic and cholinergic systems and their relationship to the behavioral profile make the Maudsley strains a useful tool to probe the interaction between two neurotransmitter systems in cognitive function.

  7. Terbutaline impairs the development of peripheral noradrenergic projections: potential implications for autism spectrum disorders and pharmacotherapy of preterm labor.

    PubMed

    Slotkin, Theodore A; Seidler, Frederic J

    2013-01-01

    Terbutaline, a β2-adrenoceptor agonist, is used off-label for long-term management of preterm labor; such use is associated with increased risk of neurodevelopmental disorders, including autism spectrum disorders. We explored the mechanisms underlying terbutaline's effects on development of peripheral sympathetic projections in developing rats. Terbutaline administration on postnatal days 2-5 led to immediate and persistent deficiencies in cardiac norepinephrine levels, with greater effects in males than in females. The liver showed a lesser effect; we reasoned that the tissue differences could represent participation of retrograde trophic signaling from the postsynaptic site to the developing neuronal projection, since hepatic β2-adrenoceptors decline in the perinatal period. Accordingly, when we gave terbutaline earlier, on gestational days 17-20, we saw the same deficiencies in hepatic norepinephrine that had been seen in the heart with the later administration paradigm. Administration of isoproterenol, which stimulates both β1- and β2-subtypes, also had trophic effects that differed in direction and critical period from those elicited by terbutaline; methoxamine, which stimulates α1-adrenoceptors, was without effect. Thus, terbutaline, operating through trophic interactions with β2-adrenoceptors, impairs development of noradrenergic projections in a manner similar to that previously reported for its effects on the same neurotransmitter systems in the immature cerebellum. Our results point to the likelihood of autonomic dysfunction in individuals exposed prenatally to terbutaline; in light of the connection between terbutaline and autism, these results could also contribute to autonomic dysregulation seen in children with this disorder. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Differential effects of unilateral olfactory deprivation on noradrenergic and cholinergic systems in the main olfactory bulb of the rat.

    PubMed

    Gómez, C; Briñón, J G; Colado, M I; Orio, L; Vidal, M; Barbado, M V; Alonso, J R

    2006-09-15

    The lack of environmental olfactory stimulation produced by sensory deprivation causes significant changes in the deprived olfactory bulb. Olfactory transmission in the main olfactory bulb (MOB) is strongly modulated by centrifugal systems. The present report examines the effects of unilateral deprivation on the noradrenergic and cholinergic centrifugal systems innervating the MOB. The morphology, distribution, and density of positive axons were studied in the MOBs of control and deprived rats, using dopamine-beta-hydroxylase (DBH)-immunohistochemistry and acetylcholinesterase (AChE) histochemistry in serial sections. Catecholamine content was compared among the different groups of MOBs (control, contralateral, and ipsilateral to the deprivation) using high-performance liquid chromatography analysis. Sensory deprivation revealed that the noradrenergic system developed adaptive plastic changes after olfactory deprivation, including important modifications in its fiber density and distribution, while no differences in cholinergic innervation were observed under the same conditions. The noradrenergic system underwent an important alteration in the glomerular layer, in which some glomeruli showed a dense noradrenergic innervation that was not detected in control animals. The DBH-positive glomeruli with the highest noradrenergic fiber density were compared with AChE-stained sections and it was observed that the strongly noradrenergic-innervated glomeruli were always atypical glomeruli (characterized by their strong degree of cholinergic innervation). In addition to the morphological findings, our biochemical data revealed that olfactory deprivation caused a decrease in the content of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the ipsilateral MOB in comparison to the contralateral and control MOBs, together with an increase in noradrenaline levels in both the ipsilateral and contralateral MOBs. Our results show that regulation of the noradrenergic

  9. Involvement of histaminergic and noradrenergic receptors in the oxytocin-induced food intake in neonatal meat-type chicks.

    PubMed

    Mirnaghizadeh, Seyed Vahid; Zendehdel, Morteza; Babapour, Vahab

    2017-03-01

    Oxytocin neurons have a physiological role in food intake and energy balance. Several studies have shown that central histaminergic and adrenergic systems synapse on oxytocin neurons but there is no information for their interaction on food intake regulation in birds. The purpose of this study was to examine the effects of intracerebroventricular (ICV) injection of α-fluoromethylhistidine (α-FMH, histidine decarboxylase inhibitor), chlorpheniramine (histamine H1 receptors antagonist), famotidine (histamine H2 receptors antagonist), thioperamide (histamine H3 receptors antagonist), prazosin (α1 receptor antagonist), yohimbine (α2 receptor antagonist), metoprolol (β1 adrenergic receptor antagonist), ICI 118,551 (β2 adrenergic receptor antagonist) and SR59230R (β3 adrenergic receptor antagonist) on oxytocin-induced hypophagia in 3-h food-deprived (FD 3 ) neonatal broiler chicken. In Experiment 1, 3 h-fasted chicks were given an ICV injection of saline, α-FMH (250 nmol), oxytocin (10 μg) and co-injection of α-FMH + oxytocin. Experiments 2-9 were similar to experiment 1 except birds were injected with chlorpheniramine (300 nmol), famotidine (82 nmol), thioperamide (300 nmol), prazosin (10 nmol), yohimbine (13 nmol), metoprolol (24 nmol), ICI 118,551(5 nmol) and SR59230R (20 nmol) instead of α-FMH, respectively. After injection cumulative food intake was measured until 120 min post injection. According to the results, ICV injection of oxytocin significantly decreased food intake in broiler chickens (P < 0.001). ICV injection of α-FMH significantly attenuated hypophagic effect of oxytocin (P < 0.001). Also, co-injection of chlorpheniramine plus oxytocin significantly decreased the effect of oxytocin on food intake (P < 0.001). Co-administration of thioperamide and oxytocin significantly amplified hypophagic effect of oxytocin in chickens (P < 0.001). In addition, ICI 118,551 attenuated hypophagic effect of oxytocin (P < 0.001); while

  10. Glucocorticoid enhancement of dorsolateral striatum-dependent habit memory requires concurrent noradrenergic activity.

    PubMed

    Goodman, J; Leong, K-C; Packard, M G

    2015-12-17

    Previous findings indicate that post-training administration of glucocorticoid stress hormones can interact with the noradrenergic system to enhance consolidation of hippocampus- or amygdala-dependent cognitive/emotional memory. The present experiments were designed to extend these findings by examining the potential interaction of glucocorticoid and noradrenergic mechanisms in enhancement of dorsolateral striatum (DLS)-dependent habit memory. In experiment 1, different groups of adult male Long-Evans rats received training in two DLS-dependent memory tasks. In a cued water maze task, rats were released from various start points and were reinforced to approach a visibly cued escape platform. In a response-learning version of the water plus-maze task, animals were released from opposite starting positions and were reinforced to make a consistent egocentric body-turn to reach a hidden escape platform. Immediately post-training, rats received peripheral injections of the glucocorticoid corticosterone (1 or 3 mg/kg) or vehicle solution. In both tasks, corticosterone (3 mg/kg) enhanced DLS-dependent habit memory. In experiment 2, a separate group of animals received training in the response learning version of the water plus-maze task and were given peripheral post-training injections of corticosterone (3 mg/kg), the β-adrenoreceptor antagonist propranolol (3 mg/kg), corticosterone and propranolol concurrently, or control vehicle solution. Corticosterone injections again enhanced DLS-dependent memory, and this effect was blocked by concurrent administration of propranolol. Propranolol administration by itself (3 mg/kg) did not influence DLS-dependent memory. Taken together, the findings indicate an interaction between glucocorticoid and noradrenergic mechanisms in DLS-dependent habit memory. Propranolol administration may be useful in treating stress-related human psychopathologies associated with a dysfunctional DLS-dependent habit memory system. Copyright © 2015

  11. Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin.

    PubMed

    Boehnlein, James K; Kinzie, J David

    2007-03-01

    This article reviews the neurobiologic rationale for and presents clinical guidance concerning the use of medications that reduce central nervous system noradrenergic activity in the treatment of intrusive symptoms of posttraumatic stress disorder. The authors reviewed neurobiological studies, nonclinical studies using animal models, clinical case reports, open-label drug studies, and blinded, placebo-controlled drug studies. This review of the basic science and clinical literature, and the authors' clinical experience with culturally and demographically diverse populations, indicate that clonidine and prazosin can play a useful role in treating sleep disturbance and hyperarousal in posttraumatic stress disorder, with minimal adverse effects and low financial cost.

  12. Autoradiographic analysis of alpha 1-noradrenergic receptors in the human brain postmortem. Effect of suicide

    SciTech Connect

    Gross-Isseroff, R.; Dillon, K.A.; Fieldust, S.J.

    1990-11-01

    In vitro quantitative autoradiography of alpha 1-noradrenergic receptors, using tritiated prazosin as a ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide victims and 12 from matched controls. We found significant lower binding to alpha 1 receptors in several brain regions of the suicide group as compared with matched controls. This decrease in receptor density was evident in portions of the prefrontal cortex, as well as the temporal cortex and in the caudate nucleus. Age, sex, presence of alcohol, and time of death to autopsy did not affect prazosin binding, in our sample, as measuredmore » by autoradiography.« less

  13. Safety concerns associated with the use of serotonin reuptake inhibitors and other serotonergic/noradrenergic antidepressants during pregnancy: a review.

    PubMed

    Tuccori, Marco; Testi, Arianna; Antonioli, Luca; Fornai, Matteo; Montagnani, Sabrina; Ghisu, Narcisa; Colucci, Rocchina; Corona, Tiberio; Blandizzi, Corrado; Del Tacca, Mario

    2009-06-01

    There is ongoing debate about the safety of selective serotonin reuptake inhibitors (SSRIs) and other serotonergic/noradrenergic antidepressants when used during pregnancy. This article reviews the available literature on the main safety concerns associated with the use of SSRIs and other serotonergic/noradrenergic antidepressants (serotonin-norepinephrine reuptake inhibitors, norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants) during pregnancy. English-language reports of analytical and descriptive studies, including case reports, case series, and meta-analyses, were identified through searches of MEDLINE, EMBASE, and PsycINFO (1966-April 2009). The search terms were fluoxetine, paroxetine, sertraline, Citalopram, escitalopram, fluvoxamine, venlafaxine, mirtazapine, reboxetine, duloxetine, SSRI, SNRI, NaSSA, and NRI in association with depression, pregnancy, prenatal exposure, miscarriage, spontaneous abortion, malformation, in utero exposure, and neonatal complications. Paroxetine has been associated with significant risks of major malformation, particularly cardiac defects, when used during pregnancy. Significant associations between maternal exposure to SSRIs and both persistent pulmonary hypertension of the newborn and a self-limiting neonatal behavioral syndrome have been reported in a number of recent original studies and meta-analyses. Some studies have suggested a relationship between the use of SSRIs or other serotonergic/noradrenergic antidepressants and the occurrence of miscarriage, although these studies had methodologic limitations that affected the strength of the data. Evidence for a possible association between in utero exposure to SSRIs or other serotonergic/noradrenergic antidepressants and alterations in neurobehavioral development, bleeding, and QTc-interval prolongation is currently weak. The available evidence suggests that SSRIs and other serotonergic/noradrenergic antidepressants should be used with

  14. Systemic dexmedetomidine augments inhibitory synaptic transmission in the superficial dorsal horn through activation of descending noradrenergic control: an in vivo patch-clamp analysis of analgesic mechanisms

    PubMed Central

    Funai, Yusuke; Pickering, Anthony Edward; Uta, Daisuke; Nishikawa, Kiyonobu; Mori, Takashi; Asada, Akira; Imoto, Keiji; Furue, Hidemasa

    2014-01-01

    α2-adrenoceptors are widely distributed throughout the central nervous system (CNS) and the systemic administration of α2-agonists such as dexmedetomidine produces clinically useful, centrally-mediated sedation and analgesia; however, these same actions also limit the utility of these agents (ie unwanted sedative actions). Despite a wealth of data on cellular and synaptic actions of α2-agonists in vitro, it is not known which neuronal circuits are modulated in vivo to produce the analgesic effect. To address this issue, we made in vivo recordings of membrane currents and synaptic activities in superficial spinal dorsal horn neurons and examined their responses to systemic dexmedetomidine. We found that dexmedetomidine at doses that produce analgesia (<10 μg/kg) enhanced inhibitory postsynaptic transmission within the superficial dorsal horn without altering excitatory synaptic transmission or evoking direct postsynaptic membrane currents. In contrast, higher doses of dexmedetomidine (>10 μg/kg) induced outward currents by a direct postsynaptic action. The dexmedetomidine-mediated inhibitory postsynaptic current (IPSC) facilitation was not mimicked by spinal application of dexmedetomidine and was absent in spinalized rats, suggesting it acts at a supraspinal site. Further it was inhibited by spinal application of the α1-antagonist prazosin. In the brain stem, low doses of systemic dexmedetomidine produced an excitation of locus coeruleus neurons. These results suggest that systemic α2-adrenoceptor stimulation may facilitate inhibitory synaptic responses in the superficial dorsal horn to produce analgesia mediated by activation of the pontospinal noradrenergic inhibitory system. This novel mechanism may provide new targets for intervention perhaps allowing analgesic actions to be dissociated from excessive sedation. PMID:24355412

  15. [Intraventricular yohimbine infusion induces noradrenergic changes in motor cerebral injured rats and enhances motor recovery].

    PubMed

    González-Piña, Rigoberto; Alfaro-Rodríguez, Alfonso; Bueno-Nava, Antonio; Ávila-Luna, Alberto

    2013-01-01

    It has been proposed that noradrenaline is one of the neurotransmitters involved in the functional recovery. In this sense, it has been proposed that the alpha-2 noradrenergic receptors play an important role in the functional reinstatement. the aim of this work was to study the role of the alpha-2 noradrenergic receptors on the noradrenaline contents in cerebellum and pons of rats iron-injured in the motor cortex. Fifteen male Wistar rats were allocated in three groups: control (n = 5) with intracortical infusion of saline (0.9%), injured (n = 5) with intracortical infusion of dextran iron and intraventricular infusion of saline, and injured + yohimbine (alpha-2 receptor antagonist; n = 5) that received an intracortical infusion of dextran iron and also an intraventricular infusion of yohimbine. Motor behavior was assessed by means of the beam-walking paradigm. Three days after surgeries, the animals were sacrificed and the left and right sides of the pons and the cerebellar hemispheres were extracted. Tissues were prepared for noradrenaline analysis by means of high performance liquid chromatography. We observed that the yohimbine-treated animals had a noradrenaline increase in the right side of the pons and a decrease in the right cerebellar hemisphere. It is concluded that the blockage of the alpha-2 receptors leads to an increase of noradrenaline in the locus coeruleus, which retards the effects of the cerebral injury.

  16. Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity.

    PubMed

    Rajkumar, Ramamoorthy; Kumar, Jigna Rajesh; Dawe, Gavin S

    2017-02-01

    Priming phenomenon, in which an earlier exposure to a stimulus or condition alters synaptic plasticity in response to a subsequent stimulus or condition, known as a challenge, is an example of metaplasticity. In this review, we make the case that the locus coeruleus noradrenergic system-medial perforant path-dentate gyrus pathway is a neural ensemble amenable to studying priming-challenge effects on synaptic plasticity. Accumulating evidence points to a tyrosine hydroxylase-dependent priming effect achieved by pharmacological (nicotine and antipsychotics) or physiological (septal theta driving) manipulations of the locus coeruleus noradrenergic system that can facilitate noradrenaline-induced synaptic plasticity in the dentate gyrus of the hippocampus. The evidence suggests the hypothesis that behavioural experiences inducing tyrosine hydroxylase expression in the locus coeruleus may be sufficient to prime this form of metaplasticity. We propose exploring this phenomenon of priming and challenge physiologically, to determine whether behavioural experiences are sufficient to prime the locus coeruleus, enabling subsequent pharmacological or behavioural challenge conditions that increase locus coeruleus firing to release sufficient noradrenaline to induce long-lasting potentiation in the dentate gyrus. Such an approach may contribute to unravelling mechanisms underlying this form of metaplasticity and its importance in stress-related mnemonic processes. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Nortriptyline Enhances Morphine-Conditioned Place Preference in Neuropathic Rats: Role of the Central Noradrenergic System.

    PubMed

    Mi, Wenli; Wang, Shuxing; You, Zerong; Lim, Grewo; McCabe, Michael F; Kim, Hyangin; Chen, Lucy; Mao, Jianren

    2017-09-01

    Combination drug therapy is commonly used to treat chronic pain conditions such as neuropathic pain, and antidepressant is often used together with opioid analgesics. While rewarding is an intrinsic property of opioid analgesics, it is unknown whether the use of an antidepressant would influence opioid reward, which may contribute to opioid addiction. In this study, we examined whether nortriptyline (a tricyclic antidepressant and a first-line medication for neuropathic pain) would enhance the morphine rewarding property in both naive and chronic constriction sciatic nerve injury (CCI) rats. The rewarding effect of these drugs was assessed using conditioned place preference (CPP). The real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay analysis were used to investigate the function of central noradrenergic system. In naive rats, coadministration of nortriptyline with morphine did not change the acquisition of morphine-induced CPP. However, nortriptyline enhanced the acquisition, delayed the extinction, and augmented the reinstatement of morphine-induced CPP in CCI rats. In CCI rats treated with both nortriptyline and morphine, the expression of α2A-adrenergic receptors, norepinephrine transporter, and tyrosine hydroxylase was markedly decreased in the locus coeruleus, whereas the norepinephrine concentration in the nucleus accumbens was remarkably increased. These results demonstrate that nortriptyline enhanced morphine reward when both drugs were used to treat neuropathic pain in rats and that this behavioral phenotype is likely to be mediated by upregulation of the central noradrenergic system. These findings may have implications in opioid therapy commonly used for chronic pain management.

  18. Consolidation of Memory After its Reactivation: Involvement of β Noradrenergic Receptors in the Late Phase

    PubMed Central

    Roullet, Pascal; Sara, Susan

    1998-01-01

    Evidence is growing that the cAMP pathway through the cAMP responsive element binding protein (CREB) transcription factor plays an important role in long-term memory formation (LTM). To study the role of β-noradrenergic receptors, positively linked to the cAMP secondmessenger system, in the dynamics of LTM processes, we used a memory-reactivation paradigm because recent studies in our laboratory confirmed that reactivated memory is labile and undergoes an extended reconsolidation process. In an eight-arm maze, rats were trained to choose the same three baited arms; 24 hr later, memory was reactivated and then the rats were injected intracerebroventricularly at 5 min, 30 min, 60 min, or 5 hr later with the β-antagonist timolol or with saline. The results showed that injection of timolol induced amnesia only at the 60 min post-reactivation interval, whereas all control groups and groups that were timolol-injected at other post-reactivation intervals displayed optimal retention. The delayed amnesic action of timoloi suggests that β noradrenergic receptors and the cAMP cascade are implicated in the late phase of reprocessing of a remembered event. PMID:9920683

  19. Power based association analysis (PBAT) of serotonergic and noradrenergic polymorphisms in bipolar patients with suicidal behaviour.

    PubMed

    De Luca, Vincenzo; Strauss, John; Kennedy, James L

    2008-01-01

    Suicidality is a major health concern worldwide particularly in affective disorder patients. Attempted suicide is familial. There is strong neurobiological evidence showing that serotonergic and noradrenergic dysfunction is implicated in suicidal behaviours. We will apply now a new family based association strategy aimed to explain the genetic influence in suicidal behaviour by power based association test statistics (PBAT) in 336 bipolar patients assessed for suicidality within nuclear families. By use of conditional power calculations, the approach screens all possible null hypotheses without biasing the nominal significance level, and it identifies the subset of phenotypes that has optimal power when tested for association by either univariate or multivariate family based association test (FBAT). Using this statistical approach (PBAT) we investigated polymorphisms in serotonergic and noradrenergic genes, considering suicidal behaviour severity instead of the dichotomous phenotype (presence of suicide attempt). COMT Val/Met polymorphism was not associated with suicide with high confidence (power=91%). On the other hand, the analysis of the other 12 markers in the adrenergic and serotonergic genes revealed that the TH allele tended towards association with higher severity of suicidal behaviour (p=0.060) but the power obtained was very low. The marginal finding of association between TH and severe suicidal behaviour are convergent with previous reports. On the other hand, our sample has enough power to exclude the other polymorphisms investigated as major candidate for suicidality in bipolar disorder.

  20. Noradrenergic-Dopaminergic Interactions Due to DSP-4-MPTP Neurotoxin Treatments: Iron Connection.

    PubMed

    Archer, Trevor

    The investigations of noradrenergic lesions and dopaminergic lesions have established particular profiles of functional deficits and accompanying alterations of biomarkers in brain regions and circuits. In the present account, the focus of these lesions is directed toward the effects upon dopaminergic neurotransmission and expression that are associated with the movement disorders and psychosis-like behavior. In this context, it was established that noradrenergic denervation, through administration of the selective noradrenaline (NA) neurotoxin, DSP-4, should be performed prior to the depletion of dopamine (DA) with the selective neurotoxin, MPTP. Employing this regime, it was shown that (i) following DSP-4 (50 mg/kg) pretreatment of C57/Bl6 mice, both the functional and neurochemical (DA loss) effects of MPTP (2 × 20 and 2 × 40 mg/kg) were markedly exacerbated, and (ii) following postnatal iron (Fe(2+), 7.5 mg/kg, on postnatal days 19-12), pretreatment with DSP-4 followed by the lower 2 × 20 mg/kg MPTP dose induced even greater losses of motor behavior and striatal DA. As yet, the combination of NA-DA depletions, and even more so Fe(2+)-NA-DA depletion, has been considered to present a movement disorder aspect although studies exploring cognitive domains are lacking. With intrusion of iron overload into this formula, the likelihood of neuropsychiatric disorder, as well, unfolds.

  1. Cerebrovascular nerve fibers immunoreactive for tryptophan-5-hydroxylase in the rat: distribution, putative origin and comparison with sympathetic noradrenergic nerves.

    PubMed

    Cohen, Z; Bovento, G; Lacombe, P; Seylaz, J; MacKenzie, E T; Hamel, E

    1992-12-11

    The distribution of serotonergic nerves in major basal and isolated small pial arteries (diameter > or = 50 microns) was investigated immunohistochemically using an antibody directed against tryptophan-5-hydroxylase (TPOH), the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT or serotonin), and compared to that of the noradrenergic system labeled for the selective noradrenaline (NA) synthesizing enzyme, dopamine-beta-hydroxylase (DBH). In addition, the possible peripheral and/or central origins of the cerebrovascular serotonergic (TPOH-positive) nerve fibers were examined. Strongly labeled TPOH-immunoreactive (TPOH-I) fiber bundles were observed in major basal arteries and gave rise to small varicose fibers organized in a meshwork pattern. The highest density of TPOH-I fibers was found in the middle cerebral artery followed by the anterior cerebral and the anterior communicating arteries, with a moderate to low density in the internal carotid and the vertebro-basilar trunk. Of the isolated pial arteries, only the larger ones (diameter > 75 microns) were significantly endowed with TPOH-I varicose fibers. However, free floating TPOH-I nerves were observed coursing through the pia-arachnoid membranes and reaching small pial vessels. In contrast, DBH-I nerve fibers were fine and were visualized primarily as numerous varicosities distributed in a circumferential manner around the vessel wall. A very high density of DBH-I varicosities was seen in the rostral part of the circle of Willis, with the internal carotid being the most richly supplied followed by the anterior cerebral and the anterior communicating arteries; comparatively, the middle cerebral artery was moderately innervated. The differences in distribution pattern and density between TPOH-I and DBH-I cerebrovascular fibers clearly suggest that these two innervation systems are not exactly superimposable. Superior cervical ganglionectomy caused an almost complete disappearance of TPOH-I nerves

  2. Both a Nicotinic Single Nucleotide Polymorphism (SNP) and a Noradrenergic SNP Modulate Working Memory Performance when Attention Is Manipulated

    ERIC Educational Resources Information Center

    Greenwood, Pamela M.; Sundararajan, Ramya; Lin, Ming-Kuan; Kumar, Reshma; Fryxell, Karl J.; Parasuraman, Raja

    2009-01-01

    We investigated the relation between the two systems of visuospatial attention and working memory by examining the effect of normal variation in cholinergic and noradrenergic genes on working memory performance under attentional manipulation. We previously reported that working memory for location was impaired following large location precues,…

  3. Ilex paraguariensis Promotes Orofacial Pain Relief After Formalin Injection: Involvement of Noradrenergic Pathway

    PubMed Central

    de Carvalho, Eudislaine Fonseca; de Oliveira, Simone Kobe; Nardi, Viviane Koepp; Gelinski, Tathiana Carla; Bortoluzzi, Marcelo Carlos; Maraschin, Marcelo; Nardi, Geisson Marcos

    2016-01-01

    Background: Drinking mate or chimarrão, a hot infusion of Ilex paraguariensis (ILEX) leaves, is a common habit in Southern South America that has a social and almost ritualistic role. It has been used as a stimulant beverage in South America and analgesic in regions of Argentina for treatment of headache and others painful inflammatory conditions such as arthritis and rheumatism. Objective: The aim of this study was to evaluate the pharmacological activity of I. paraguariensis infusion (ILEX) on orofacial nociception model induced by formalin, and study its mechanism of action. Materials and Methods: The analgesic effect of ILEX was assessed through writhing test, paw formalin test, paw edema induced by carrageenan, and orofacial pain induced by formalin. To study the action mechanism of ILEX, opioidergic, dopaminergic, nitrergic, and adrenergic pathways were investigated. Results: The high-performance liquid chromatography analysis of ILEX infusion revealed caffeine and theobromine. The treatment with ILEX reduced the number of writhing. However, it was effective neither in the formalin paw test nor in the paw edema induced by carrageenan. Different from formalin paw test, ILEX was able to reduce the orofacial reactivity to formalin in 31.8% (70.4 ± 2.5 s; first phase), and 20% (127.3 ± 18.9 s; second phase). The analgesic effect of ILEX results from the modulation of noradrenergic pathways since prazosin (α1-adrenoceptor antagonist, 0.15 mg/kg; intraperitoneal) reversed the analgesic effect of ILEX. Conclusions: The present report demonstrates that analgesic effect of ILEX in orofacial formalin test is due mainly to modulation of noradrenergic pathways. SUMMARY Ilex paraguariensis (ILEX) has been used as a stimulant beverage in South America and analgesic in regions of Argentina for the treatment of headache and others painful inflammatory conditions such arthritis and rheumatism.The aim of this study was to evaluate the pharmacological activity of ILEX on

  4. Astrocytic and neuronal accumulation of elevated extracellular K+ with a 2/3 K+/Na+ flux ratio—consequences for energy metabolism, osmolarity and higher brain function

    PubMed Central

    Hertz, Leif; Xu, Junnan; Song, Dan; Yan, Enzhi; Gu, Li; Peng, Liang

    2013-01-01

    Brain excitation increases neuronal Na+ concentration by 2 major mechanisms: (i) Na+ influx caused by glutamatergic synaptic activity; and (ii) action-potential-mediated depolarization by Na+ influx followed by repolarizating K+ efflux, increasing extracellular K+ concentration. This review deals mainly with the latter and it concludes that clearance of extracellular K+ is initially mainly effectuated by Na+,K+-ATPase-mediated K+ uptake into astrocytes, at K+ concentrations above ~10 mM aided by uptake of Na+,K+ and 2 Cl− by the cotransporter NKCC1. Since operation of the astrocytic Na+,K+-ATPase requires K+-dependent glycogenolysis for stimulation of the intracellular ATPase site, it ceases after normalization of extracellular K+ concentration. This allows K+ release via the inward rectifying K+ channel Kir4.1, perhaps after trans-astrocytic connexin- and/or pannexin-mediated K+ transfer, which would be a key candidate for determination by synchronization-based computational analysis and may have signaling effects. Spatially dispersed K+ release would have little effect on extracellular K+ concentration and allow K+ accumulation by the less powerful neuronal Na+,K+-ATPase, which is not stimulated by increases in extracellular K+. Since the Na+,K+-ATPase exchanges 3 Na+ with 2 K+, it creates extracellular hypertonicity and cell shrinkage. Hypertonicity stimulates NKCC1, which, aided by β-adrenergic stimulation of the Na+,K+-ATPase, causes regulatory volume increase, furosemide-inhibited undershoot in [K+]e and perhaps facilitation of the termination of slow neuronal hyperpolarization (sAHP), with behavioral consequences. The ion transport processes involved minimize ionic disequilibria caused by the asymmetric Na+,K+-ATPase fluxes. PMID:23986689

  5. Interactive dopaminergic and noradrenergic systems in the regulation of thirst in the rat.

    PubMed

    Zabik, J E; Sprague, J E; Odio, M

    1993-07-01

    Twenty-three hours of fluid deprivation led to elevated plasma levels of corticosterone and free fatty acids, as well as increased whole brain dopamine levels, in rats. Drinking could be initiated in water-replete rats by administration of single doses of the dopamine agonist, pergolide, the dopamine beta-hydroxylase inhibitor, diethyldithiocarbamate, the alpha-adrenergic antagonist, phenoxybenzamine, or the beta-adrenergic agonist, isoproterenol. In each case, the response to these agents was reduced or ameliorated by cotreatment with the dopamine antagonist, pimozide. Taken together, the results of the stress and pharmacological studies support the concept that drinking is initiated by a dopaminergically mediated thirst drive, which in turn is regulated by a noradrenergically mediated satiety system.

  6. C1 neurons: the body's EMTs

    PubMed Central

    Stornetta, Ruth L.; Bochorishvili, Genrieta; DePuy, Seth D.; Burke, Peter G. R.; Abbott, Stephen B. G.

    2013-01-01

    The C1 neurons reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM, IVLM). They use glutamate as a fast transmitter and synthesize catecholamines plus various neuropeptides. These neurons regulate the hypothalamic pituitary axis via direct projections to the paraventricular nucleus and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The presympathetic C1 cells, located in the RVLM, are probably organized in a roughly viscerotopic manner and most of them regulate the circulation. C1 cells are variously activated by hypoglycemia, infection or inflammation, hypoxia, nociception, and hypotension and contribute to most glucoprivic responses. C1 cells also stimulate breathing and activate brain stem noradrenergic neurons including the locus coeruleus. Based on the various effects attributed to the C1 cells, their axonal projections and what is currently known of their synaptic inputs, subsets of C1 cells appear to be differentially recruited by pain, hypoxia, infection/inflammation, hemorrhage, and hypoglycemia to produce a repertoire of stereotyped autonomic, metabolic, and neuroendocrine responses that help the organism survive physical injury and its associated cohort of acute infection, hypoxia, hypotension, and blood loss. C1 cells may also contribute to glucose and cardiovascular homeostasis in the absence of such physical stresses, and C1 cell hyperactivity may contribute to the increase in sympathetic nerve activity associated with diseases such as hypertension. PMID:23697799

  7. Effects of Chronic Sleep Fragmentation on Wake-Active Neurons and the Hypercapnic Arousal Response

    PubMed Central

    Li, Yanpeng; Panossian, Lori A.; Zhang, Jing; Zhu, Yan; Zhan, Guanxia; Chou, Yu-Ting; Fenik, Polina; Bhatnagar, Seema; Piel, David A.; Beck, Sheryl G.; Veasey, Sigrid

    2014-01-01

    Study Objectives: Delayed hypercapnic arousals may occur in obstructive sleep apnea. The impaired arousal response is expected to promote more pronounced oxyhemoglobin desaturations. We hypothesized that long-term sleep fragmentation (SF) results in injury to or dysfunction of wake-active neurons that manifests, in part, as a delayed hypercapnic arousal response. Design: Adult male mice were implanted for behavioral state recordings and randomly assigned to 4 weeks of either orbital platform SF (SF4wk, 30 events/h) or control conditions (Ct4wk) prior to behavioral, histological, and locus coeruleus (LC) whole cell electrophysiological evaluations. Measurements and Results: SF was successfully achieved across the 4 week study, as evidenced by a persistently increased arousal index, P < 0.01 and shortened sleep bouts, P < 0.05, while total sleep/wake times and plasma corticosterone levels were unaffected. A multiple sleep latency test performed at the onset of the dark period showed a reduced latency to sleep in SF4wk mice (P < 0.05). The hypercapnic arousal latency was increased, Ct4wk 64 ± 5 sec vs. SF4wk 154 ± 6 sec, P < 0.001, and remained elevated after a 2 week recovery (101 ± 4 sec, P < 0.001). C-fos activation in noradrenergic, orexinergic, histaminergic, and cholinergic wake-active neurons was reduced in response to hypercapnia (P < 0.05-0.001). Catecholaminergic and orexinergic projections into the cingulate cortex were also reduced in SF4wk (P < 0.01). In addition, SF4wk resulted in impaired LC neuron excitability (P < 0.01). Conclusions: Four weeks of sleep fragmentation (SF4wk) impairs arousal responses to hypercapnia, reduces wake neuron projections and locus coeruleus neuronal excitability, supporting the concepts that some effects of sleep fragmentation may contribute to impaired arousal responses in sleep apnea, which may not reverse immediately with therapy. Citation: Li Y; Panossian LA; Zhang J; Zhu Y; Zhan G; Chou YT; Fenik P; Bhatnagar S; Piel

  8. Noradrenergic Mechanisms of Arousal’s Bidirectional Effects on Episodic Memory

    PubMed Central

    Clewett, David; Sakaki, Michiko; Nielsen, Shawn; Petzinger, Giselle; Mather, Mara

    2016-01-01

    Arousal’s selective effects on cognition go beyond the simple enhancement of emotional stimuli, sometimes enhancing and other times impairing processing of proximal neutral information. Past work shows that arousal impairs encoding of subsequent neutral stimuli regardless of their top-down priority via the engagement of β-adrenoreceptors. In contrast, retrograde amnesia induced by emotional arousal can flip to enhancement when preceding neutral items are prioritized in top-down attention. Whether β-adrenoreceptors also contribute to this retrograde memory enhancement of goal-relevant neutral stimuli is unclear. In this pharmacological study, we administered 40mg of propranolol or 40mg of placebo to healthy young adults to examine whether emotional arousal’s bidirectional effects on declarative memory relies on β-adrenoreceptor activation. Following pill intake, participants completed an emotional oddball task in which they were asked to prioritize a neutral object appearing just before an emotional or neutral oddball image within a sequence of 7 neutral objects. Under placebo, emotional oddballs impaired memory for lower priority oddball+1 objects but had no effect on memory for high priority oddball−1 objects. Propranolol blocked this anterograde amnesic effect of arousal. Emotional oddballs also enhanced selective memory trade-offs significantly more in the placebo than drug condition, such that high priority oddball−1 objects were more likely to be remembered at the cost of their corresponding lower priority oddball+1 objects under arousal. Lastly, those who recalled more high priority oddball−1 objects preceding an emotional versus neutral oddball image showed greater increases in salivary alpha-amylase, a biomarker of noradrenergic system activation, across the task. Together these findings suggest that different noradrenergic mechanisms contribute to the anterograde and retrograde mnemonic effects of arousal on proximal neutral memoranda. PMID

  9. Is the Noradrenergic Symptom Cluster a Valid Construct in Adjunctive Treatment of Major Depressive Disorder?

    PubMed

    Stauffer, Virginia L; Liu, Peng; Goldberger, Celine; Marangell, Lauren B; Nelson, Craig; Gorwood, Philip; Fava, Maurizio

    2017-03-01

    To identify symptoms potentially representative of a noradrenergic symptom cluster as possible predictors of response to the selective norepinephrine reuptake inhibitor (NRI) edivoxetine when used as monotherapy or adjunctive treatment in patients with DSM-IV-TR major depressive disorder (MDD). Pooled data from 4 adjunctive treatment trials (selective serotonin reuptake inhibitor [SSRI] + edivoxetine 6-18 mg/d vs SSRI + placebo; N = 2,066) and data from 1 monotherapy trial (edivoxetine 6-18 mg/d versus placebo; N = 495) were used to identify predictors of response related to noradrenergic symptoms using a resampling-based ensemble tree method. The trials were conducted from 2008 to 2013. In the pooled adjunctive trials, no subgroup was identified that demonstrated a greater edivoxetine-placebo treatment difference than the overall patient cohort. In the edivoxetine monotherapy trial, no subgroup showing greater mean edivoxetine-placebo differences on the Montgomery-Asberg Depression Rating Scale versus the overall patient cohort was identified; a subgroup (67%) with high b​aseline Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) total score (≥ 28) showed statistically significantly (P = .02) greater mean edivoxetine-placebo differences on the Sheehan Disability Scale versus the overall patient cohort, and subgroups with baseline CPFQ total score ≥ 28 (65%), CPFQ cognition dimension score ≥ 16 (63%), or CPFQ physical dimension score ≥ 13 (59%) showed statistically significantly (P ≤ .025) greater mean edivoxetine-placebo differences on the CPFQ total score versus the overall patient cohort. While we could not identify symptoms predictive of response to the selective NRI edivoxetine used as adjunctive treatment, impaired cognition and physical symptoms may predict greater improvement during monotherapy. ClinicalTrials.gov identifiers: NCT00840034, NCT01173601, NCT01187407, NCT01185340, NCT00795821. © Copyright 2017

  10. On the central noradrenergic mechanism underlying the social play-suppressant effect of methylphenidate in rats.

    PubMed

    Achterberg, E J Marijke; Damsteegt, Ruth; Vanderschuren, Louk J M J

    2018-03-08

    Social play behaviour is a vigorous, highly rewarding social activity abundant in the young of most mammalian species, including humans. Social play is thought to be important for social, emotional and cognitive development, yet its neural underpinnings are incompletely understood. We have previously shown that low doses of methylphenidate suppress social play behaviour through a noradrenergic mechanism of action, and that methylphenidate exerts its effect within the prefrontal cortex, amygdala and habenula. In the present study, we sought to reveal whether these regions work in parallel or in series to mediate the play-suppressant effect of methylphenidate. To that aim, we tested whether infusion of the α2-adrenoceptor antagonist RX821002 into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala or habenula prevents the effect of methylphenidate on social play behaviour, or the psychomotor stimulant effect of methylphenidate. We found that the social play-suppressant effect of methylphenidate was not prevented by infusion of the α2-adrenoceptor antagonist into either region, or by infusion of RX821002 into both the anterior cingulate and infralimbic cortex. By contrast, RX821002 infusion into the anterior cingulate modestly enhanced social play, and infusion of the antagonist into the infralimbic cortex attenuated the psychomotor stimulant effect of methylphenidate. We conclude that there is redundancy in the neural circuitry that mediates the play-suppressant effect of methylphenidate, whereby prefrontal cortical and subcortical limbic mechanisms act in parallel. Moreover, our data support the notion that prefrontal noradrenergic mechanisms contribute to the locomotor enhancing effect of psychostimulant drugs. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. CXCR4 and NMDA Receptors Are Functionally Coupled in Rat Hippocampal Noradrenergic and Glutamatergic Nerve Endings.

    PubMed

    Di Prisco, Silvia; Olivero, Guendalina; Merega, Elisa; Bonfiglio, Tommaso; Marchi, Mario; Pittaluga, Anna

    2016-12-01

    Previous studies had shown that the HIV-1 capsidic glycoprotein gp120 (strain IIIB) modulates presynaptic release-regulating NMDA receptors on noradrenergic and glutamatergic terminals. This study aims to assess whether the chemokine CXC4 receptors (CXCR4s) has a role in the gp120-mediated effects. The effect of CXCL12, the endogenous ligand at CXCR4, on the NMDA-mediated releasing activity was therefore investigated. Rat hippocampal synaptosomes were preloaded with [ 3 H]noradrenaline ([ 3 H]NA) or [ 3 H]D-aspartate ([ 3 H]D-Asp) and acutely exposed to CXCL12, to NMDA or to both agonists. CXCL12, inactive on its own, facilitated the NMDA-evoked tritium release. The NMDA antagonist MK-801 abolished the NMDA/CXCL12-evoked tritium release of both radiolabelled tracers, while the CXCR4 antagonist AMD 3100 halved it, suggesting that rat hippocampal nerve endings possess presynaptic release-regulating CXCR4 receptors colocalized with NMDA receptors. Accordingly, Western blot analysis confirmed the presence of CXCR4 proteins in synaptosomal plasmamembranes. In both synaptosomal preparations, CXCL12-induced facilitation of NMDA-mediated release was dependent upon PLC-mediated src-induced events leading to mobilization of Ca 2+ from intraterminal IP 3 -sensitive stores Finally, the gp120-induced facilitation of NMDA-mediated release of [ 3 H]NA and [ 3 H]D-Asp was prevented by AMD 3100. We propose that CXCR4s are functionally coupled to NMDA receptors in rat hippocampal noradrenergic and glutamatergic terminals and account for the gp120-induced modulation of the NMDA-mediated central effects. The NMDA/CXCR4 cross-talk could have a role in the neuropsychiatric symptoms often observed in HIV-1 positive patients.

  12. Atomoxetine reverses attentional deficits produced by noradrenergic deafferentation of medial prefrontal cortex.

    PubMed

    Newman, Lori A; Darling, Jenna; McGaughy, Jill

    2008-09-01

    The majority of studies assessing executive function in attention deficit disorder (ADD) have shown deficits in attentional set shifting using either the Wisconsin card sorting task or the intra-dimensional/extra-dimensional set-shifting task (ID/ED). Damage to the prefrontal cortex in humans, primates, and rodents impairs extra-dimensional (ED) shifts. Noradrenergic depletion of the medial prefrontal cortex in rats is sufficient to impair attentional set shifting. Atomoxetine, a selective norepinephrine (NE) re-uptake inhibitor, is hypothesized to produce beneficial effects in patient with ADD by augmenting NE release in prefrontal cortex. We assessed the effects of systemic administration of atomoxetine (0.0, 0.1, 0.3, and 0.9 mg/kg/ml) in normal and noradrenergically lesioned (NE-LX) rats on attentional-set shifts. We replicated findings showing NE-LX rats are selectively impaired on the ED shifts but not reversals or other discriminations. Atomoxetine remediated the attentional set-shifting impairments in NE-LX rats but impaired ED performance of non-lesioned rats. Though atomoxetine is neurochemically selective, it is not wholly specific at doses >0.3 mg/kg. All doses of the drug were similar in their efficacy in reversing the ED deficit, but the effectiveness of the 0.1 mg/kg dose supports the hypothesis that increases in prefrontal NE alone are sufficient to improve attention in NE-LX rats. Moreover, the detrimental effects of the drug in non-lesioned rats support the hypothesis that optimal levels of NE in prefrontal cortex are critical to attentional set shifting with both supra- and sub-optimal levels producing attentional impairments.

  13. Adrenoceptor-Mediated Post- and Pre-Synaptic Regulations of the Reticulospinal Neurons in Rat Caudal Pontine Reticular Nucleus.

    PubMed

    Yang, Nian; Qiao, Qi-Cheng; Liu, Yu-Hui; Zhang, Ji-Qiang; Hu, Zhi-An; Zhang, Jun

    2016-12-01

    The central noradrenergic system participates in diverse nervous functions. Nevertheless, our knowledge of the action of adrenoceptors in motor regulation is still lacking. Intriguingly, reticulospinal neurons in the caudal pontine reticular nucleus (PnC) receive fairly dense noradrenergic innervation and play an important role in motor control. Here, after demonstrating the expression of α1- and α2-adrenoceptors in the PnC, we found that noradrenaline elicited a post-synaptic effect (inward or outward whole-cell current at -70 mV holding) on PnC reticulospinal neurons. The α1- and α2-adrenoceptors were co-expressed in individual PnC reticulospinal neurons to mediate an inward and an outward current component at -70 mV holding, respectively, which, when superposed, produced the overall post-synaptic effects of noradrenaline (NA). More importantly, the activation of post-synaptic α1- or α2-adrenoceptors indeed exerted opposing modulations (excitation vs. inhibition) on the firing activities of individual PnC reticulospinal neurons. Furthermore, the activation and inhibition of the Na + -permeable non-selective cationic conductance (NSCC) were demonstrated to be coupled to α1- and α2-adrenoceptors, respectively. Additionally, the activation of α2-adrenoceptors activated K + conductance. Pre-synaptically, the α2-adrenoceptors were expressed to attenuate the miniature excitatory postsynaptic current (mEPSC) in PnC reticulospinal neurons, but not to affect the miniature inhibitory postsynaptic current (mIPSC). Consistently, the evoked EPSC in PnC reticulospinal neurons was suppressed after the activation of pre-synaptic α2-adrenoceptors. Thus, the excitatory input and post-synaptic dynamics of PnC reticulospinal neurons are indeed intricately modulated by the activation of α1- and α2-adrenoceptors, through which motor control may be regulated in an adaptive manner by the central noradrenergic system.

  14. Origin and characterization of retrograde labeled neurons supplying the rat urethra using fiberoptic confocal fluorescent microscopy in vivo and immunohistochemistry.

    PubMed

    Lee, Keon-Cheol; Sharma, Seema; Tuttle, Jeremy B; Steers, William D

    2010-10-01

    Autonomic innervation of urethral smooth muscle may influence urinary continence after prostatectomy. It is unclear whether the cavernous nerves carry fibers that influence continence. Using a retrograde axonal tracer combined with real-time in vivo imaging and ex vivo immunohistochemistry we determined the course and type of neurons supplying urethral smooth muscle distal to the prostate in the rat. We injected the retrograde axonal tracers cholera toxin B fragment-Alexa Fluor 488 and Fast Blue in the distal urethral smooth muscle in 10 rats each. Five days later the cavernous nerves and pelvic ganglion were imaged using fiberoptic confocal fluorescence microscopy (cholera toxin B fragment-Alexa Fluor 488) or harvested for immunohistochemistry (Fast Blue). Dual immunofluorescence of Fast Blue neurons with tyrosine hydroxylase or neuronal nitric oxide synthase was done to characterize neurons as noradrenergic or nitrergic. To ascertain whether the cavernous nerves contain fibers to the urethra that originate in the pelvic ganglia we cut the cavernous nerves with their ancillary branches in 3 rats and imaged them for Fast Blue. Fluorescent neurons and axons were detected in cavernous nerves and the pelvic ganglion. Few neurons were seen in rats with cavernous nerve section. Of urethral neurons 53.1% showed neuronal nitric oxide synthase positivity while 40.6% were immunoreactive for tyrosine hydroxylase. About 6.2% of urethral neurons failed to show tyrosine hydroxylase or neuronal nitric oxide synthase immunoreactivity. Most of the autonomic innervation to the urethra beyond the prostatic apex travels in the cavernous nerves. Many nerves may be parasympathetic based on neuronal nitric oxide synthase immunoreactivity. Nerves supplying the urethra outside the cavernous nerves may course posterior to the prostate. Along with afferent fibers, tyrosine hydroxylase immunoreactivity expressing neuron fibers, ie noradrenergic nerves, traveling in the cavernous nerves may

  15. A noradrenergic lesion aggravates the effects of systemic inflammation on the hippocampus of aged rats.

    PubMed

    Bharani, Krishna L; Derex, Rebecca; Granholm, Ann-Charlotte; Ledreux, Aurélie

    2017-01-01

    Neuroinflammation is potentiated by early degeneration of the locus coeruleus noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In animal models, lipopolysaccharide (LPS) induces strong peripheral immune responses that can cause cognitive changes secondary to neuroinflammation. The influence of the peripheral immune response on cognition might be exacerbated by LC-NE degeneration, but this has not been well characterized previously. In this study, we investigated how systemic inflammation affects neuroinflammation and cognition in aged rats that have had either normal or damaged LC-NE transmitter systems. Rats were first exposed to the selective noradrenergic (NE) neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of central NE pathways. Two weeks later, the rats received a low dose of LPS. This resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several pro-inflammatory cytokines, increased astroglial and microglial activation in the hippocampus, and poorer performance in the novel object recognition task (NORT) compared to controls and LPS-treated rats. Additionally, serum and brain tissue levels of brain-derived neurotrophic factor (BDNF) were modulated over time in the DSP4+LPS group compared to the other two groups. Specifically, DSP4+LPS-treated rats in the short-term subgroup had lower hippocampal BDNF levels (~25%) than controls and LPS-treated rats, which negatively correlated with hippocampal astrogliosis and positively correlated with hippocampal IL-1β levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the long-term subgroup returned to levels similar to the control group. These results show that systemic inflammation in LC

  16. Activation of oxytocin neurones by systemic cholecystokinin is unchanged by morphine dependence or withdrawal excitation in the rat.

    PubMed Central

    Brown, C H; Munro, G; Murphy, N P; Leng, G; Russell, J A

    1996-01-01

    1. Morphine inhibits supraoptic nucleus oxytocin neurones directly and presynaptically via inhibition of afferent noradrenergic endings. 2. We studied whether morphine tolerance/dependence (induced by intracerebroventricular (I.C.V.) morphine infusion) alters the responsiveness of oxytocin neurones to systemic cholecystokinin (CCK), a stimulus which activates oxytocin neurones via the release of noradrenaline. 3. CCK (20 micrograms kg-1, i.v.) increased plasma oxytocin concentrations similarly in urethane-anaesthetized morphine-naive and -dependent rats. In naive rats, I.C.V. (10 micrograms) and i.v. morphine (0.5 mg kg-1) reduced CCK-induced oxytocin secretion by 95 +/- 4 and 49 +/- 10%, respectively. In dependent rats, i.v. morphine reduced CCK-induced release by only 8 +/- 9%, indicating tolerance. 4. In urethane-anaesthetized rats, i.v. CCK increased the firing rates of oxytocin neurones similarly in morphine-naive and -dependent rats (by 1.2 +/- 0.2 and 1.4 +/- 0.3 spikes s-1 maximum, respectively, over 5 min). Naloxone did not alter spontaneous or CCK-induced activity in naive rats but increased activity in dependent rats (by 3.4 +/- 0.5 spikes s-1), indicative of withdrawal excitation; however, the response to CCK remained unchanged after naloxone. 5. Systemic CCK did not trigger withdrawal, nor did it have a greater excitatory effect in dependent rats. Thus, morphine withdrawal excitation of oxytocin neurones does not involve supersensitivity to the noradrenergic input, or hypersensitivity of this input to i.v. CCK. Tolerance apparently occurs both at the cell bodies of oxytocin neurones in the supraoptic nucleus and in their noradrenergic input. However, dependence is apparent only at the cell bodies. PMID:8930844

  17. Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.

    PubMed

    Gaval-Cruz, Meriem; Goertz, Richard B; Puttick, Daniel J; Bowles, Dawn E; Meyer, Rebecca C; Hall, Randy A; Ko, Daijin; Paladini, Carlos A; Weinshenker, David

    2016-01-01

    Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts DA to NE, increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh -/-) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh -/- animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh -/- MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh -/- MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G-protein coupling in NAc MSNs. © 2014 Society for the Study of Addiction.

  18. Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens

    PubMed Central

    Gaval-Cruz, Meriem; Goertz, Richard B.; Puttick, Daniel J.; Bowles, Dawn E.; Meyer, Rebecca C.; Hall, Randy A.; Ko, Daijin; Paladini, Carlos A.; Weinshenker, David

    2014-01-01

    Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE), and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts dopamine (DA) to norepinephrine (NE), increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh −/−) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh −/− animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh −/− MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh −/− MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G protein coupling in NAc MSNs. PMID:25123018

  19. Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells

    PubMed Central

    Linster, Christiane

    2015-01-01

    Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function. PMID:26334007

  20. Exercise offers anxiolytic potential: A role for stress and brain noradrenergic-galaninergic mechanisms

    PubMed Central

    Sciolino, Natale R.; Holmes, Philip V.

    2016-01-01

    Although physical activity reduces anxiety in humans, the neural basis for this response is unclear. Rodent models are essential to understand the mechanisms that underlie the benefits of exercise. However, it is controversial whether exercise exerts anxiolytic-like potential in rodents. Evidence is reviewed to evaluate the effects of wheel running, an experimental mode of exercise in rodents, on behavior in tests of anxiety and on norepinephrine and galanin systems in neural circuits that regulate stress. Stress is proposed to account for mixed behavioral findings in this literature. Indeed, running promotes an adaptive response to stress and alters anxiety-like behaviors in a manner dependent on stress. Running amplifies galanin expression in noradrenergic locus coeruleus (LC) and suppresses stress-induced activity of the LC and norepinephrine output in LC-target regions. Thus, enhanced galanin-mediated suppression of brain norepinephrine in runners is supported by current literature as a mechanism that may contribute to the stress-protective effects of exercise. These data support the use of rodents to study the emotional and neurobiological consequences of exercise. PMID:22771334

  1. Contributions of the Nucleus Accumbens Shell in Mediating the Enhancement in Memory Following Noradrenergic Activation of Either the Amygdala or Hippocampus

    PubMed Central

    Kerfoot, Erin C.; Williams, Cedric L.

    2018-01-01

    The nucleus accumbens shell is a site of converging inputs during memory processing for emotional events. The accumbens receives input from the nucleus of the solitary tract (NTS) regarding changes in peripheral autonomic functioning following emotional arousal. The shell also receives input from the amygdala and hippocampus regarding affective and contextual attributes of new learning experiences. The successful encoding of affect or context is facilitated by activating noradrenergic systems in either the amygdala or hippocampus. Recent findings indicate that memory enhancement produced by activating NTS neurons, is attenuated by suppressing accumbens functioning after learning. This finding illustrates the significance of the shell in integrating information from the periphery to modulate memory for arousing events. However, it is not known if the accumbens shell plays an equally important role in consolidating information that is initially processed in the amygdala and hippocampus. The present study determined if the convergence of inputs from these limbic regions within the nucleus accumbens contributes to successful encoding of emotional events into memory. Male Sprague-Dawley rats received bilateral cannula implants 2 mm above the accumbens shell and a second bilateral implant 2 mm above either the amygdala or hippocampus. The subjects were trained for 6 days to drink from a water spout. On day 7, a 0.35 mA footshock was initiated as the rat approached the spout and was terminated once the rat escaped into a white compartment. Subjects were then given intra-amygdala or hippocampal infusions of PBS or a dose of norepinephrine (0.2 μg) previously shown to enhance memory. Later, all subjects were given intra-accumbens infusion of muscimol to functionally inactivate the shell. Muscimol inactivation of the accumbens shell was delayed to allow sufficient time for norepinephrine to activate intracellular cascades that lead to long-term synaptic modifications

  2. Contributions of the Nucleus Accumbens Shell in Mediating the Enhancement in Memory Following Noradrenergic Activation of Either the Amygdala or Hippocampus.

    PubMed

    Kerfoot, Erin C; Williams, Cedric L

    2018-01-01

    The nucleus accumbens shell is a site of converging inputs during memory processing for emotional events. The accumbens receives input from the nucleus of the solitary tract (NTS) regarding changes in peripheral autonomic functioning following emotional arousal. The shell also receives input from the amygdala and hippocampus regarding affective and contextual attributes of new learning experiences. The successful encoding of affect or context is facilitated by activating noradrenergic systems in either the amygdala or hippocampus. Recent findings indicate that memory enhancement produced by activating NTS neurons, is attenuated by suppressing accumbens functioning after learning. This finding illustrates the significance of the shell in integrating information from the periphery to modulate memory for arousing events. However, it is not known if the accumbens shell plays an equally important role in consolidating information that is initially processed in the amygdala and hippocampus. The present study determined if the convergence of inputs from these limbic regions within the nucleus accumbens contributes to successful encoding of emotional events into memory. Male Sprague-Dawley rats received bilateral cannula implants 2 mm above the accumbens shell and a second bilateral implant 2 mm above either the amygdala or hippocampus. The subjects were trained for 6 days to drink from a water spout. On day 7, a 0.35 mA footshock was initiated as the rat approached the spout and was terminated once the rat escaped into a white compartment. Subjects were then given intra-amygdala or hippocampal infusions of PBS or a dose of norepinephrine (0.2 μg) previously shown to enhance memory. Later, all subjects were given intra-accumbens infusion of muscimol to functionally inactivate the shell. Muscimol inactivation of the accumbens shell was delayed to allow sufficient time for norepinephrine to activate intracellular cascades that lead to long-term synaptic modifications

  3. Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

    PubMed Central

    Chai, Ning; Liu, Jian-Feng; Xue, Yan-Xue; Yang, Chang; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao; Shi, Hai-Shui; Wang, Ji-Shi; Bao, Yan-Ping; Meng, Shi-Qiu; Ding, Zeng-Bo; Wang, Xue-Yi; Lu, Lin

    2014-01-01

    Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the β-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the β-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another β-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM. PMID:24553734

  4. Effects of Propranolol, a β-noradrenergic Antagonist, on Memory Consolidation and Reconsolidation in Mice

    PubMed Central

    Villain, Hélène; Benkahoul, Aïcha; Drougard, Anne; Lafragette, Marie; Muzotte, Elodie; Pech, Stéphane; Bui, Eric; Brunet, Alain; Birmes, Philippe; Roullet, Pascal

    2016-01-01

    Memory reconsolidation impairment using the β-noradrenergic receptor blocker propranolol is a promising novel treatment avenue for patients suffering from pathogenic memories, such as post-traumatic stress disorder (PTSD). However, in order to better inform targeted treatment development, the effects of this compound on memory need to be better characterized via translational research. We examined the effects of systemic propranolol administration in mice undergoing a wide range of behavioral tests to determine more specifically which aspects of the memory consolidation and reconsolidation are impaired by propranolol. We found that propranolol (10 mg/kg) affected memory consolidation in non-aversive tasks (object recognition and object location) but not in moderately (Morris water maze (MWM) to highly (passive avoidance, conditioned taste aversion) aversive tasks. Further, propranolol impaired memory reconsolidation in the most and in the least aversive tasks, but not in the moderately aversive task, suggesting its amnesic effect was not related to task aversion. Moreover, in aquatic object recognition and location tasks in which animals were forced to behave (contrary to the classic versions of the tasks); propranolol did not impair memory reconsolidation. Taken together our results suggest that the memory impairment observed after propranolol administration may result from a modification of the emotional valence of the memory rather than a disruption of the contextual component of the memory trace. This is relevant to the use of propranolol to block memory reconsolidation in individuals with PTSD, as such a treatment would not erase the traumatic memory but only reduce the emotional valence associated with this event. PMID:27014009

  5. [Neuronal mechanisms underlying pain-induced negative emotions].

    PubMed

    Minami, Masabumi

    2012-11-01

    Pain consists of sensory-discriminative and negative emotional components. Although the neuronal basis of the sensory component of pain has been studied extensively, the neuronal mechanisms underlying the negative emotional component are not well understood. Recently, behavioral studies using a conditioned place paradigm have successfully elucidated the neuronal circuits and mechanisms underlying the negative emotional component of pain. Excitotoxic lesions of the anterior cingulate cortex (ACC), central amygdaloid nucleus, basolateral amygdaloid nucleus (BLA), or bed nucleus of the stria terminalis (BNST) suppress intraplantar formalin-induced aversive responses. Glutamatergic transmission within the ACC and BLA via N-methyl-D-asparate (NMDA) receptors has been shown to play a critical role in these aversive responses. In the BNST, especially its ventral part, noradrenergic transmission via β-adrenergic receptors has been shown to be important for pain-induced aversion. Because persistent pain is frequently associated with psychological and emotional dysfunctions, studies on the neuronal circuits and molecular mechanisms involved in the negative emotional component of pain may have considerable clinical importance in the treatment of chronic pain. Here, I have reviewed behavioral studies investigating the neuronal mechanisms underlying the negative emotional component of pain and have introduced our data showing the pivotal role of amygdala and BNST in pain-induced aversion.

  6. The dorsal noradrenergic bundle modulates DNA remodeling in the rat brain upon exposure to a spatial novelty.

    PubMed

    Sadile, A G; Cerbone, A; Lamberti-D'Mello, C; Amoroso, S; Annunziato, L; Menna, T; Buono, C; Rafti, F; Giuditta, A

    1995-01-01

    A series of experiments were designed to study the role of the dorsal noradrenergic bundle (DNB) in the modulation of genomic remodeling in the mammalian brain. A series of experiments were designed to study the role of the dorsal noradrenergic system in relation to nonassociative tasks. Adult male Sprague-Dawley rats were either bilaterally lesioned in the DNB by intrabundle microinjection of 6-hydroxydopamine or were sham lesioned. All rats were given 50 microCi [3H-methyl]-thymidine and were sacrificed 0.5 h later. After the injection of the tracer, rats were either left undisturbed in the home cage or were exposed to a Làt-maze for 15 min after 15 min had passed from the time of injection. During the exposure to the maze, corner crossings and rearings were monitored. The rate of DNA synthesis was determined in several brain regions by measuring the amount of tracer incorporated into the DNA over a 0.5-h duration pulse. Under baseline conditions DNB-lesioned rats showed an increase in DNA synthesis in the hippocampus, hypothalamus, and rest of the brain. On the other hand, following exposure to the Làt-maze, sham-lesioned rats only showed an increase in DNA synthesis in the hippocampus, as compared to baseline conditions. Conversely, DNB-lesioned rats did not show an increase in hippocampal DNA synthesis as in the sham-lesioned rats. In contrast, DNA synthesis was increased in the neocortex and rest of the brain. In conclusion, the data support a role for noradrenergic systems in modulating brain DNA synthesis, probably of the unscheduled type, during information processing and storage.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Supraspinal Projection of Serotonergic and Noradrenergic Pathways Modulates Nociceptive Transmission in the Lower Urinary Tract of Rats.

    PubMed

    Mitsui, Takahiko; Kanno, Yukiko; Kitta, Takeya; Moriya, Kimihiko; Nonomura, Katsuya

    2016-09-01

    To investigate the effect of descending serotonergic and noradrenergic pathways on nociception in the lower urinary tract (LUT). Female Sprague-Dawley rats were used. Following intraperitoneal administration of Vehicle or Milnacipran (30 mg/kg), which is one of serotonin-noradrenaline reuptake inhibitors (SNRI), 0.1% AA was infused into the bladder in normal (n = 4, each) and spinal cord injury (SCI) (n = 4, each) rats for 2 h on consciousness, and c-Fos, 5-HT and DβH were stained using immunohistochemistry at the L6 spinal cord as spinal areas associated with LUT. In SCI rats, 5-HT or DβH-positive fibers were not observed at the L6 spinal cord, while there were many 5-HT and DβH-positive fibers in normal rats. The total number of c-Fos-positive cells was significantly increased in SCI rats compared to Normal rats (209.4 ± 7.1 in Normal, 336.4 ± 28.9 in SCI, P < 0.05), which indicated that interruption of supraspinal modulation enhances nocieptive transmission in the LUT. Regarding the effect of Milnacipran administration, the number of c-Fos-positive cells was significantly decreased at all region of the L6 spinal cord in normal rats (P < 0.05), while this reduction was not observed in SCI rats. This result demonstrated that administration of SNRI attenuates nocieptive transmission in the LUT, indicating that 5-HT and noradrenaline work as mediators of endogenous analgesic mechanisms through the supraspinal descending pain pathways. Supraspinal projections of descending serotonergic and noradrenergic pathways to the lower lumbar spinal cord modulate nocieptive transmission in the LUT. Administration of SNRI attenuates nocieptive transmission in the LUT, which could result from enhancement of modulating descending serotonergic and noradrenergic pathways. © 2015 Wiley Publishing Asia Pty Ltd.

  8. Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating.

    PubMed

    Tew, Garry A; Saxton, John M; Klonizakis, Markos; Moss, James; Ruddock, Alan D; Hodges, Gary J

    2011-05-01

    Sedentary aging results in a diminished rapid cutaneous vasodilator response to local heating. We investigated whether this diminished response was due to altered contributions of noradrenergic sympathetic nerves by assessing 1) the age-related decline and 2) the effect of aerobic fitness. Using laser-Doppler flowmetry, we measured skin blood flow (SkBF) in young (24 ± 1 yr) and older (64 ± 1 yr) endurance-trained and sedentary men (n = 7 per group) at baseline and during 35 min of local skin heating to 42°C at 1) untreated forearm sites, 2) forearm sites treated with bretylium tosylate (BT), which prevents neurotransmitter release from noradrenergic sympathetic nerves, and 3) forearm sites treated with yohimbine + propranolol (YP), which antagonizes α- and β-adrenergic receptors. SkBF was converted to cutaneous vascular conductance (CVC = SkBF/mean arterial pressure) and normalized to maximal CVC (%CVC(max)) achieved by skin heating to 44°C. Pharmacological agents were administered using microdialysis. In the young trained group, the rapid vasodilator response was reduced at BT and YP sites (P < 0.05); by contrast, in the young sedentary and older trained groups, YP had no effect (P > 0.05), but BT did (P > 0.05). Neither BT nor YP affected the rapid vasodilator response in the older sedentary group (P > 0.05). These data suggest that the age-related reduction in the rapid vasodilator response is due to an impairment of sympathetic-dependent mechanisms, which can be partly attenuated with habitual aerobic exercise. Rapid vasodilation involves noradrenergic neurotransmitters in young trained men and nonadrenergic sympathetic cotransmitters (e.g., neuropeptide Y) in young sedentary and older trained men, possibly as a compensatory mechanism. Finally, in older sedentary men, the rapid vasodilation appears not to involve the sympathetic system.

  9. Opiate-Induced Molecular and Cellular Plasticity of Ventral Tegmental Area and Locus Coeruleus Catecholamine Neurons

    PubMed Central

    Mazei-Robison, Michelle S.; Nestler, Eric J.

    2012-01-01

    The study of neuronal adaptations induced by opiate drugs is particularly relevant today given their widespread prescription and nonprescription use. Although much is known about the acute actions of such drugs on the nervous system, a great deal of work remains to fully understand their chronic effects. Here, we focus on longer-lasting adaptations that occur in two catecholaminergic brain regions that mediate distinct behavioral actions of opiates: ventral tegmental area (VTA) dopaminergic neurons, important for drug reward, and locus coeruleus (LC) noradrenergic neurons, important for physical dependence and withdrawal. We focus on changes in cellular, synaptic, and structural plasticity in these brain regions that contribute to opiate dependence and addiction. Understanding the molecular determinants of this opiate–induced plasticity will be critical for the development of better treatments for opiate addiction and perhaps safer opiate drugs for medicinal use. PMID:22762025

  10. Bilateral thoracoscopic splanchnicectomy for pain in patients with chronic pancreatitis impairs adrenomedullary but not noradrenergic sympathetic function.

    PubMed

    Buscher, H C J L; Lenders, J W M; Wilder-Smith, O H G; Sweep, C G J; van Goor, H

    2012-08-01

    Bilateral thoracoscopic splanchnicectomy (BTS) is a well-known technique to alleviate intractable pain in patients with chronic pancreatitis. BTS not only disrupts afferent fibers from the pancreas that mediate pain but also postganglionic sympathetic fibers, which originate in segments T5-T12 and which innervate the vasculature of the liver, pancreas, and the adrenal gland. The purpose of this study was to assess whether and how BTS affects sympathetic noradrenergic and adrenomedullary function in patients with chronic pancreatitis. Sixteen patients with chronic pancreatitis for at least 1 year underwent autonomic function testing before and 6 weeks after BTS for intractable pain. Testing was performed during supine rest and during sympathetic stimulation when standing. Supine and standing systolic and diastolic blood pressure were significantly lower post-BTS compared with pre-BTS (P = 0.001). One patient showed orthostatic hypotension after BTS. Baseline plasma norepinephrine levels and plasma norepinephrine responses to sympathetic activation during standing were not reduced by BTS. In contrast, supine plasma epinephrine levels and responses during standing were significantly reduced (P < 0.001). Parasympathetic activity was unaffected by BTS as shown by unaltered Valsalva ratio, I-E difference, and ΔHRmax. BTS for pain relief in patients with chronic pancreatitis reduced adrenomedullary function, due to disruption of the efferent sympathetic fibers to the adrenal gland. BTS did not affect noradrenergic sympathetic activity, although blood pressure was lower after the sympathectomy.

  11. [Mirror neurons].

    PubMed

    Rubia Vila, Francisco José

    2011-01-01

    Mirror neurons were recently discovered in frontal brain areas of the monkey. They are activated when the animal makes a specific movement, but also when the animal observes the same movement in another animal. Some of them also respond to the emotional expression of other animals of the same species. These mirror neurons have also been found in humans. They respond to or "reflect" actions of other individuals in the brain and are thought to represent the basis for imitation and empathy and hence the neurobiological substrate for "theory of mind", the potential origin of language and the so-called moral instinct.

  12. Addictive neurons

    PubMed Central

    Kodirov, Sodikdjon A.

    2017-01-01

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

  13. Chronic Alterations in Monoaminergic Cells in the Locus Coeruleus in Orexin Neuron-Ablated Narcoleptic Mice

    PubMed Central

    Tsujino, Natsuko; Tsunematsu, Tomomi; Uchigashima, Motokazu; Konno, Kohtarou; Yamanaka, Akihiro; Kobayashi, Kazuto; Watanabe, Masahiko; Koyama, Yoshimasa; Sakurai, Takeshi

    2013-01-01

    Narcolepsy patients often suffer from insomnia in addition to excessive daytime sleepiness. Narcoleptic animals also show behavioral instability characterized by frequent transitions between all vigilance states, exhibiting very short bouts of NREM sleep as well as wakefulness. The instability of wakefulness states in narcolepsy is thought to be due to deficiency of orexins, neuropeptides produced in the lateral hypothalamic neurons, which play a highly important role in maintaining wakefulness. However, the mechanism responsible for sleep instability in this disorder remains to be elucidated. Because firing of orexin neurons ceases during sleep in healthy animals, deficiency of orexins does not explain the abnormality of sleep. We hypothesized that chronic compensatory changes in the neurophysiologica activity of the locus coeruleus (LC) and dorsal raphe (DR) nucleus in response to the progressive loss of endogenous orexin tone underlie the pathological regulation of sleep/wake states. To evaluate this hypothesis, we examined firing patterns of serotonergic (5-HT) neurons and noradrenergic (NA) neurons in the brain stem, two important neuronal populations in the regulation of sleep/wakefulness states. We recorded single-unit activities of 5-HT neurons and NA neurons in the DR nucleus and LC of orexin neuron-ablated narcoleptic mice. We found that while the firing pattern of 5-HT neurons in narcoleptic mice was similar to that in wildtype mice, that of NA neurons was significantly different from that in wildtype mice. In narcoleptic mice, NA neurons showed a higher firing frequency during both wakefulness and NREM sleep as compared with wildtype mice. In vitro patch-clamp study of NA neurons of narcoleptic mice suggested a functional decrease of GABAergic input to these neurons. These alterations might play roles in the sleep abnormality in narcolepsy. PMID:23922890

  14. Calcium-activated SK potassium channels are key modulators of the pacemaker frequency in locus coeruleus neurons.

    PubMed

    Matschke, Lina A; Rinné, Susanne; Snutch, Terrance P; Oertel, Wolfgang H; Dolga, Amalia M; Decher, Niels

    2018-04-01

    The physiological, intrinsic activity of noradrenergic locus coeruleus (LC) neurons is important for the control of sleep/wakefulness, cognition and autonomous body functions. Dysregulations of the LC-noradrenergic network contribute to the pathogenesis of psychiatric disorders and are key findings in early stages of neurodegenerative diseases. Therefore, identifying ion channels mediating the intrinsic pacemaking mechanism of LC neurons, which is in turn directly coupled to Ca 2+ homeostasis and cell survival signaling pathways, can help to foster our understanding of the vulnerability of these neurons in neurodegenerative diseases. Small-conductance Ca 2+ -activated K + (SK) channels regulate the intrinsic firing patterns in different central neurons and are essential regulators of the intracellular Ca 2+ homeostasis. However, the role of SK channels for the intrinsic pacemaking of LC neurons in mice is still unclear. Therefore we performed qPCR expression analysis as well as patch clamp recordings of in vitro brainstem slices, for instance testing SK channel blockers and activators like apamin and NS309, respectively. Although we found a transcriptional expression of SK1, SK2 and SK3 channels, SK2 was the predominantly expressed subunit in mouse LC neurons. Using perforated-patch clamp experiments, we found that SK channels are essential regulators of the intrinsic pacemaking of LC neurons, mediating a large fraction of the afterhyperpolarization (AHP) in these cells. Consistent with a previous observation that a concerted action of L- and T-type Cav channels is essential for the pacemaking of LC neurons, we found that SK channel activation, and the respective AHP amplitude, is primarily coupled to Ca 2+ influx via these types of Ca 2+ channels. Our study identified SK2 channels as drug targets for the tuning of the pacemaker frequency in disorders involving a dysregulation of the LC. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Transcriptional profiling of striatal neurons in response to single or concurrent activation of dopamine D2, adenosine A(2A) and metabotropic glutamate type 5 receptors: focus on beta-synuclein expression.

    PubMed

    Canela, Laia; Selga, Elisabet; García-Martínez, Juan Manuel; Amaral, Olavo B; Fernández-Dueñas, Víctor; Alberch, Jordi; Canela, Enric I; Franco, Rafael; Noé, Véronique; Lluís, Carme; Ciudad, Carlos J; Ciruela, Francisco

    2012-10-25

    G protein-coupled receptor oligomerization is a concept which is changing the understanding of classical pharmacology. Both, oligomerization and functional interaction between adenosine A(2A,) dopamine D(2) and metabotropic glutamate type 5 receptors have been demonstrated in the striatum. However, the transcriptional consequences of receptors co-activation are still unexplored. We aim here to determine the changes in gene expression of striatal primary cultured neurons upon isolated or simultaneous receptor activation. Interestingly, we found that 95 genes of the total analyzed (15,866 transcripts and variants) changed their expression in response to simultaneous stimulation of all three receptors. Among these genes, we focused on the β-synuclein (β-Syn) gene (SCNB). Quantitative PCR verified the magnitude and direction of change in expression of SCNB. Since β-Syn belongs to the homologous synuclein family and may be considered a natural regulator of α-synuclein (α-Syn), it has been proposed that β-Syn might act protectively against α-Syn neuropathology. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. CHOLINERGIC AND NORADRENERGIC MODULATION OF LONG-TERM EXPLICIT MEMORY ARE ALTERED BY CHRONIC LOW-LEVEL LEAD EXPOSURE. (U915393)

    EPA Science Inventory

    Recent evidence suggests that septohippocampal cholinergic activity is suppressed in rats exposed to low levels of lead (Pb). As a result, noradrenergic activity may be elevated due to compensatory sympathetic sprouting. Therefore, the goals of this study were to (a) determine...

  17. Development of F-18 Labeled Radiotracers for PET Imaging of Brain Alpha-1 Noradrenergic Receptors: Potential PTSD Vulnerability and Diagnostic Biomarkers

    DTIC Science & Technology

    2012-09-01

    exaggeration of acoustic startle response in rats. Pharmacol Biochem Behav 2007;86:559-565. 7. O’Donnell T, Hegadoren KM, Coupland NC. Noradrenergic...Naunyn Schmiedebergs Arch Pharmacol 1981;317:273-275. 14. Daly CM, Doyle ME, Radkind M, Raskind E, Daniels C. Clinical case series: the use of

  18. Ageing is a process where the growth effect of neuronal noradrenaline changes progressively in favour of the flow mediated, neurodegenerative and inflammatory effect of plasma noradrenaline.

    PubMed

    Crotty, T P

    2016-08-01

    The noradrenaline stimulus has two components, one excitor, the other inhibitory. Neuronal noradrenaline is the excitor component and plasma noradrenaline is the inhibitory. The balance of effect between the two, the noradrenergic balance, is the controlled variable of the sympathetic system and determines the effect of noradrenaline. Neuronal noradrenaline stimulates tissues by diffusion from their sympathetic nerve endings, plasma noradrenaline does so by diffusion from their microcirculations. Changes in microcirculatory flow, by altering the flow mediated effect of plasma noradrenaline, are mainly responsible for altering the noradrenergic balance in the peripheral tissues; changes in CSF flow are speculated to be mainly responsible for doing the same in the brain, by altering the balance between synaptic noradrenaline in the brain and nonsynaptic noradrenaline in the subarachnoid CSF. When plasma noradrenaline alters the noradrenergic balance it triggers afferent sympathetic activity that alerts hypothalamic neurons to the event and they restore the balance and tissue homeostasis, within milliseconds, by adjusting the level of efferent sympathetic activity they project back to the affected tissue. Because the restoration is so rapid the effect of plasma noradrenaline is normally unobservable and dismissed as not having occurred. Because the hypothalamus is not involved with the responses of isolated canine lateral saphenous vein segments to noradrenaline, the effects of plasma noradrenaline in that preparation are not countered by reactive efferent activity and, consequently, are readily apparent in it. Quantitatively, they have been found to be a function of microcirculatory flow and noradrenaline concentration and, qualitatively, to be inhibitory, dilator, pro inflammatory and neurodegenerative. In life, due to a progressive increase in plasma noradrenaline concentration and, more so, in microcirculatory flow, the noradrenergic balance moves progressively in

  19. Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: possible role of disrupted noradrenergic signaling

    PubMed Central

    Skelly, M. J.; Chappell, A. E.; Carter, E.; Weiner, J. L.

    2015-01-01

    Alcohol use disorder, anxiety disorders, and post-traumatic stress disorder (PTSD) are highly comorbid, and exposure to chronic stress during adolescence may increase the incidence of these conditions in adulthood. Efforts to identify the common stress-related mechanisms driving these disorders have been hampered, in part, by a lack of reliable preclinical models that replicate their comorbid symptomatology. Prior work by us, and others, has shown that adolescent social isolation increases anxiety-like behaviors and voluntary ethanol consumption in adult male Long-Evans rats. Here we examined whether social isolation also produces deficiencies in extinction of conditioned fear, a hallmark symptom of PTSD. Additionally, as disrupted noradrenergic signaling may contribute to alcoholism, we examined the effect of anxiolytic medications that target noradrenergic signaling on ethanol intake following adolescent social isolation. Our results confirm and extend previous findings that adolescent social isolation increases anxiety-like behavior and enhances ethanol intake and preference in adulthood. Additionally, social isolation is associated with a significant deficit in the extinction of conditioned fear and a marked increase in the ability of noradrenergic therapeutics to decrease ethanol intake. These results suggest that adolescent social isolation not only leads to persistent increases in anxiety-like behaviors and ethanol consumption, but also disrupts fear extinction, and as such may be a useful preclinical model of stress-related psychopathology. Our data also suggest that disrupted noradrenergic signaling may contribute to escalated ethanol drinking following social isolation, thus further highlighting the potential utility of noradrenergic therapeutics in treating the deleterious behavioral sequelae associated with early life stress. PMID:26044636

  20. Evidence that BDNF regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability

    PubMed Central

    Wan, Ruiqian; Weigand, Letitia A.; Bateman, Ryan; Griffioen, Kathleen; Mendelowitz, David; Mattson, Mark P.

    2014-01-01

    Autonomic control of heart rate is mediated by cardioinhibitory parasympathetic cholinergic neurons located in the brainstem and stimulatory sympathetic noradrenergic neurons. During embryonic development the survival and cholinergic phenotype of brainstem autonomic neurons is promoted by brain-derived neurotrophic factor (BDNF). We now provide evidence that BDNF regulates heart rate by a mechanism involving increased brainstem cardioinhibitory parasympathetic activity. Mice with a BDNF haploinsufficiency exhibit elevated resting heart rate, and infusion of BDNF intracerebroventricularly reduces heart rate in both wild-type and BDNF+/− mice. The atropine-induced elevation of heart rate is diminished in BDNF+/− mice and is restored by BDNF infusion, whereas the atenolol-induced decrease in heart rate is unaffected by BDNF levels, suggesting that BDNF signaling enhances parasympathetic tone which is diminished with BDNF haploinsufficiency. Whole-cell recordings from pre-motor cholinergic cardioinhibitory vagal neurons in the nucleus ambiguus indicate that BDNF haploinsufficiency reduces cardioinhibitory vagal neuron activity by increased inhibitory GABAergic and diminished excitatory glutamatergic neurotransmission to these neurons. Our findings reveal a previously unknown role for BDNF in the control of heart rate by a mechanism involving increased activation of brainstem cholinergic parasympathetic neurons. PMID:24475741

  1. Serotonergic, noradrenergic and dopaminergic markers are related to cognitive function in adults with 22q11 deletion syndrome.

    PubMed

    Evers, Laurens J M; Curfs, Leopold M G; Bakker, Jaap A; Boot, Erik; da Silva Alves, Fabiana; Abeling, Nico; Bierau, Jörgen; Drukker, Marjan; van Amelsvoort, Therese A M J

    2014-08-01

    Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of psychiatric disorders and intellectual disability. At present the neurobiology underlying psychopathology in 22q11DS is still not understood. In the present study, we analyzed urinary serotonergic, dopaminergic and noradrenergic markers in 67 adults with 22q11DS. Levels of serotonin and the catecholamine metabolite homovanillic acid were significantly lower in the 22q11DS subjects compared to healthy controls. Within the 22q11DS group, levels of dopamine, homovanillic acid, norepinephrine, vanillyl mandelic acid and serotonin positively correlated with Full Scale Intelligence Quotient scores. Our results suggest that cognitive deficits in 22q11DS are associated with abnormal function of several neurotransmitters.

  2. Noradrenergic modulation of masseter muscle activity during natural rapid eye movement sleep requires glutamatergic signalling at the trigeminal motor nucleus

    PubMed Central

    Schwarz, Peter B; Mir, Saba; Peever, John H

    2014-01-01

    Noradrenergic neurotransmission in the brainstem is closely coupled to changes in muscle activity across the sleep–wake cycle, and noradrenaline is considered to be a key excitatory neuromodulator that reinforces the arousal-related stimulus on motoneurons to drive movement. However, it is unknown if α-1 noradrenoceptor activation increases motoneuron responsiveness to excitatory glutamate (AMPA) receptor-mediated inputs during natural behaviour. We studied the effects of noradrenaline on AMPA receptor-mediated motor activity at the motoneuron level in freely behaving rats, particularly during rapid eye movement (REM) sleep, a period during which both AMPA receptor-triggered muscle twitches and periods of muscle quiescence in which AMPA drive is silent are exhibited. Male rats were subjected to electromyography and electroencephalography recording to monitor sleep and waking behaviour. The implantation of a cannula into the trigeminal motor nucleus of the brainstem allowed us to perfuse noradrenergic and glutamatergic drugs by reverse microdialysis, and thus to use masseter muscle activity as an index of motoneuronal output. We found that endogenous excitation of both α-1 noradrenoceptor and AMPA receptors during waking are coupled to motor activity; however, REM sleep exhibits an absence of endogenous α-1 noradrenoceptor activity. Importantly, exogenous α-1 noradrenoceptor stimulation cannot reverse the muscle twitch suppression induced by AMPA receptor blockade and nor can it elevate muscle activity during quiet REM, a phase when endogenous AMPA receptor activity is subthreshold. We conclude that the presence of an endogenous glutamatergic drive is necessary for noradrenaline to trigger muscle activity at the level of the motoneuron in an animal behaving naturally. PMID:24860176

  3. Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease.

    PubMed

    Vermeiren, Yannick; Janssens, Jana; Aerts, Tony; Martin, Jean-Jacques; Sieben, Anne; Van Dam, Debby; De Deyn, Peter P

    2016-06-15

    Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer's disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) 6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α1/2/β1-blockers, seem to have a rationale and should be considered.

  4. Neurons other than motor neurons in motor neuron disease.

    PubMed

    Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

  5. Neuronal activity in primate dorsal anterior cingulate cortex signals task conflict and predicts adjustments in pupil-linked arousal.

    PubMed

    Ebitz, R Becket; Platt, Michael L

    2015-02-04

    Whether driving a car, shopping for food, or paying attention in a classroom of boisterous teenagers, it's often hard to maintain focus on goals in the face of distraction. Brain imaging studies in humans implicate the dorsal anterior cingulate cortex (dACC) in regulating the conflict between goals and distractors. Here we show that single dACC neurons signal conflict between task goals and distractors in the rhesus macaque, particularly for biologically relevant social stimuli. For some neurons, task conflict signals predicted subsequent changes in pupil size-a peripheral index of arousal linked to noradrenergic tone-associated with reduced distractor interference. dACC neurons also responded to errors, and these signals predicted adjustments in pupil size. These findings provide the first neurophysiological endorsement of the hypothesis that dACC regulates conflict, in part, via modulation of pupil-linked processes such as arousal. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Alpha2 antagonist yohimbine suppresses maintained firing of rat prefrontal neurons in vivo.

    PubMed

    Kovács, Péter; Hernádi, István

    2003-05-06

    As a general alpha2 adrenergic antagonist, yohimbine has been widely used for research needs and in the therapy of malfunction of the noradrenergic system. In this study we analysed the effects of iontophoretically applied yohimbine on 79 prefrontal cortical (PFC) neurons of the rat in vivo. Our results indicate the inhibitory effect of norepinephrine on PFC neurons, which was simulated by yohimbine. The effect of yohimbine was not blocked by known alpha1 or postsynaptic alpha2 receptor agents. These results indicate that yohimbine exerts its antagonising and hyperpolarising effect on presynaptic rather than postsynaptic alpha2 receptors. Since these receptors have a permissive role in maintaining neural activity, their malfunction may contribute to the behavioural deficits observed in prefrontal disorders.

  7. Immediate post-defeat infusions of the noradrenergic receptor antagonist propranolol impair the consolidation of conditioned defeat in male Syrian hamsters.

    PubMed

    Gray, Cloe Luckett; Krebs-Kraft, Desiree L; Solomon, Matia B; Norvelle, Alisa; Parent, Marise B; Huhman, Kim L

    2015-12-01

    Social defeat occurs when an animal is attacked and subjugated by an aggressive conspecific. Following social defeat, male Syrian hamsters fail to display species-typical territorial aggression and instead exhibit submissive or defensive behaviors even when in the presence of a non-aggressive intruder. We have termed this phenomenon conditioned defeat (CD). The mechanisms underlying CD are not fully understood, but data from our lab suggest that at least some of the mechanisms are similar to those that mediate classical fear conditioning. The goal of the present experiment was to test the hypothesis that noradrenergic signaling promotes the consolidation of CD, as in classical fear conditioning, by determining whether CD is disrupted by post-training blockade of noradrenergic activity. In Experiment 1, we determined whether systemic infusions of the noradrenergic receptor antagonist propranolol (0, 1.0, 10, or 20mg/kg) given immediately after a 15 min defeat by a resident aggressor would impair CD tested 48 h later. Hamsters that were given immediate post-training infusions of propranolol (1.0, but not 10 or 20mg/kg) showed significantly less submissive behavior than did those given vehicle infusions supporting the hypothesis that there is noradrenergic modulation of the consolidation of a social defeat experience. In Experiment 2, we demonstrated that propranolol (1.0mg/kg) given immediately, but not 4 or 24h, after defeat impaired CD tested 48 h after defeat indicating that the window within which the memory for social defeat is susceptible to beta-adrenergic modulation is temporary. In Experiment 3, we examined whether central blockade of noradrenergic receptors could recapitulate the effect of systemic injections by giving an intracerebroventricular infusion of propranolol immediately after defeat and examining the effect on CD 24h later. Centrally administered propranolol (20 μg/3 μl but not 2 μg/3 μl) was also effective in dose-dependently reducing

  8. Role of the NR2A/2B subunits of the N-methyl-D-aspartate receptor in glutamate-induced glutamic acid decarboxylase alteration in cortical GABAergic neurons in vitro.

    PubMed

    Monnerie, H; Hsu, F-C; Coulter, D A; Le Roux, P D

    2010-12-29

    The vulnerability of brain neuronal cell subpopulations to neurologic insults varies greatly. Among cells that survive a pathological insult, for example ischemia or brain trauma, some may undergo morphological and/or biochemical changes that may compromise brain function. The present study is a follow-up of our previous studies that investigated the effect of glutamate-induced excitotoxicity on the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67)'s expression in surviving DIV 11 cortical GABAergic neurons in vitro [Monnerie and Le Roux, (2007) Exp Neurol 205:367-382, (2008) Exp Neurol 213:145-153]. An N-methyl-D-aspartate receptor (NMDAR)-mediated decrease in GAD expression was found following glutamate exposure. Here we examined which NMDAR subtype(s) mediated the glutamate-induced change in GAD protein levels. Western blotting techniques on cortical neuron cultures showed that glutamate's effect on GAD proteins was not altered by NR2B-containing diheteromeric (NR1/NR2B) receptor blockade. By contrast, blockade of triheteromeric (NR1/NR2A/NR2B) receptors fully protected against a decrease in GAD protein levels following glutamate exposure. When receptor location on the postsynaptic membrane was examined, extrasynaptic NMDAR stimulation was observed to be sufficient to decrease GAD protein levels similar to that observed after glutamate bath application. Blocking diheteromeric receptors prevented glutamate's effect on GAD proteins after extrasynaptic NMDAR stimulation. Finally, NR2B subunit examination with site-specific antibodies demonstrated a glutamate-induced, calpain-mediated alteration in NR2B expression. These results suggest that glutamate-induced excitotoxic NMDAR stimulation in cultured GABAergic cortical neurons depends upon subunit composition and receptor location (synaptic vs. extrasynaptic) on the neuronal membrane. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered

  9. Glutamatergic neurotransmission between the C1 neurons and the parasympathetic preganglionic neurons of the dorsal motor nucleus of the vagus

    PubMed Central

    DePuy, Seth D.; Stornetta, Ruth L.; Bochorishvili, Genrieta; Deisseroth, Karl; Witten, Ilana; Coates, Melissa; Guyenet, Patrice G.

    2013-01-01

    Summary The C1 neurons are a nodal point for blood pressure control and other autonomic responses. Here we test whether these rostral ventrolateral medullary catecholaminergic (RVLM-CA) neurons use glutamate as a transmitter in the dorsal motor nucleus of the vagus (DMV). After injecting Cre-dependent AAV2 DIO-Ef1α-channelrhodopsin2(ChR2)-mCherry (AAV2) into the RVLM of dopamine-beta-hydroxylase Cre transgenic mice (DβHCre/0), mCherry was detected exclusively in RVLM-CA neurons. Within the DMV >95% mCherry-immunoreactive (-ir) axonal varicosities were tyrosine hydroxylase-ir and the same proportion were vesicular glutamate transporter 2 (VGLUT2)-ir. VGLUT2-mCherry co-localization was virtually absent when AAV2 was injected into the RVLM of DβHCre/0;VGLUT2flox/flox mice, into the caudal VLM (A1 noradrenergic neuron-rich region) of DβHCre/0 mice or into the raphe of ePetCre/0 mice. Following injection of AAV2 into RVLM of TH-Cre rats, phenylethanolamine N-methyl transferase (PNMT) and VGLUT2 immunoreactivities were highly co-localized in DMV within EYFP-positive or EYFP-negative axonal varicosities. Ultrastructurally, mCherry terminals from RVLM-CA neurons in DβHCre/0 mice made predominantly asymmetric synapses with ChAT-ir DMV neurons. Photostimulation of ChR2-positive axons in DβHCre/0 mouse brain slices produced EPSCs in 71% of tested DMV preganglionic neurons (PGNs) but no IPSCs. Photostimulation (20 Hz) activated PGNs up to 8 spikes/sec (current clamp). EPSCs were eliminated by tetrodotoxin, reinstated by 4-aminopyridine and blocked by ionotropic glutamate receptor blockers. In conclusion, VGLUT2 is expressed by RVLM-CA (C1) neurons in rats and mice regardless of the presence of AAV2, the C1 neurons activate DMV parasympathetic preganglionic neurons monosynaptically and this connection uses glutamate as an ionotropic transmitter. PMID:23345223

  10. Effect of DSP-4 induced central noradrenergic depletion on tactile learning in rat.

    PubMed

    Rajabi, Soodeh; Shamsizadeh, Ali; Amini, Hossein; Shirazi, Mohsen; Allahtavakoli, Mohammad; Abbasnejad, Mehdi; Sheibani, Vahid

    2012-01-01

    There is general agreement that norepinephrine could modulate neuronal responses to non-monoaminergic synaptic inputs in the somatosensory cortex. In the present study, we investigated the effect of central norepinephrine depletion on tactile learning in rats. Central norepinephrine depletion was induced using 50 mg/kg of N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP-4) and verified by high performance liquid chromatography. Memory performance was assessed 1 and 5 weeks after DSP-4 treatment using novel object recognition test. We observed a learning impairment in both DSP-4 groups, as the preference index was not significantly altered when compared to chance level (50%). These findings suggest that depletion of central norepinephrine by DSP-4 leads to impairment of the tactile learning in rats, which can last at least for 35 days.

  11. Functional distribution of Ca2+-coupled P2 purinergic receptors among adrenergic and noradrenergic bovine adrenal chromaffin cells.

    PubMed

    Tomé, Angelo R; Castro, Enrique; Santos, Rosa M; Rosário, Luís M

    2007-06-14

    Adrenal chromaffin cells mediate acute responses to stress through the release of epinephrine. Chromaffin cell function is regulated by several receptors, present both in adrenergic (AD) and noradrenergic (NA) cells. Extracellular ATP exerts excitatory and inhibitory actions on chromaffin cells via ionotropic (P2X) and metabotropic (P2Y) receptors. We have taken advantage of the actions of the purinergic agonists ATP and UTP on cytosolic free Ca2+ concentration ([Ca2+]i) to determine whether P2X and P2Y receptors might be asymmetrically distributed among AD and NA chromaffin cells. The [Ca2+]i and the [Na+]i were recorded from immunolabeled bovine chromaffin cells by single-cell fluorescence imaging. Among the ATP-sensitive cells ~40% did not yield [Ca2+]i responses to ATP in the absence of extracellular Ca2+ (Ca2+o), indicating that they expressed P2X receptors and did not express Ca2+- mobilizing P2Y receptors; the remainder expressed Ca2+-mobilizing P2Y receptors. Relative to AD-cells approximately twice as many NA-cells expressed P2X receptors while not expressing Ca2+- mobilizing P2Y receptors, as indicated by the proportion of cells lacking [Ca2+]i responses and exhibiting [Na+]i responses to ATP in the absence and presence of Ca2+o, respectively. The density of P2X receptors in NA-cells appeared to be 30-50% larger, as suggested by comparing the average size of the [Na+]i and [Ca2+]i responses to ATP. Conversely, approximately twice as many AD-cells expressed Ca2+-mobilizing P2Y receptors, and they appeared to exhibit a higher (~20%) receptor density. UTP raised the [Ca2+]i in a fraction of the cells and did not raise the [Na+]i in any of the cells tested, confirming its specificity as a P2Y agonist. The cell density of UTP-sensitive P2Y receptors did not appear to vary among AD- and NA-cells. Although neither of the major purinoceptor types can be ascribed to a particular cell phenotype, P2X and Ca2+-mobilizing P2Y receptors are preferentially located to

  12. alpha(1B) adrenergic receptors in gonadotrophin-releasing hormone neurones: relation to Transport-P.

    PubMed

    Al-Damluji, S; Shen, W B; White, S; Barnard, E A

    2001-01-01

    1. Peptidergic neurones accumulate amines via an unusual uptake process, designated Transport-P. [(3)H]-prazosin binds to alpha(1) adrenoceptors on these cells and is displaceable by unlabelled prazosin in concentrations up to 10(-7) M. However, at greater concentrations of prazosin, there is a paradoxical accumulation of [(3)H]-prazosin which we have attributed to Transport-P. Uptake of prazosin via Transport-P is detectable at 10(-10) M prazosin concentration, is linear up to 10(-7) M and at greater concentrations becomes non-linear. In contrast, in noradrenergic neurones, noradrenaline uptake is linear and saturates above 10(-7) M. In noradrenergic neurones and in non-neuronal cells, there is no uptake of prazosin in concentrations up to 10(-6) M, suggesting that Transport-P is a specialised function of peptidergic neurones. 2. Using a mouse peptidergic (gonadotrophin-releasing hormone, GnRH) neuronal cell line which possesses Transport-P, we have studied the interaction of alpha(1) adrenoceptors with Transport-P. Polymerase chain reactions and DNA sequencing of the products demonstrated that only the alpha(1B) sub-type of adrenoceptors is present in GnRH cells. 3. In COS cells transfected with alpha(1b) adrenoceptor cDNA and in DDT(1) MF-2 cells which express native alpha(1B) adrenoceptors, [(3)H]-prazosin was displaced by unlabelled prazosin in a normal equilibrium process, with no prazosin paradox in concentrations up to 10(-6) M. In DDT(1) MF-2 cells, [(3)H]-prazosin was displaced likewise by a series of alpha(1) adrenergic agonists, none of which increased the binding of [(3)H]-prazosin. Hence, the prazosin paradox is not due to some function of alpha(1) adrenoceptors, such as internalization of ligand-receptor complexes. 4. In neurones which possess Transport-P, transfection with alpha(1b) adrenoceptor cDNA resulted in over-expression of alpha(1B) adrenoceptors, but the prazosin paradox was unaltered. Thus, alpha(1) adrenoceptors and Transport-P mediate

  13. α1B adrenergic receptors in gonadotrophin-releasing hormone neurones: relation to Transport-P

    PubMed Central

    Al-Damluji, S; Shen, W B; White, S; Barnard, E A

    2001-01-01

    Peptidergic neurones accumulate amines via an unusual uptake process, designated Transport-P. [3H]-prazosin binds to α1 adrenoceptors on these cells and is displaceable by unlabelled prazosin in concentrations up to 10−7 M. However, at greater concentrations of prazosin, there is a paradoxical accumulation of [3H]-prazosin which we have attributed to Transport-P. Uptake of prazosin via Transport-P is detectable at 10−10 M prazosin concentration, is linear up to 10−7 M and at greater concentrations becomes non-linear. In contrast, in noradrenergic neurones, noradrenaline uptake is linear and saturates above 10−7 M. In noradrenergic neurones and in non-neuronal cells, there is no uptake of prazosin in concentrations up to 10−6 M, suggesting that Transport-P is a specialised function of peptidergic neurones. Using a mouse peptidergic (gonadotrophin-releasing hormone, GnRH) neuronal cell line which possesses Transport-P, we have studied the interaction of α1 adrenoceptors with Transport-P. Polymerase chain reactions and DNA sequencing of the products demonstrated that only the α1B sub-type of adrenoceptors is present in GnRH cells. In COS cells transfected with α1b adrenoceptor cDNA and in DDT1 MF-2 cells which express native α1B adrenoceptors, [3H]-prazosin was displaced by unlabelled prazosin in a normal equilibrium process, with no prazosin paradox in concentrations up to 10−6 M. In DDT1 MF-2 cells, [3H]-prazosin was displaced likewise by a series of α1 adrenergic agonists, none of which increased the binding of [3H]-prazosin. Hence, the prazosin paradox is not due to some function of α1 adrenoceptors, such as internalization of ligand-receptor complexes. In neurones which possess Transport-P, transfection with α1b adrenoceptor cDNA resulted in over-expression of α1B adrenoceptors, but the prazosin paradox was unaltered. Thus, α1 adrenoceptors and Transport-P mediate distinct functions in peptidergic neurones. PMID:11156594

  14. Characterisation of axons expressing the artemin receptor in the female rat urinary bladder: a comparison with other major neuronal populations

    PubMed Central

    Forrest, Shelley L.; Osborne, Peregrine B.; Keast, Janet R.

    2014-01-01

    Artemin is a member of the glial cell line-derived neurotrophic factor (GDNF) family that has been strongly implicated in development and regeneration of autonomic nerves, and modulation of nociception. Whereas other members of this family (GDNF and neurturin) primarily target parasympathetic and non-peptidergic sensory neurons, the artemin receptor (GFRα3) is expressed by sympathetic and peptidergic sensory neurons that are also the primary sites of action of nerve growth factor, a powerful modulator of bladder nerves. Many bladder sensory neurons express GFRα3 but it is not known if they represent a specific functional subclass. Therefore, our initial aim was to map the distribution of GFRα3-immunoreactive (-IR) axons in the female rat bladder, using cryostat sections and whole wall thickness preparations. We found that GFRα3-IR axons innervated the detrusor, vasculature and urothelium, but only part of this innervation was sensory. Many noradrenergic sympathetic axons innervating the vasculature were GFRα3-IR, but the noradrenergic innervation of the detrusor was GFRα3-negative. We also identified a prominent source of non-neuronal GFRα3-IR that is likely to be glial. Further characterisation of bladder nerves revealed specific structural features of chemically distinct classes of axon terminals, and a major autonomic source of axons labelled with neurofilament-200, which is commonly used to identify myelinated sensory axons within organs. Intramural neurons were also characterised and quantified. Together, these studies reveal a diverse range of potential targets by which artemin could influence bladder function, nerve regeneration and pain, and provide a strong micro-anatomical framework for understanding bladder physiology and pathophysiology. PMID:25043933

  15. Pressor response to L-cysteine injected into the cisterna magna of conscious rats involves recruitment of hypothalamic vasopressinergic neurons.

    PubMed

    Takemoto, Yumi

    2013-03-01

    The sulfur-containing non-essential amino acid L-cysteine injected into the cisterna magna of adult conscious rats produces an increase in blood pressure. The present study examined if the pressor response to L-cysteine is stereospecific and involves recruitment of hypothalamic vasopressinergic neurons and medullary noradrenergic A1 neurons. Intracisternally injected D-cysteine produced no cardiovascular changes, while L-cysteine produced hypertension and tachycardia in freely moving rats, indicating the stereospecific hemodynamic actions of L-cysteine via the brain. The double labeling immunohistochemistry combined with c-Fos detection as a marker of neuronal activation revealed significantly higher numbers of c-Fos-positive vasopressinergic neurons both in the supraoptic and paraventricular nuclei and tyrosine hydroxylase containing medullary A1 neurons, of L-cysteine-injected rats than those injected with D-cysteine as iso-osmotic control. The results indicate that the cardiovascular responses to intracisternal injection of L-cysteine in the conscious rat are stereospecific and include recruitment of hypothalamic vasopressinergic neurons both in the supraoptic and paraventricular nuclei, as well as of medullary A1 neurons. The findings may suggest a potential function of L-cysteine as an extracellular signal such as neuromodulators in central regulation of blood pressure.

  16. Dysfunctional Inhibitory Mechanisms in Locus Coeruleus Neurons of the Wistar Kyoto Rat

    PubMed Central

    Bruzos-Cidón, C; Llamosas, N; Ugedo, L

    2015-01-01

    Background: The noradrenergic nucleus locus coeruleus (LC) has functional relevance in several psychopathologies such as stress, anxiety, and depression. In addition to glutamatergic and GABAergic synaptic inputs, the activation of somatodendritic α2-adrenoceptors is the main responsible for LC activity regulation. The Wistar Kyoto (WKY) rat exhibits depressive- and anxiety-like behaviors and hyperresponse to stressors. Thus, the goal of the present study was to investigate in vitro the sensitivity of α2-adrenoceptors, as well as the glutamatergic and GABAergic synaptic activity on LC neurons of the WKY strain. Methods: For that purpose patch-clamp whole-cell recordings were done in LC slices. Results: The α2-adrenoceptors of LC neurons from WKY rats were less sensitive to the effect induced by the agonist UK 14 304 as compared to that recorded in the Wistar (Wis) control strain. In addition, the GABAergic input to LC neurons of WKY rats was significantly modified compared to that in Wis rats, since the amplitude of spontaneous GABAergic postsynaptic currents was reduced and the half-width increased. On the contrary, no significant alterations were detected regarding glutamatergic input to LC neurons between rat strains. Conclusions: These results point out that in WKY rats the inhibitory control exerted by α2-adrenoceptors and GABAergic input onto LC neurons is dysregulated. Overall, this study supports in this animal model the hypothesis that claims an imbalance between the glutamatergic-GABAergic systems as a key factor in the pathophysiology of depression. PMID:25586927

  17. Reversal of noradrenergic depletion and lipid peroxidation in the pons after brain injury correlates with motor function recovery in rats.

    PubMed

    Bueno-Nava, Antonio; Montes, Sergio; DelaGarza-Montano, Paloma; Alfaro-Rodriguez, Alfonso; Ortiz, Ascencion; Gonzalez-Pina, Rigoberto

    2008-09-26

    Functional impairment after brain injury (BI) has been attributed to the inhibition of regions that are related to the injured site. Therefore, noradrenaline (NA) is thought to play a critical role in recovery from motor injury. However, the mechanism of this recovery process has not been completely elucidated. Moreover, the locus coeruleus (LC) projects from the pons through the rat sensorimotor cortex, and injury axotomizes LC fibers, depressing NA function. This was tested by measuring lipid peroxidation (LP) in the pons after sensorimotor cortex injury. Depression of function in the pons would be expected to alter areas receiving pontine efferents. Male Wistar rats were divided into three groups: control (n=16), injured (n=10) and recovering (n=16), and they were evaluated using a beam-walking assay between 2 and 20 days after cortical injury. We performed measures of NA and LP in both sides of the pons and cerebellum. We found a decrease of NA in the pons and the cerebellum, and a concomitant increase in the motor deficit and LP in the pons of injured animals. Recovering rats had NA and LP levels that were very similar to those observed in control rats. These observations suggest that the mechanism of remote inhibition after BI involves lipid peroxidation, and that the NA decrease found in the cerebellum of injured animals is mediated by a noradrenergic depression in the pons, or in areas receiving NA projections from the pons.

  18. Presynaptic beta-adrenoceptors in guinea pig papillary muscle: evidence for adrenaline-mediated positive feedback on noradrenergic transmission

    SciTech Connect

    Valenta, B.; Singer, E.A.

    1991-02-01

    Guinea pig papillary muscles were preincubated in the presence of 5 x 10{sup {minus} 9} mol/L unlabeled noradrenaline or adrenaline then incubated with ({sup 3}H)-noradrenaline and superfused. Electrical field stimulation with 180 pulses delivered at 1 or 3 Hz was used to induce overflow of radioactivity. Comparison of the effects of preexposure of the tissue to adrenaline or noradrenaline revealed that adrenaline incubation caused an enhancement of stimulation-evoked overflow of ({sup 3}H)noradrenaline and a reduction of the effect of exogenously added isoprenaline. Furthermore, the selective beta 2-adrenoceptor antagonist ICI 118,551 (10{sup {minus} 7} mol/L), but not the selective beta 1-adrenoceptormore » antagonist ICI 89,406 (10{sup {minus} 7} mol/L), reduced electrically evoked overflow of ({sup 3}H)noradrenaline in tissue preincubated with adrenaline but not in tissue preincubated with noradrenaline. The overflow-reducing effect of ICI 118.551 occurred at stimulation with 3 Hz but not at stimulation with 1 Hz. The present results support the hypothesis that noradrenergic transmission in guinea pig papillary muscle is facilitated via beta 2-adrenoceptors, and that adrenaline may serve as transmitter in this positive feedback mechanism after its incorporation into sympathetic nerves.« less

  19. Electrophysiological characterization of neurons in the dorsolateral pontine REM sleep induction zone of the rat: intrinsic membrane properties and responses to carbachol and orexins

    PubMed Central

    Brown§, Ritchie E.; Winston, Stuart; Basheer, Radhika; Thakkar, Mahesh M; McCarley, Robert W.

    2006-01-01

    Pharmacological, lesion and single-unit recording techniques in several animal species have identified a region of the pontine reticular formation (Subcoeruleus, SubC) just ventral to the locus coeruleus as critically involved in the generation of rapid-eye-movement (REM) sleep. However, the intrinsic membrane properties and responses of SubC neurons to neurotransmitters important in REM sleep control, such as acetylcholine and orexins/hypocretins, have not previously been examined in any animal species and thus were targeted in this study. We obtained whole-cell patch-clamp recordings from visually identified SubC neurons in rat brain slices in vitro. Two groups of large neurons (mean diameter 30 and 27μm) were tentatively identified as cholinergic (rostral SubC) and noradrenergic (caudal SubC) neurons. SubC reticular neurons (non-cholinergic, non-noradrenergic) showed a medium-sized depolarizing sag during hyperpolarizing current pulses and often had a rebound depolarization (low-threshold spike, LTS). During depolarizing current pulses they exhibited little adaptation and fired maximally at 30–90 Hz. Those SubC reticular neurons excited by carbachol (n=27) fired spontaneously at 6 Hz, often exhibited a moderately sized LTS, and varied widely in size (17–42 μm). Carbachol-inhibited SubC reticular neurons were medium-sized (15–25 μm) and constituted two groups. The larger group (n=22) was silent at rest and possessed a prominent LTS and associated 1–4 action potentials. The second, smaller group (n=8) had a delayed return to baseline at the offset of hyperpolarizing pulses. Orexins excited both carbachol excited and carbachol inhibited SubC reticular neurons. SubC reticular neurons had intrinsic membrane properties and responses to carbachol similar to those described for other reticular neurons but a larger number of carbachol inhibited neurons were found (> 50 %), the majority of which demonstrated a prominent LTS and may correspond to PGO-on neurons

  20. Dendritic arbor of locus coeruleus neurons contributes to opioid inhibition.

    PubMed

    Travagli, R A; Wessendorf, M; Williams, J T

    1996-05-01

    1. The nucleus locus coeruleus (LC) is made up of noradrenergic cells all of which are hyperpolarized by opioids. Recent work has shown that the reversal potential of the opioid-induced current is more negative than the potassium equilibrium potential. The aim of the present study was to determine whether the extent of the dendritic field could contribute to the very negative opioid reversal potential. 2. Individual LC cells were labeled in the brain slice preparation. The number of dendrites found on cells in slices sectioned in the horizontal plane was greater than cells in coronal slices. However, the dimensions of the cell body slices from each plane were not significantly different. 3. The resting conductance of neurons from slices cut in the horizontal plane was significantly larger than in cells from coronal plane. 4. The amplitude of the outward current induced by [Met5]-enkephalin (ME) was larger in cells from horizontal slices and the reversal potential was more negative than that of cells in coronal slices. 5. The results show that the plane of section influences the membrane properties and opioid actions of LC neurons in vitro and suggest that these differences correlate with the numbers of dendrites. The results suggest that in vivo, in addition to intrinsic membrane properties and synaptic inputs, the structural makeup of the nucleus is an important factor in determining the activity.

  1. Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour.

    PubMed

    Isingrini, Elsa; Perret, Lea; Rainer, Quentin; Sagueby, Sara; Moquin, Luc; Gratton, Alain; Giros, Bruno

    2016-04-01

    The monoaminergic transmitters dopamine (DA), noradrenaline (NE) and serotonin (5-HT) modulate cerebral functions via their extensive effects in the brain. Investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (VMAT2) knockout (KO) mice. While this mutation results in postnatal death, VMAT2-heterozygous (HET) mice are viable and show a complex behavioural phenotype. However, the simultaneous alteration of the 3 systems prevents investigations into their individual functions. To assess the specific role of NE, 5-HT and DA, we genetically disrupted their neurotransmission by creating conditional VMAT2-KO mice with targeted recombination. These specific recombinations were obtained by breeding VMAT2(lox/lox) mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system. Conditional VMAT2-KO mice revealed an absence of VMAT2 expression, and a specific decrease in the whole brain levels of each monoamine. Although NE- and 5-HT-depleted mice are viable into adulthood, DA depletion results in postnatal death before weaning. Interestingly, alteration of the DA transmission fully accounted for the increased amphetamine response formerly observed in the VMAT2-HET mice, whereas alteration of the 5-HT system was solely responsible for the increase in cocaine response. We used VMAT2-HET mice that displayed a mild phenotype. Because the VMAT2-KO in DA neurons is lethal, it precluded a straightforward comparison of the full KOs in the 3 systems. Given the intermingled functions of NE, 5-HT and DA in regulating cognitive and affective functions, this model will enhance understanding of their respective roles in the pathophysiology of psychiatric disorders.

  2. [3H]mazindol binding associated with neuronal dopamine and norepinephrine uptake sites.

    PubMed

    Javitch, J A; Blaustein, R O; Snyder, S H

    1984-07-01

    [3H]Mazindol labels neuronal dopamine uptake sites in corpus striatum membranes (KD = 18 nM) and neuronal norepinephrine uptake sites in cerebral cortex and submaxillary/sublingual gland membranes (KD = 4 nM). The potencies of various inhibitors of biogenic amine uptake in reducing [3H]mazindol binding in striatal membranes correlate with their potencies for inhibition of neuronal [3H]dopamine accumulation, whereas their potencies in reducing [3H]mazindol binding to cortical and salivary gland membranes correlate with their potencies for inhibition of neuronal [3H]norepinephrine accumulation. Similar to the dopamine and norepinephrine uptake systems, [3H]mazindol binding in all three tissues is dependent upon sodium (with potassium, lithium, rubidium, and Tris being ineffective substitutes) and chloride (with sulfate and phosphate being ineffective substitutes). In membranes of the cerebral cortex and salivary gland, half-maximal stimulation is observed at 50-80 mM NaCl, whereas in membranes of the corpus striatum half-maximal stimulation occurs at 240 mM NaCl. In striatal membranes NaCl increases the affinity of [3H]mazindol binding with no effect on the maximal number of sites. The enhancement of affinity is due to a selective slowing of the dissociation of the ligand from its binding site. The association of [3H]mazindol binding sites with neuronal dopamine uptake sites in the corpus striatum is further supported by the reduction of [3H]mazindol binding sites in striatal membranes following destruction of dopaminergic neurons by 6-hydroxydopamine. Similarly, the association of [3H]mazindol binding sites with neuronal norepinephrine uptake sites in cerebral cortex is supported by the reduction of [3H]mazindol binding to cortical membranes following destruction of noradrenergic neurons by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine.

  3. p38α and p38β mitogen-activated protein kinases determine cholinergic transdifferentiation of sympathetic neurons.

    PubMed

    Loy, Bernhard; Apostolova, Galina; Dorn, Roland; McGuire, Victoria A; Arthur, J Simon C; Dechant, Georg

    2011-08-24

    Although the p38 mitogen-activated protein kinases are active in many neuronal populations in the peripheral and central nervous systems, little is known about the physiological functions of p38 in postmitotic neurons. We report that p38 activity determines in vitro and in vivo the switch from noradrenergic to cholinergic neurotransmission that occurs in sympathetic neurons on exposure to the neuropoietic cytokines CNTF and LIF. This transdifferentiation serves as a model for the plastic mechanisms that enable mature neurons to change some of their central functions without passing through the cell cycle. We demonstrate that in postmitotic neurons, p38 and STAT pathways are concurrently activated by neuropoietic cytokine treatment for at least 12 h overlapping with changes in neurotransmitter marker gene expression. Inhibition of p38 blocks the upregulation of the nuclear matrix protein Satb2 and of cholinergic markers by CNTF without affecting STAT3 phosphorylation. Conversely, overexpression of p38α or β in the absence of cytokines stimulates cholinergic marker expression. The neurotransmitter switch in vitro is impaired in neurons isolated from p38β(-/-) mice. Consistent with these in vitro results, a substantial loss of cells expressing cholinergic properties is observed in vivo in the stellate ganglion of mature mice deficient in the p38β isoform.

  4. Acquisition and extinction of continuously and partially reinforced running in rats with lesions of the dorsal noradrenergic bundle.

    PubMed

    Owen, S; Boarder, M R; Gray, J A; Fillenz, M

    1982-05-01

    Local injection of 6-hydroxydopamine was used to selectively destroy the dorsal ascending noradrenergic bundle (DB) in rats. Two lesion procedures were used, differing in the extent of depletion of forebrain noradrenaline they produced (greater than 90% or 77%). In Experiments 1-3 the rats were run in a straight alley for food reward on continuous (CR) or partial (PR) reinforcement schedules. The smaller lesion reduced and the larger lesion eliminated the partial reinforcement acquisition effect (i.e. the faster start and run speeds produced by PR during training) and the partial reinforcement extinction effect (PREE, i.e. the greater resistance to extinction produced by PR training); these changes were due to altered performance only in the PR condition. Abolition of the PREE by the larger DB lesion occurred with 50 acquisition trials, but with 100 trials the lesion had no effect. In Experiment 4 rats were run in a double runway with food reward on CR in the second goal box, and on CR, PR or without reinforcement in the first. The larger lesion again eliminated the PREE in the first runway, but did not block the frustration effect in the second runway (i.e. the faster speeds observed in the PR condition after non-reward than after reward in the first goal box). These results are consistent with the hypothesis that DB lesions alter behavioural responses to signals of non-reward, but not to non-reward itself. They cannot be predicted from two other hypotheses: that the DB mediates responses to reward or that it subserves selective attention. Since septal and hippocampal, but not amygdalar, lesions have been reported to produced similar behavioural changes, it is proposed that the critical DB projection for the effects observed in these experiments is to the septo-hippocampal system.

  5. Relationships among the behavioral, noradrenergic, and pituitary–adrenal responses to interleukin-1 and the effects of indomethacin

    PubMed Central

    Wieczorek, Marek; Dunn, Adrian J.

    2007-01-01

    Peripheral administration of interleukin-1 (IL-1) is known to activate the hypothalamo–pituitary–adrenal axis (HPA axis) and brain noradrenergic systems. We studied the relationship between these responses using in vivo microdialysis to assess the release of hypothalamic norepinephrine (NE), while simultaneously sampling blood for ACTH and corticosterone, and monitoring body temperature and behavior in freely moving rats. Rats were implanted with microdialysis probes in the medial hypothalamus, with intravenous catheters, and with telethermometers in the abdomen. Each rat was injected with saline and IL-1β (1 μg ip) in random order, monitoring microdialysate NE, body temperature and plasma ACTH and corticosterone for 2–4 h after injection. Saline injections were followed by transient increases in microdialysate NE and in plasma ACTH and corticosterone. IL-1β injections resulted in prolonged elevations of microdialysate NE, as well as plasma ACTH and corticosterone, and body temperature. IL-1β also induced shivering and a prolonged depression of locomotor activity. Pretreatment with indomethacin (10 mg/kg sc) prevented the IL-1β-induced increases in body temperature and the apparent increase in hypothalamic NE release, but only attenuated the IL-1β-induced shivering and the increase in plasma ACTH. The results indicate a close temporal relationship between the release of NE and HPA axis activation. Such a relationship is also supported by the similar effects of indomethacin pretreatment on NE and ACTH. The shivering is likely involved in the increase in body temperature, but indomethacin only attenuated the shivering while it blocked the fever. However, the effects of indomethacin clearly indicate that neither the increase in body temperature nor the increase in hypothalamic NE release was essential for HPA axis activation. These results suggest that hypothalamic NE is involved in the IL-1-induced HPA axis activation, but that this is not the only

  6. Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

    PubMed

    Cubells, Joseph F; Schroeder, Jason P; Barrie, Elizabeth S; Manvich, Daniel F; Sadee, Wolfgang; Berg, Tiina; Mercer, Kristina; Stowe, Taylor A; Liles, L Cameron; Squires, Katherine E; Mezher, Andrew; Curtin, Patrick; Perdomo, Dannie L; Szot, Patricia; Weinshenker, David

    2016-01-01

    Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a "C" or a "T" at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency

  7. Changes in HPA reactivity and noradrenergic functions regulate spatial memory impairments at delayed time intervals following cerebral ischemia.

    PubMed

    Milot, Marc R; Plamondon, Hélène

    2011-04-01

    This study investigates the association of ischemia-induced spatial memory impairment to alterations of the HPA axis and noradrenergic activation post insult. Experiment 1 characterized the effects of 10 min forebrain ischemia on corticosterone (CORT) secretion following ischemia and in response to spatial memory assessment in the Barnes maze, as well as the impact of pre-ischemia treatment with the glucocorticoid inhibitor metyrapone (175 mg/kg; s.c.). The results showed that cerebral ischemia represents a significant physiological stressor that upregulated CORT secretion 1, 24 and 72 h post-ischemia but not at 7 days. In response to testing in the Barnes maze ischemic animals showed elevated CORT secretion simultaneously with spatial memory deficits. The single dose of metyrapone attenuated the ischemia-induced adrenocortical hyper-responsiveness and subsequent memory deficits despite not providing neuroprotection in the hippocampal CA1 pyramidal cells. To complement these findings, we examined whether norepinephrine which provides positive feedback to the HPA axis and is upregulated following brain ischemia could influence memory performance at delayed intervals after ischemia. Experiment 2 demonstrated that pre-testing administration of the alpha2-adrenoceptor agonist clonidine (.04 mg/kg, s.c.) attenuated ischemia-induced working memory impairments in a radial maze while opposite effects were obtained with the antagonist yohimbine (.3 mg/kg, s.c.). Post-testing administration of clonidine produced spatial reference memory impairments in ischemic rats. The findings from the current study demonstrate increased sensitization and responsiveness of systems regulating stress hormones at long intervals post ischemia. Importantly, we demonstrate that these effects contribute to post ischemic cognitive impairments which can be attenuated pharmacologically even in the presence of hippocampal degeneration at time of testing. Copyright © 2011 Elsevier Inc. All rights

  8. Enhanced noradrenergic axon regeneration into schwann cell-filled PVDF-TrFE conduits after complete spinal cord transection.

    PubMed

    Lee, Yee-Shuan; Wu, Siliang; Arinzeh, Treena Livingston; Bunge, Mary Bartlett

    2017-02-01

    Schwann cell (SC) transplantation has been utilized for spinal cord repair and demonstrated to be a promising therapeutic strategy. In this study, we investigated the feasibility of combining SC transplantation with novel conduits to bridge the completely transected adult rat spinal cord. This is the first and initial study to evaluate the potential of using a fibrous piezoelectric polyvinylidene fluoride trifluoroethylene (PVDF-TrFE) conduit with SCs for spinal cord repair. PVDF-TrFE has been shown to enhance neurite growth in vitro and peripheral nerve repair in vivo. In this study, SCs adhered and proliferated when seeded onto PVDF-TrFE scaffolds in vitro. SCs and PVDF-TrFE conduits, consisting of random or aligned fibrous inner walls, were transplanted into transected rat spinal cords for 3 weeks to examine early repair. Glial fibrillary acidic protein (GFAP) + astrocyte processes and GFP (green fluorescent protein)-SCs were interdigitated at both rostral and caudal spinal cord/SC transplant interfaces in both types of conduits, indicative of permissivity to axon growth. More noradrenergic/DβH + (dopamine-beta-hydroxylase) brainstem axons regenerated across the transplant when greater numbers of GFAP + astrocyte processes were present. Aligned conduits promoted extension of DβH + axons and GFAP + processes farther into the transplant than random conduits. Sensory CGRP + (calcitonin gene-related peptide) axons were present at the caudal interface. Blood vessels formed throughout the transplant in both conduits. This study demonstrates that PVDF-TrFE conduits harboring SCs are promising for spinal cord repair and deserve further investigation. Biotechnol. Bioeng. 2017;114: 444-456. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Intermittent Short Sleep Results in Lasting Sleep Wake Disturbances and Degeneration of Locus Coeruleus and Orexinergic Neurons

    PubMed Central

    Zhu, Yan; Fenik, Polina; Zhan, Guanxia; Somach, Rebecca; Xin, Ryan; Veasey, Sigrid

    2016-01-01

    Study Objectives: Intermittent short sleep (ISS) is pervasive among students and workers in modern societies, yet the lasting consequences of repeated short sleep on behavior and brain health are largely unexplored. Wake-activated neurons may be at increased risk of metabolic injury across sustained wakefulness. Methods: To examine the effects of ISS on wake-activated neurons and wake behavior, wild-type mice were randomized to ISS (a repeated pattern of short sleep on 3 consecutive days followed by 4 days of recovery sleep for 4 weeks) or rested control conditions. Subsets of both groups were allowed a recovery period consisting of 4-week unperturbed activity in home cages with littermates. Mice were examined for immediate and delayed (following recovery) effects of ISS on wake neuron cell metabolics, cell counts, and sleep/wake patterns. Results: ISS resulted in sustained disruption of sleep/wake activity, with increased wakefulness during the lights-on period and reduced wake bout duration and wake time during the lights-off period. Noradrenergic locus coeruleus (LC) and orexinergic neurons showed persistent alterations in morphology, and reductions in both neuronal stereological cell counts and fronto-cortical projections. Surviving wake-activated neurons evidenced persistent reductions in sirtuins 1 and 3 and increased lipofuscin. In contrast, ISS resulted in no lasting injury to the sleep-activated melanin concentrating hormone neurons. Conclusions: Collectively these findings demonstrate for the first time that ISS imparts significant lasting disturbances in sleep/wake activity, degeneration of wake-activated LC and orexinergic neurons, and lasting metabolic changes in remaining neurons most consistent with premature senescence. Citation: Zhu Y, Fenik P, Zhan G, Somach R, Xin R, Veasey S. Intermittent short sleep results in lasting sleep wake disturbances and degeneration of locus coeruleus and orexinergic neurons. SLEEP 2016;39(8):1601–1611. PMID:27306266

  10. Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

    PubMed Central

    Jett, Julianne D; Morilak, David A

    2013-01-01

    Cognitive impairments associated with dysfunction of the medial prefrontal cortex (mPFC) are prominent in stress-related psychiatric disorders. We have shown that enhancing noradrenergic tone acutely in the rat mPFC facilitated extra-dimensional (ED) set-shifting on the attentional set-shifting test (AST), whereas chronic unpredictable stress (CUS) impaired ED. In this study, we tested the hypothesis that the acute facilitatory effect of norepinephrine (NE) in mPFC becomes detrimental when activated repeatedly during CUS. Using microdialysis, we showed that the release of NE evoked in mPFC by acute stress was unchanged at the end of CUS treatment. Thus, to then determine if repeated elicitation of this NE activity in mPFC during CUS may have contributed to the ED deficit, we infused a cocktail of α1-, β1-, and β2-adrenergic receptor antagonists into the mPFC prior to each CUS session, then tested animals drug free on the AST. Antagonist treatment prevented the CUS-induced ED deficit, suggesting that NE signaling during CUS compromised mPFC function. We confirmed that this was not attributable to sensitization of adrenergic receptor function following chronic antagonist treatment, by administering an additional microinjection into the mPFC immediately prior to ED testing. Acute antagonist treatment did not reverse the beneficial effects of chronic drug treatment during CUS, nor have any effect on baseline ED performance in chronic vehicle controls. Thus, we conclude that blockade of noradrenergic receptors in mPFC protected against the detrimental cognitive effects of CUS, and that repeated elicitation of noradrenergic facilitatory activity is one mechanism by which chronic stress may promote mPFC cognitive dysfunction. PMID:23132268

  11. Endoplasmic reticulum stress in wake-active neurons progresses with aging.

    PubMed

    Naidoo, Nirinjini; Zhu, Jingxu; Zhu, Yan; Fenik, Polina; Lian, Jie; Galante, Ray; Veasey, Sigrid

    2011-08-01

    Fragmentation of wakefulness and sleep are expected outcomes of advanced aging. We hypothesize that wake neurons develop endoplasmic reticulum dyshomeostasis with aging, in parallel with impaired wakefulness. In this series of experiments, we sought to more fully characterize age-related changes in wakefulness and then, in relevant wake neuronal populations, explore functionality and endoplasmic reticulum homeostasis. We report that old mice show greater sleep/wake transitions in the active period with markedly shortened wake periods, shortened latencies to sleep, and less wake time in the subjective day in response to a novel social encounter. Consistent with sleep/wake instability and reduced social encounter wakefulness, orexinergic and noradrenergic wake neurons in aged mice show reduced c-fos response to wakefulness and endoplasmic reticulum dyshomeostasis with increased nuclear translocation of CHOP and GADD34. We have identified an age-related unfolded protein response injury to and dysfunction of wake neurons. It is anticipated that these changes contribute to sleep/wake fragmentation and cognitive impairment in aging. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

  12. Intermittent Short Sleep Results in Lasting Sleep Wake Disturbances and Degeneration of Locus Coeruleus and Orexinergic Neurons.

    PubMed

    Zhu, Yan; Fenik, Polina; Zhan, Guanxia; Somach, Rebecca; Xin, Ryan; Veasey, Sigrid

    2016-08-01

    Intermittent short sleep (ISS) is pervasive among students and workers in modern societies, yet the lasting consequences of repeated short sleep on behavior and brain health are largely unexplored. Wake-activated neurons may be at increased risk of metabolic injury across sustained wakefulness. To examine the effects of ISS on wake-activated neurons and wake behavior, wild-type mice were randomized to ISS (a repeated pattern of short sleep on 3 consecutive days followed by 4 days of recovery sleep for 4 weeks) or rested control conditions. Subsets of both groups were allowed a recovery period consisting of 4-week unperturbed activity in home cages with littermates. Mice were examined for immediate and delayed (following recovery) effects of ISS on wake neuron cell metabolics, cell counts, and sleep/wake patterns. ISS resulted in sustained disruption of sleep/wake activity, with increased wakefulness during the lights-on period and reduced wake bout duration and wake time during the lights-off period. Noradrenergic locus coeruleus (LC) and orexinergic neurons showed persistent alterations in morphology, and reductions in both neuronal stereological cell counts and fronto-cortical projections. Surviving wake-activated neurons evidenced persistent reductions in sirtuins 1 and 3 and increased lipofuscin. In contrast, ISS resulted in no lasting injury to the sleep-activated melanin concentrating hormone neurons. Collectively these findings demonstrate for the first time that ISS imparts significant lasting disturbances in sleep/wake activity, degeneration of wake-activated LC and orexinergic neurons, and lasting metabolic changes in remaining neurons most consistent with premature senescence. © 2016 Associated Professional Sleep Societies, LLC.

  13. Glucocorticoids interact with the noradrenergic arousal system in the nucleus accumbens shell to enhance memory consolidation of both appetitive and aversive taste learning.

    PubMed

    Wichmann, Romy; Fornari, Raquel V; Roozendaal, Benno

    2012-09-01

    It is well established that glucocorticoid hormones strengthen the consolidation of long-term memory of emotionally arousing experiences but have little effect on memory of low-arousing experiences. Although both positive and negative emotionally arousing events tend to be well remembered, studies investigating the neural mechanism underlying glucocorticoid-induced memory enhancement focused primarily on negatively motivated training experiences. In the present study we show an involvement of glucocorticoids within the nucleus accumbens (NAc) in enhancing memory consolidation of both an appetitive and aversive form of taste learning. The specific glucocorticoid receptor (GR) agonist RU 28362 (1 or 3ng) administered bilaterally into the NAc shell, but not core, of male Sprague-Dawley rats immediately after an appetitive saccharin drinking experience dose-dependently enhanced 24-h retention of the safe taste, resulting in a facilitated attenuation of neophobia. Similarly, GR agonist infusions given into the NAc shell immediately after pairing of the saccharin taste with a malaise-inducing agent enhanced memory of this negative experience, resulting in an intensified conditioned aversion. Importantly, a suppression of noradrenergic activity within the NAc shell with the β-adrenoceptor antagonist propranolol blocked the facilitating effect of a concurrently administered GR agonist on memory consolidation in both the appetitive and aversive learning task. Thus, these findings indicate that GR activation interacts with the noradrenergic arousal system within the NAc to enhance memory consolidation of emotionally arousing training experiences regardless of valence. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Imidazoline(2) (I(2)) binding site- and alpha(2)-adrenoceptor-mediated modulation of central noradrenergic and HPA axis function in control rats and chronically stressed rats with adjuvant-induced arthritis.

    PubMed

    Finn, D P; Lalies, M D; Harbuz, M S; Jessop, D S; Hudson, A L; Nutt, D J

    2002-06-01

    The aim of this study was to investigate imidazoline(2) (I(2)) binding site- and alpha(2)-adrenoceptor-mediated control of central noradrenergic and HPA axis activity in control rats and chronically stressed rats with adjuvant-induced arthritis (AA). Basal levels of extracellular nonadrenaline (NA) in the region of the hypothalamic paraventricular nucleus (PVN) of AA rats were significantly greater than controls. Both the I(2) binding site selective ligand BU224 (10 mg kg(-1) i.p.) and the alpha(2)-adrenoceptor antagonist RX821002 (2.5 mg kg(-1) i.p.) significantly elevated extracellular levels of NA in the PVN region and plasma corticosterone (CORT) in a rapid and transient manner in both control and AA rats. The noradrenergic response of AA rats to BU224 was significantly enhanced compared with drug treated controls. There was a significant correlation between extracellular NA in the PVN region and plasma CORT following BU224 and RX821002. In conclusion, central noradrenergic and HPA axis activity in control and chronically stressed AA rats appear to be under the control of both I(2) binding sites and alpha(2)-adrenoceptors. Increased basal levels of extracellular NA in the PVN region of AA rats suggests increased noradrenergic activity in these animals which is modulated to a greater extent by I(2) binding sites than by alpha(2)-adrenoceptors.

  15. Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

    PubMed Central

    Samaco, Rodney C.; Mandel-Brehm, Caleigh; Chao, Hsiao-Tuan; Ward, Christopher S.; Fyffe-Maricich, Sharyl L.; Ren, Jun; Hyland, Keith; Thaller, Christina; Maricich, Stephen M.; Humphreys, Peter; Greer, John J.; Percy, Alan; Glaze, Daniel G.; Zoghbi, Huda Y.; Neul, Jeffrey L.

    2009-01-01

    Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes. PMID:20007372

  16. Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities.

    PubMed

    Samaco, Rodney C; Mandel-Brehm, Caleigh; Chao, Hsiao-Tuan; Ward, Christopher S; Fyffe-Maricich, Sharyl L; Ren, Jun; Hyland, Keith; Thaller, Christina; Maricich, Stephen M; Humphreys, Peter; Greer, John J; Percy, Alan; Glaze, Daniel G; Zoghbi, Huda Y; Neul, Jeffrey L

    2009-12-22

    Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes.

  17. Comparison of the effects of caffeine and procaine on noradrenergic transmission in the guinea-pig mesenteric artery.

    PubMed Central

    Fujii, K.; Miyahara, H.; Suzuki, H.

    1985-01-01

    The effects of caffeine and procaine on noradrenergic transmission in the guinea-pig mesenteric artery were investigated by recording electrical responses of smooth muscle cells and by measuring the outflow of noradrenaline (NA) and 3,4-dihydroxyphenylglycol (DOPEG) induced by perivascular nerve stimulation. Caffeine possessed dual actions on the membrane, i.e., at low concentrations (2.5 X 10(-4)-5 X 10(-4)M), it hyperpolarized the membrane and decreased the membrane resistance and at high concentrations (over 2.5 X 10(-3)M) it depolarized the membrane and increased the membrane resistance. Procaine (over 10(-4)M) consistently depolarized the membrane and increased the membrane resistance. The amplitude of the excitatory junction potential (e.j.p.) produced by perivascular nerve stimulation was increased by low concentrations of procaine (2.5 X 10(-5)-10(-4)M) or high concentrations (10(-3)-5 X 10(-3)M) of caffeine and was decreased by low concentrations of caffeine (2.5 X 10(-5)-10(-4)M) or high concentrations of procaine (5 X 10(-4)-10(-3)M). Higher concentrations of caffeine (over 5 X 10(-3)M) induced a spike potential on the e.j.p., while higher concentrations of procaine (over 2.5 X 10(-3)M) inhibited the generation of e.j.ps. Facilitation of e.j.ps produced by repetitive stimulation of perivascular nerves remained unchanged by caffeine, while it was enhanced by procaine at any given concentration (caffeine 2.5 X 10(-4)-10(-3)M; procaine 10(-4)-10(-3)M). The membrane depolarization produced by exogenously applied NA (10(-5)M) was not blocked by pretreatment with procaine. Conduction velocity of perivascular nerve excitation remained unchanged by application of caffeine (up to 5 X 10(-3)M), and was reduced by application of procaine (over 2.5 X 10(-4)M). Outflow of NA during perivascular nerve stimulation remained unchanged by caffeine (10(-4)-3 X 10(-3)M), while it was enhanced by procaine (over 2.5 X 10(-4)M). The outflow of DOPEG was slightly reduced by

  18. Corticospinal mirror neurons.

    PubMed

    Kraskov, A; Philipp, R; Waldert, S; Vigneswaran, G; Quallo, M M; Lemon, R N

    2014-01-01

    Here, we report the properties of neurons with mirror-like characteristics that were identified as pyramidal tract neurons (PTNs) and recorded in the ventral premotor cortex (area F5) and primary motor cortex (M1) of three macaque monkeys. We analysed the neurons' discharge while the monkeys performed active grasp of either food or an object, and also while they observed an experimenter carrying out a similar range of grasps. A considerable proportion of tested PTNs showed clear mirror-like properties (52% F5 and 58% M1). Some PTNs exhibited 'classical' mirror neuron properties, increasing activity for both execution and observation, while others decreased their discharge during observation ('suppression mirror-neurons'). These experiments not only demonstrate the existence of PTNs as mirror neurons in M1, but also reveal some interesting differences between M1 and F5 mirror PTNs. Although observation-related changes in the discharge of PTNs must reach the spinal cord and will include some direct projections to motoneurons supplying grasping muscles, there was no EMG activity in these muscles during action observation. We suggest that the mirror neuron system is involved in the withholding of unwanted movement during action observation. Mirror neurons are differentially recruited in the behaviour that switches rapidly between making your own movements and observing those of others.

  19. NGF-dependent axon growth and regeneration are altered in sympathetic neurons of dystrophic mdx mice.

    PubMed

    Lombardi, Loredana; Persiconi, Irene; Gallo, Alessandra; Hoogenraad, Casper C; De Stefano, Maria Egle

    2017-04-01

    Duchenne muscular dystrophy (DMD) is a lethal disease, determined by lack of dystrophin (Dp427), a muscular cytoskeletal protein also expressed by selected neuronal populations. Consequently, besides muscular wasting, both human patients and DMD animal models suffer several neural disorders. In previous studies on the superior cervical ganglion (SCG) of wild type and dystrophic mdx mice (Lombardi et al. 2008), we hypothesized that Dp427 could play some role in NGF-dependent axonal growth, both during development and adulthood. To address this issue, we first analyzed axon regeneration potentials of SCG neurons of both genotypes after axotomy in vivo. While noradrenergic innervation of mdx mouse submandibular gland, main source of nerve growth factor (NGF), recovered similarly to wild type, iris innervation (muscular target) never did. We, therefore, evaluated whether dystrophic SCG neurons were poorly responsive to NGF, especially at low concentration. Following in vitro axotomy in the presence of either 10 or 50ng/ml NGF, the number of regenerated axons in mdx mouse neuron cultures was indeed reduced, compared to wild type, at the lower concentration. Neurite growth parameters (i.e. number, length), growth cone dynamics and NGF/TrkA receptor signaling in differentiating neurons (not injured) were also significantly reduced when cultured with 10ng/ml NGF, but also with higher NGF concentrations. In conclusion, we propose a role for Dp427 in NGF-dependent cytoskeletal dynamics associated to growth cone advancement, possibly through indirect stabilization of TrkA receptors. Considering NGF activity in nervous system development/remodeling, this aspect could concur in some of the described DMD-associated neural dysfunctions. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Vasopressinergic neurons of the supraoptic nucleus in perinatal rats: reaction to osmotic stimulation and its regulation.

    PubMed

    Abramova, M A; Calas, A; Ugrumov, M

    2011-01-01

    Osmotic stimulation (OS) of vasopressin (VP) neurons of the supraoptic nucleus (SON) promotes VP secretion and tyrosine hydroxylase (TH) expression in adult mammals. VP secretion is under a noradrenaline control, whereas the regulation of TH expression remains uncertain. This study was aimed to determine at what period of ontogenesis: (1) VP neurons begin to react to OS by modifying simultaneously VP and TH gene expression and synthesis, (2) the noradrenergic control of VP neurons is established. Rats on the 21st embryonic day (E), third postnatal day (P), P13 were salt loaded or salt loaded and treated with an antagonist (prazosin) or agonist (phenylephrine) of α1-adrenoreceptors. According to our immunocytochemical and in situ hybridization data, OS resulted in an increased amount of VP mRNA in each age group and of VP on E21 and P3. TH gene and synthesis was initially expressed under OS on P3. The number of TH-expressing neurons diminished by threefold in salt loaded rats from P3 to P13. OS combined with prazosin administration resulted in an increased level of VP mRNA on P3 and P13, but not on E21 suggesting the onset of the noradrenaline inhibitory control after birth. OS together with prazosin treatment stimulated TH expression on P3 and P13, whereas phenylephrine provided an opposite effect. Thus, VP neurons begin to react to OS by an increased VP synthesis at the end of fetal life and by the onset of TH expression shortly after birth; the expression of both substances appears to be under the inhibitory control of noradrenaline. © Springer-Verlag 2010

  1. NEURON and Python.

    PubMed

    Hines, Michael L; Davison, Andrew P; Muller, Eilif

    2009-01-01

    The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because all existing models written in Hoc, including graphical user interface tools, continue to work without change and are also available within the Python context. An example of the benefits of Python availability is the use of the xml module in implementing NEURON's Import3D and CellBuild tools to read MorphML and NeuroML model specifications.

  2. NEURON and Python

    PubMed Central

    Hines, Michael L.; Davison, Andrew P.; Muller, Eilif

    2008-01-01

    The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because all existing models written in Hoc, including graphical user interface tools, continue to work without change and are also available within the Python context. An example of the benefits of Python availability is the use of the xml module in implementing NEURON's Import3D and CellBuild tools to read MorphML and NeuroML model specifications. PMID:19198661

  3. Cajal bodies in neurons

    PubMed Central

    Lafarga, Miguel; Tapia, Olga; Romero, Ana M.; Berciano, Maria T.

    2017-01-01

    ABSTRACT Cajal is commonly regarded as the father of modern neuroscience in recognition of his fundamental work on the structure of the nervous system. But Cajal also made seminal contributions to the knowledge of nuclear structure in the early 1900s, including the discovery of the “accessory body” later renamed “Cajal body” (CB). This important nuclear structure has emerged as a center for the assembly of ribonucleoproteins (RNPs) required for splicing, ribosome biogenesis and telomere maintenance. The modern era of CB research started in the 1990s with the discovery of coilin, now known as a scaffold protein of CBs, and specific probes for small nuclear RNAs (snRNAs). In this review, we summarize what we have learned in the recent decades concerning CBs in post-mitotic neurons, thereby ruling out dynamic changes in CB functions during the cell cycle. We show that CBs are particularly prominent in neurons, where they frequently associate with the nucleolus. Neuronal CBs are transcription-dependent nuclear organelles. Indeed, their number dynamically accommodates to support the high neuronal demand for splicing and ribosome biogenesis required for sustaining metabolic and bioelectrical activity. Mature neurons have canonical CBs enriched in coilin, survival motor neuron protein and snRNPs. Disruption and loss of neuronal CBs associate with severe neuronal dysfunctions in several neurological disorders such as motor neuron diseases. In particular, CB depletion in motor neurons seems to reflect a perturbation of transcription and splicing in spinal muscular atrophy, the most common genetic cause of infant mortality. PMID:27627892

  4. Neuromorphic Silicon Neuron Circuits

    PubMed Central

    Indiveri, Giacomo; Linares-Barranco, Bernabé; Hamilton, Tara Julia; van Schaik, André; Etienne-Cummings, Ralph; Delbruck, Tobi; Liu, Shih-Chii; Dudek, Piotr; Häfliger, Philipp; Renaud, Sylvie; Schemmel, Johannes; Cauwenberghs, Gert; Arthur, John; Hynna, Kai; Folowosele, Fopefolu; Saighi, Sylvain; Serrano-Gotarredona, Teresa; Wijekoon, Jayawan; Wang, Yingxue; Boahen, Kwabena

    2011-01-01

    Hardware implementations of spiking neurons can be extremely useful for a large variety of applications, ranging from high-speed modeling of large-scale neural systems to real-time behaving systems, to bidirectional brain–machine interfaces. The specific circuit solutions used to implement silicon neurons depend on the application requirements. In this paper we describe the most common building blocks and techniques used to implement these circuits, and present an overview of a wide range of neuromorphic silicon neurons, which implement different computational models, ranging from biophysically realistic and conductance-based Hodgkin–Huxley models to bi-dimensional generalized adaptive integrate and fire models. We compare the different design methodologies used for each silicon neuron design described, and demonstrate their features with experimental results, measured from a wide range of fabricated VLSI chips. PMID:21747754

  5. Postnatal development changes in excitatory synaptic activity in the rat locus coeruleus neurons.

    PubMed

    Arami, Masoumeh Kourosh; Hajizadeh, Sohrab; Semnanian, Saeed

    2016-10-01

    Glutamatergic synapses are shown to mature during activity and development. In order to further explore how glutamate can change the excitability of noradrenergic neurons of locus coeruleus (LC) and to better understand the involvement of Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors complements across the LC, we investigated developmental changes in their activity during first postnatal weeks. Spontaneous and evoked excitatory postsynaptic currents (sEPSC and eEPSCs) were recorded in neurons of LC slices from 7, 14 and 21 days old rats using the whole cell patch clamp method. Also, the AMPA/NMDA current ratio (A/N) was measured. A pronounced AMPAR and NMDAR components mediated involvement in synaptic transmission were seen from the first postnatal week. Over this period of development, we have demonstrated that AMPA sEPSCs show an increase in frequency without major changes in their amplitude, while NMDA sEPSCs show an increase in frequency with a major change in amplitude. Neither the probability of release nor the AMPA/NMDA ratio was found to change significantly with age. It is concluded that NMDAR activity as well as AMPAR activity may be involved in coerulear excitability and modulatory effect during postnatal development. Copyright © 2016. Published by Elsevier B.V.

  6. Corticospinal mirror neurons

    PubMed Central

    Kraskov, A.; Philipp, R.; Waldert, S.; Vigneswaran, G.; Quallo, M. M.; Lemon, R. N.

    2014-01-01

    Here, we report the properties of neurons with mirror-like characteristics that were identified as pyramidal tract neurons (PTNs) and recorded in the ventral premotor cortex (area F5) and primary motor cortex (M1) of three macaque monkeys. We analysed the neurons’ discharge while the monkeys performed active grasp of either food or an object, and also while they observed an experimenter carrying out a similar range of grasps. A considerable proportion of tested PTNs showed clear mirror-like properties (52% F5 and 58% M1). Some PTNs exhibited ‘classical’ mirror neuron properties, increasing activity for both execution and observation, while others decreased their discharge during observation (‘suppression mirror-neurons’). These experiments not only demonstrate the existence of PTNs as mirror neurons in M1, but also reveal some interesting differences between M1 and F5 mirror PTNs. Although observation-related changes in the discharge of PTNs must reach the spinal cord and will include some direct projections to motoneurons supplying grasping muscles, there was no EMG activity in these muscles during action observation. We suggest that the mirror neuron system is involved in the withholding of unwanted movement during action observation. Mirror neurons are differentially recruited in the behaviour that switches rapidly between making your own movements and observing those of others. PMID:24778371

  7. Binuclear Purkinje neurons.

    PubMed

    Paltsyn, A A; Komissarova, S V

    2016-01-01

    Until the end of the XX century binuclear neurons of Purkinje in rodents and the humans were a subject of casual finds. However already then it was noticed that such cells are in old and sick mammals more often. It is therefore assumed that the appearance of the second nucleus has a regenerative value - compensation age-related or pathogenic loss of Purkinje cells. In 2003, in research on stem cell transplantation was made the first observations related to the mechanism of the appearance of the second nucleus in Purkinje neurons. The transgender studies in humans and in transgenic experiments on mice have shown that bone marrow derived donor cells can fuse with Purkinje neurons of the recipient, thus transfer to neuron its nucleus. It is very important that the binuclear neurons can appear in old and sick people and rodents without transplantation. But in that case neither the donor cell, nor the mechanism of origin of the second nucleus remain not clear. Relevance of clarification of this question increases of the fact that literature of the last years proves: emergence of the second nucleus is a form of physiological and reparative regeneration of neurons of Purkinje.

  8. Single bumps in a 2-population homogenized neuronal network model

    NASA Astrophysics Data System (ADS)

    Kolodina, Karina; Oleynik, Anna; Wyller, John

    2018-05-01

    We investigate existence and stability of single bumps in a homogenized 2-population neural field model, when the firing rate functions are given by the Heaviside function. The model is derived by means of the two-scale convergence technique of Nguetseng in the case of periodic microvariation in the connectivity functions. The connectivity functions are periodically modulated in both the synaptic footprint and in the spatial scale. The bump solutions are constructed by using a pinning function technique for the case where the solutions are independent of the local variable. In the weakly modulated case the generic picture consists of two bumps (one narrow and one broad bump) for each admissible set of threshold values for firing. In addition, a new threshold value regime for existence of bumps is detected. Beyond the weakly modulated regime the number of bumps depends sensitively on the degree of heterogeneity. For the latter case we present a configuration consisting of three coexisting bumps. The linear stability of the bumps is studied by means of the spectral properties of a Fredholm integral operator, block diagonalization of this operator and the Fourier decomposition method. In the weakly modulated regime, one of the bumps is unstable for all relative inhibition times, while the other one is stable for small and moderate values of this parameter. The latter bump becomes unstable as the relative inhibition time exceeds a certain threshold. In the case of the three coexisting bumps detected in the regime of finite degree of heterogeneity, we have at least one stable bump (and maximum two stable bumps) for small and moderate values of the relative inhibition time.

  9. Noradrenergic modulation of vicarious trial-and-error behavior during a spatial decision-making task in rats.

    PubMed

    Amemiya, S; Noji, T; Kubota, N; Nishijima, T; Kita, I

    2014-04-18

    Deliberation between possible options before making a decision is crucial to responding with an optimal choice. However, the neural mechanisms regulating this deliberative decision-making process are still unclear. Recent studies have proposed that the locus coeruleus-noradrenaline (LC-NA) system plays a role in attention, behavioral flexibility, and exploration, which contribute to the search for an optimal choice under uncertain situations. In the present study, we examined whether the LC-NA system relates to the deliberative process in a T-maze spatial decision-making task in rats. To quantify deliberation in rats, we recorded vicarious trial-and-error behavior (VTE), which is considered to reflect a deliberative process exploring optimal choices. In experiment 1, we manipulated the difficulty of choice by varying the amount of reward pellets between the two maze arms (0 vs. 4, 1 vs. 3, 2 vs. 2). A difficulty-dependent increase in VTE was accompanied by a reduction of choice bias toward the high reward arm and an increase in time required to select one of the two arms in the more difficult manipulation. In addition, the increase of c-Fos-positive NA neurons in the LC depended on the task difficulty and the amount of c-Fos expression in LC-NA neurons positively correlated with the occurrence of VTE. In experiment 2, we inhibited LC-NA activity by injection of clonidine, an agonist of the alpha2 autoreceptor, during a decision-making task (1 vs. 3). The clonidine injection suppressed occurrence of VTE in the early phase of the task and subsequently impaired a valuable choice later in the task. These results suggest that the LC-NA system regulates the deliberative process during decision-making. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Synergistic effects of noradrenergic modulation with atomoxetine and 10 Hz repetitive transcranial magnetic stimulation on motor learning in healthy humans.

    PubMed

    Sczesny-Kaiser, Matthias; Bauknecht, Alica; Höffken, Oliver; Tegenthoff, Martin; Dinse, Hubert R; Jancke, Dirk; Funke, Klaus; Schwenkreis, Peter

    2014-04-02

    Repetitive transcranial magnetic stimulation (rTMS) is able to induce changes in neuronal activity that outlast stimulation. The underlying mechanisms are not completely understood. They might be analogous to long-term potentiation or depression, as the duration of the effects seems to implicate changes in synaptic plasticity. Norepinephrine (NE) has been shown to play a crucial role in neuronal plasticity in the healthy and injured human brain. Atomoxetine (ATX) and other NE reuptake inhibitors have been shown to increase excitability in different systems and to influence learning processes. Thus, the combination of two facilitative interventions may lead to further increase in excitability and motor learning. But in some cases homeostatic metaplasticity might protect the brain from harmful hyperexcitability. In this study, the combination of 60 mg ATX and 10 Hz rTMS over the primary motor cortex was used to examine changes in cortical excitability and motor learning and to investigate their influence on synaptic plasticity mechanisms. The results of this double-blind placebo-controlled study showed that ATX facilitated corticospinal and intracortical excitability in motor cortex. 10 Hertz rTMS applied during a motor task was able to further increase intracortical excitability only in combination with ATX. In addition, only the combination of 10 Hz rTMS and ATX was capable of enhancing the total number of correct responses and reaction time significantly, indicating an interaction effect between rTMS and ATX without signs of homeostatic metaplasticity. These results suggest that pharmacologically enhanced NE transmission and 10 Hz rTMS exert a synergistic effect on motor cortex excitability and motor learning in healthy humans.

  11. Binding and competitive inhibition of amine uptake at postsynaptic neurones (transport-P) by tricyclic antidepressants.

    PubMed Central

    Al-Damluji, S.; Kopin, I. J.

    1996-01-01

    1. We have provided evidence for a novel amine uptake process for which prazosin is a substrate in postsynaptic neurones, characterized by a paradoxical increase in accumulation of the radioligand when the concentration of the unlabelled drug is increased above 10(-7) M. This increase is due to activation of a proton-dependent, vacuolar type-ATPase-linked uptake process which is blocked by desipramine but is resistant to reserpine. We have now examined the effects of tricyclic antidepressants on this uptake system in a cell line derived from hypothalamic peptidergic neurones, known to be innervated by noradrenergic nerve terminals in vivo. 2. [3H]-imipramine bound to the cells and was displaced by unlabelled imipramine, desipramine, amitriptyline and nortriptyline. The data fitted a single binding site model. This is the first demonstration of antidepressant binding sites in postsynaptic neurones. 3. There was no increase in the binding of [3H]-imipramine at high concentrations of unlabelled imipramine, suggesting that antidepressants inhibit uptake but are not themselves accumulated by peptidergic gonadotrophin releasing hormone neurones. 4. Accumulation of prazosin was competitively inhibited by antidepressants. Tertiary amines were slightly more potent than secondary amines and the presence of a nitrogen atom in the heterocyclic ring enhanced blocking activity. 5. The affinities of the antidepressants for the uptake process are within the range of plasma concentrations that are observed during therapeutic use of these compounds. Since it is likely that this uptake process has a physiological function, its inhibition by antidepressants may provide a new avenue for investigating the mechanism of action of these compounds. PMID:8851495

  12. Activation and Inhibition of Neurons in the Hippocampal Ventral Subiculum by Norepinephrine and Locus Coeruleus Stimulation

    PubMed Central

    Lipski, Witold J; Grace, Anthony A

    2013-01-01

    The ventral subiculum (vSub) has been implicated in a wide range of neurocognitive functions, including responses to fear, stress, and anxiety. The vSub receives dense noradrenergic (NE) inputs from the locus coeruleus (LC), and the LC-NE system is heavily implicated in attention and is known to be activated by stressors. However, the way in which the neurons in the vSub respond to activation of the LC-NE is not well understood. In this study, the direct LC innervation of the vSub was investigated. The effect of norepinephrine (NE) on single vSub neurons was examined using microiontophoresis combined with electrophysiological recordings in anesthetized rats, and this response compared with the effect of electrical stimulation of the LC. Iontophoretic NE inhibited all vSub neurons tested, whereas LC stimulation inhibited 16% and activated 38% of neurons. Inhibition was mediated primarily by alpha-2 receptors, whereas activation was mediated by beta-adrenergic receptors. Furthermore, this effect was not mediated via the LC-basolateral amygdala (BLA) pathway, because BLA inactivation did not block LC stimulation-evoked activation of the vSub. These results indicate that the LC-NE system is a potent modulator of vSub activity. Based on these findings, stress-induced activation of the LC-NE system is expected to evoke inhibition and activation in the vSub, both of which may contribute to stress adaptation, whereas an imbalance of this system may lead to pathological stress responses in mental disorders. PMID:23032074

  13. Simultaneous modulation of retrieval by dopaminergic D(1), beta-noradrenergic, serotonergic-1A and cholinergic muscarinic receptors in cortical structures of the rat.

    PubMed

    Barros, D M; Mello e Souza, T; De David, T; Choi, H; Aguzzoli, A; Madche, C; Ardenghi, P; Medina, J H; Izquierdo, I

    2001-09-28

    Retrieval of inhibitory avoidance has been recently shown to require intact glutamate receptors, protein kinases A and C and mitogen-activated protein kinase in the CA1 region of the rat hippocampus and in the entorhinal, posterior parietal and anterior cingulate cortex. These enzymatic activities are known to be modulated by dopamine D(1), beta-noradrenergic, 5HT1A and cholinergic muscarinic receptors. Here we study the effect on retrieval of this task of well-known agonists and antagonists of these receptors infused in the same brain cortical regions and into the basolateral amygdala, in rats. The drugs used were SKF38393 (D(1) agonist), noradrenaline, 8-HO-DPAT (5HT1A agonist), oxotremorine (muscarinic agonist), SCH23390 (D(1) antagonist), timolol (beta antagonist), NAN-190 (5HT1A antagonist) and scopolamine (muscarinic antagonist). All were studied at two different dose levels. The localised infusion of SKF38393, noradrenaline, NAN-190 and oxotremorine into any of the cortical structures mentioned 10 min prior to a 24-h retention test session of one-trial step-down inhibitory avoidance enhanced retention test performance. SCH2330, timolol, 8-HO-DPAT and scopolamine hindered retention test performance. In the basolateral amygdala only an enhancing effect of noradrenaline and an inhibitory effect of timolol were seen. Three hours after the infusions, retention test performance returned to normal in all cases. None of the treatments affected locomotion or rearing in an open field or behaviour in the elevated plus maze. Therefore, their effects on retention testing can be attributed to an influence on retrieval. In conclusion, memory retrieval of this apparently simple task requires the participation of CA1, entorhinal, posterior parietal and anterior cingulate cortex, and is strongly modulated by, dopaminergic D(1), beta-noradrenergic, muscarinic cholinergic and 5HT1A receptors in the four areas. The first three types of receptor enhance, and the latter inhibits

  14. Neuronal targeting in diabetes mellitus: a story of sensory neurons and motor neurons.

    PubMed

    Zochodne, D W; Ramji, N; Toth, C

    2008-08-01

    Diabetes mellitus targets the peripheral nervous system in unique but disabling ways. Although several mechanisms may target peripheral neurons, they render a degenerative pattern of damage that begins in distal terminals. Moreover, sensory neurons are involved early, motor neurons later. By studying a variety of diabetic neuropathy models in rats, mice, and other species, an overall appreciation of its neurodegeneration emerges. Understanding how mechanisms of diabetes complications target peripheral neurons selectively may offer opportunities to intervene before irretrievable neuron loss develops.

  15. Neuronal survival in the brain: neuron type-specific mechanisms.

    PubMed

    Pfisterer, Ulrich; Khodosevich, Konstantin

    2017-03-02

    Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether a particular neuron will die. To accommodate this signaling, immature neurons in the brain express a number of transmembrane factors as well as intracellular signaling molecules that will regulate the cell survival/death decision, and many of these factors cease being expressed upon neuronal maturation. Furthermore, pro-survival factors and intracellular responses depend on the type of neuron and region of the brain. Thus, in addition to some common neuronal pro-survival signaling, different types of neurons possess a variety of 'neuron type-specific' pro-survival constituents that might help them to adapt for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various types of immature neurons. Importantly, we mainly focus on in vivo data to describe neuronal survival specifically in the brain, without extrapolating data obtained in the PNS or spinal cord, and thus emphasize the influence of the complex brain environment on neuronal survival during development.

  16. Kappe neurons, a novel population of olfactory sensory neurons.

    PubMed

    Ahuja, Gaurav; Bozorg Nia, Shahrzad; Zapilko, Veronika; Shiriagin, Vladimir; Kowatschew, Daniel; Oka, Yuichiro; Korsching, Sigrun I

    2014-02-10

    Perception of olfactory stimuli is mediated by distinct populations of olfactory sensory neurons, each with a characteristic set of morphological as well as functional parameters. Beyond two large populations of ciliated and microvillous neurons, a third population, crypt neurons, has been identified in teleost and cartilaginous fishes. We report here a novel, fourth olfactory sensory neuron population in zebrafish, which we named kappe neurons for their characteristic shape. Kappe neurons are identified by their Go-like immunoreactivity, and show a distinct spatial distribution within the olfactory epithelium, similar to, but significantly different from that of crypt neurons. Furthermore, kappe neurons project to a single identified target glomerulus within the olfactory bulb, mdg5 of the mediodorsal cluster, whereas crypt neurons are known to project exclusively to the mdg2 glomerulus. Kappe neurons are negative for established markers of ciliated, microvillous and crypt neurons, but appear to have microvilli. Kappe neurons constitute the fourth type of olfactory sensory neurons reported in teleost fishes and their existence suggests that encoding of olfactory stimuli may require a higher complexity than hitherto assumed already in the peripheral olfactory system.

  17. Imaging voltage in neurons

    PubMed Central

    Peterka, Darcy S.; Takahashi, Hiroto; Yuste, Rafael

    2011-01-01

    In the last decades, imaging membrane potential has become a fruitful approach to study neural circuits, especially in invertebrate preparations with large, resilient neurons. At the same time, particularly in mammalian preparations, voltage imaging methods suffer from poor signal to noise and secondary side effects, and they fall short of providing single-cell resolution when imaging of the activity of neuronal populations. As an introduction to these techniques, we briefly review different voltage imaging methods (including organic fluorophores, SHG chromophores, genetic indicators, hybrid, nanoparticles and intrinsic approaches), and illustrate some of their applications to neuronal biophysics and mammalian circuit analysis. We discuss their mechanisms of voltage sensitivity, from reorientation, electrochromic or electro-optical phenomena, to interaction among chromophores or membrane scattering, and highlight their advantages and shortcomings, commenting on the outlook for development of novel voltage imaging methods. PMID:21220095

  18. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder.

    PubMed

    Herrera-Guzmán, Ixchel; Gudayol-Ferré, Esteve; Herrera-Guzmán, Daniel; Guàrdia-Olmos, Joan; Hinojosa-Calvo, Erika; Herrera-Abarca, Jorge E

    2009-06-01

    Patients with major depressive disorder (MDD) usually suffer from altered cognitive functions of episodic memory, working memory, mental processing speed and motor response. Diverse studies suggest that different antidepressant agents may improve cognitive functions in patients with MDD. The aim of this work is to study the effects of serotonergic reuptake inhibitors (SSRIs) and serotonergic-noradrenergic reuptake inhibitors (SNRIs) treatments to improve the performance on memory tasks and mental processing speed in MDD. Seventy-three subjects meeting criteria for major depressive disorder were assessed with the Hamilton depression rating scale and a neuropsychological battery. The subjects were medicated with escitalopram (n=36) or duloxetine (n=37) for 24 weeks. At the end of the trial, the subjects were assessed again with the same neuropsychological battery used prior to the treatment. Both treatments improved importantly the episodic memory and to a lesser extent, working memory, mental processing speed and motor performance. Our results suggest that cognition is partially independent from improvement in clinical symptoms. Both groups achieved remission rates in the HAM-D-17 after 24 weeks of treatment, but SNRI was superior to SSRI at improving episodic and working memory. Our work indicates that the superiority of SNRI over the SSRI at episodic memory improvement is clinically relevant.

  19. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on attention and executive functions in patients with major depressive disorder.

    PubMed

    Herrera-Guzmán, Ixchel; Herrera-Abarca, Jorge E; Gudayol-Ferré, Esteve; Herrera-Guzmán, Daniel; Gómez-Carbajal, Lizbeth; Peña-Olvira, Miriam; Villuendas-González, Erwin; Joan, Guàrdia-Olmos

    2010-05-30

    Several reports suggest that antidepressants may improve cognitive functioning in patients with major depressive disorder (MDD). The present work aims to study the effects of selective serotonin reuptake inhibitors (SSRIs) and serotonergic-noradrenergic reuptake inhibitors (SNRIs) treatments on the performance of working memory, attention and executive functions in patients with MDD. A total of 73 subjects meeting the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV) criteria for MDD, and 37 control subjects were assessed with the Hamilton Depression Rating Scale and a neuropsychological battery. The subjects were medicated with escitalopram (n=36) or duloxetine (n=37) for 24 weeks. At the end of the trial, the subjects were assessed again with the same tests. The depressed subjects showed alterations in attention and cognitive functions when compared to the control group. The administration of both treatments improved working memory, as well as attention and all the executive functions, but the cognitive functions of depressed patients do not improve enough to reach the levels of performance of the control subjects. Our results suggest that both SSRI and SNRI treatments presented the same efficacy in improving attention and the remaining executive functions. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  20. Decreased noradrenergic and serotonergic reactivity of vas deferens of newborn rats from mothers treated with the serotonin reuptake inhibitor fluoxetine during pregnancy and breast-feeding.

    PubMed

    Pereira, Janaina D; Caricati-Neto, Afonso; Jurkiewicz, Aron; Jurkiewicz, Neide H

    2007-11-10

    Female Wistar rats were treated with the serotonin reuptake inhibitor fluoxetine (10 mg/kg/i.p/day), during pregnancy and breast-feeding, for the study of the corresponding newborn rats. At the end of the preweaning period, the 30-day old litters had their vas deferens removed for testing peripheral sympathetic reactivity, through the following experiments in vitro: (a) concentration-contraction curves for serotonin and for the adrenergic agonists noradrenaline, phenylephrine, clonidine and dopamine or for the indirect agonist tyramine (b) contractions induced by electric field stimulation, as an indicator of sympathetic neurotransmission (c) release of endogenous noradrenaline, measured by real-time determinations on HPLC (d) Ca(+2) time-contraction curves, to check for changes on Ca(+2) translocation. Our results showed that the affinity (pD(2)) for serotonin was strikingly decreased by about 1.5 log units. The pD(2) for adrenergic agonists was decreased by about 0.5 log units, except for dopamine and clonidine. The maximum effects and intrinsic activity were decreased only for dopamine. On the other hand, the response to Ca(+2) and the release of noradrenaline from nerve terminals were not modified. In additional experiments, the mother's body weights were measured, showing a decrease during gestation and a recovery during lactation while the offspring's weights were lower than controls. It is concluded that, besides the alterations on body weights, changes on noradrenergic and serotonergic mechanisms were observed and persisted in the newborn, at least one month after parturition.

  1. Modulation of noradrenergic and serotonergic transmission by noxious stimuli and intrathecal morphine differs in the dorsal raphe nucleus of anesthetized rat: in vivo voltammetric studies.

    PubMed

    Chuma, Toichiro; Taguchi, Kyoji; Kato, Masatoshi; Abe, Kenji; Utsunomiya, Iku; Miyamoto, Ken-ichi; Miyatake, Tadashi

    2002-09-01

    We examined the effects of cutaneous noxious heat as well as the intrathecal administration of morphine on the oxidation current of peaks 1 and 2 in the dorsal raphe nucleus (DRN) of anesthetized rats. Differential normal pulse voltammetry with carbon fiber electrodes identified distinct oxidation currents at +120 mV (peak 1: catechol signals) and +280 mV (peak 2: 5-hydroxyindole signals). The catechol signal was significantly increased by 22.9 +/- 4.2% after applying cutaneous noxious heat at 52 degrees C. The 5-hydroxyindole signal was decreased by 39.8 +/- 4.3 and by 25.2 +/- 4.7% after stimulation with cutaneous noxious heat at 52 and 45 degrees C, respectively. A low dose of morphine (2.5 microg) potentiated the increase in the catechol signal and the decrease in the 5-hydroxyindole signal induced by noxious heat, and a high dose (10.0 microg) attenuated both. The effects of morphine at low (2.5 microg) and high doses (10.0 microg) were antagonized by naloxone (0.5 mg/kg, i.p.). These results indicate that noxious heat stimulation increased the catechol signal and decreased the 5-hydroxyindole signal in the DRN. The intrathecal administration of morphine affects the noxious stimulation-induced activity of noradrenergic and serotonergic neurotransmission in the DRN.

  2. Acupuncture Stimulation Attenuates Impaired Emotional-Like Behaviors and Activation of the Noradrenergic System during Protracted Abstinence following Chronic Morphine Exposure in Rats

    PubMed Central

    Lee, Bombi; Sur, Bong-Jun; Shim, Insop; Hahm, Dae-Hyun; Lee, Hyejung

    2014-01-01

    The purpose of this study was to evaluate whether acupuncture stimulation attenuates withdrawal-induced behaviors in the rats during protracted abstinence following chronic morphine exposure. To do this, male rats were first exposed to morphine gradually from 20 to 100 mg/kg for 5 days, and subsequently naloxone was injected once to extend despair-related withdrawal behaviors for 4 weeks. Acupuncture stimulation was performed once at the SP6 (Sanyinjiao) acupoint on rat's; hind leg for 5 min during protracted abstinence from morphine. The acupuncture stimulation significantly decreased despair-like behavior deficits in the forced swimming test and low sociability in the open-field test as well as increased open-arm exploration in the elevated plus maze test in the last week of 4-week withdrawal period. Also the acupuncture stimulation significantly suppressed the increase in the hypothalamic corticotropin-releasing factor (CRF) expression, the decrease in the tyrosine hydroxylase expression in the locus coeruleus, and the decrease in the hippocampal brain-derived neurotrophic factor mRNA expression, induced by repeated injection of morphine. Taken together, these findings demonstrate that the acupuncture stimulation of SP6 significantly reduces withdrawal-induced behaviors, induced by repeated administration of morphine in rats, possibly through the modulation of hypothalamic CRF and the central noradrenergic system. PMID:24527041

  3. Nanoresolution radiology of neurons

    SciTech Connect

    Wu, H. R.; Chen, S. T.; Chu, Y. S.

    2012-05-29

    We report recent advances in hard-x-ray optics—including record spatial resolution—and in staining techniques that enable synchrotron microradiology to produce neurobiology images of quality comparable to electron and visible microscopy. In addition, microradiology offers excellent penetration and effective three-dimensional detection as required for many neuron studies. Our tests include tomographic reconstruction based on projection image sets.

  4. Nanoresolution radiology of neurons

    SciTech Connect

    Wu, H.R.; Chen, S.T.; Chu, Y.S.

    2013-04-08

    We report recent advances in hard-x-ray optics - including record spatial resolution - and in staining techniques that enable synchrotron microradiology to produce neurobiology images of quality comparable to electron and visible microscopy. In addition, microradiology offers excellent penetration and effective three-dimensional detection as required for many neuron studies. Our tests include tomographic reconstruction based on projection image sets.

  5. Nanoresolution radiology of neurons

    NASA Astrophysics Data System (ADS)

    Wu, H. R.; Chen, S. T.; Chu, Y. S.; Conley, R.; Bouet, N.; Chien, C. C.; Chen, H. H.; Lin, C. H.; Tung, H. T.; Chen, Y. S.; Margaritondo, G.; Je, J. H.; Hwu, Y.

    2012-06-01

    We report recent advances in hard-x-ray optics—including record spatial resolution—and in staining techniques that enable synchrotron microradiology to produce neurobiology images of quality comparable to electron and visible microscopy. In addition, microradiology offers excellent penetration and effective three-dimensional detection as required for many neuron studies. Our tests include tomographic reconstruction based on projection image sets.

  6. The influence of intravesical administration of resiniferatoxin (RTX) on the chemical coding of sympathetic chain ganglia (SChG) neurons supplying the porcine urinary bladder.

    PubMed

    Lepiarczyk, Ewa; Majewski, Mariusz; Bossowska, Agnieszka

    2015-11-01

    Resiniferatoxin (RTX) is used as an experimental drug in therapy of neurogenic urinary bladder disorders. The present study investigated the chemical coding of sympathetic chain ganglia (SChG) neurons supplying porcine urinary bladder after intravesical RTX instillation. The SChG neurons were visualized with retrograde tracing method and their chemical profile was disclosed with double-labeling immunohistochemistry using antibodies against dopamine β-hydroxylase (DβH; marker of noradrenergic neurons), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), galanin, Leu(5)-enkephalin and neuronal nitric oxide synthase (nNOS). It was found that in both the control (n = 5) and RTX-treated pigs (n = 5), the vast majority (90.4 ± 2.8 and 89.7 ± 2.3%, respectively) of FB-positive (FB+) nerve cells were DβH+. RTX instillation caused a decrease in the number of FB+/DβH+ neurons immunopositive to NPY (71.1 ± 12.1 vs 43.2 ± 6.7%), VIP (21.3 ± 10.7 vs 5.3 ± 4.3%) or SOM (16.5 ± 4.6 vs 2.3 ± 2.6%) and a distinct increase in the number of FB+/DβH+ neurons immunoreactive to nNOS (0.8 ± 1 vs 5.3 ± 1.9 %). The present study for the first time has provided some information that therapeutic effects of RTX on the mammalian urinary bladder can be partly mediated by SChG neurons.

  7. Hypothermia protects human neurons

    PubMed Central

    Antonic, Ana; Dottori, Mirella; Leung, Jessie; Sidon, Kate; Batchelor, Peter E; Wilson, William; Macleod, Malcolm R; Howells, David W

    2014-01-01

    Background and Aims Hypothermia provides neuroprotection after cardiac arrest, hypoxic-ischemic encephalopathy, and in animal models of ischemic stroke. However, as drug development for stroke has been beset by translational failure, we sought additional evidence that hypothermia protects human neurons against ischemic injury. Methods Human embryonic stem cells were cultured and differentiated to provide a source of neurons expressing β III tubulin, microtubule-associated protein 2, and the Neuronal Nuclei antigen. Oxygen deprivation, oxygen-glucose deprivation, and H2O2-induced oxidative stress were used to induce relevant injury. Results Hypothermia to 33°C protected these human neurons against H2O2-induced oxidative stress reducing lactate dehydrogenase release and Terminal deoxynucleotidyl transferase dUTP nick end labeling-staining by 53% (P ≤ 0·0001; 95% confidence interval 34·8–71·04) and 42% (P ≤ 0·0001; 95% confidence interval 27·5–56·6), respectively, after 24 h in culture. Hypothermia provided similar protection against oxygen-glucose deprivation (42%, P ≤ 0·001, 95% confidence interval 18·3–71·3 and 26%, P ≤ 0·001; 95% confidence interval 12·4–52·2, respectively) but provided no protection against oxygen deprivation alone. Protection (21%) persisted against H2O2-induced oxidative stress even when hypothermia was initiated six-hours after onset of injury (P ≤ 0·05; 95% confidence interval 0·57–43·1). Conclusion We conclude that hypothermia protects stem cell-derived human neurons against insults relevant to stroke over a clinically relevant time frame. Protection against H2O2-induced injury and combined oxygen and glucose deprivation but not against oxygen deprivation alone suggests an interaction in which protection benefits from reduction in available glucose under some but not all circumstances. PMID:24393199

  8. Life and Death of a Neuron

    MedlinePlus

    ... free mailed brochure Table of Contents Introduction The Architecture of the Neuron Birth Migration Differentiation Death Hope ... generated neurons in learning and memory. Neuron The Architecture of the Neuron The central nervous system (which ...

  9. Effect of the blockade of mu1-opioid and 5HT2A-serotonergic/alpha1-noradrenergic receptors on sweet-substance-induced analgesia.

    PubMed

    Rebouças, E C C; Segato, E N; Kishi, R; Freitas, R L; Savoldi, M; Morato, S; Coimbra, N C

    2005-05-01

    Sweet-substance-induced analgesia has been widely studied, and the investigation of the neurotransmitters involved in this antinociceptive process is an important way for understanding the involvement of the neural system controlling this kind of antinociception. The aim of this study was to investigate the involvement of opioid and monoaminergic systems in sweet-substance-induced analgesia. The present work was carried out in an animal model with the aim of investigating whether acute (24 h) or chronic (14 days) intake of a sweet substance, such as sucrose (250 g/l), is followed by antinociception. Tail withdrawal latencies in the tail-flick test were measured before and immediately after this treatment. Immediately after the recording of baseline values, independent groups of rats were submitted to sucrose or tap-water intake and, after chronic treatment, they were pretreated with intraperitoneal administration of (1) naltrexone at 0.5, 1, 2 or 3 mg/kg; (2) naloxonazine at 5, 10, 20 or 30 mg/kg; (3) methysergide at 0.5, 1, 2 or 3 mg/kg; (4) ketanserin at 0.5, 1, 2 or 3 mg/kg; or (5) physiological saline. Naltrexone and methysergide at two major doses decreased sweet-substance-induced analgesia after chronic intake of a sweet substance. These effects were corroborated by peripheral administration of naloxonazine and ketanserin. These data give further evidence for: (a) the involvement of endogenous opioids and a mu1-opioid receptor in the sweet-substance-induced antinociception; (b) the involvement of monoamines and 5HT2A serotonergic/alpha1-noradrenergic receptors in the central regulation of the sweet-substance-produced analgesia.

  10. Cerebellar sub-divisions differ in exercise-induced plasticity of noradrenergic axons and in their association with resilience to activity-based anorexia.

    PubMed

    Nedelescu, Hermina; Chowdhury, Tara G; Wable, Gauri S; Arbuthnott, Gordon; Aoki, Chiye

    2017-01-01

    The vermis or "spinocerebellum" receives input from the spinal cord and motor cortex for controlling balance and locomotion, while the longitudinal hemisphere region or "cerebro-cerebellum" is interconnected with non-motor cortical regions, including the prefrontal cortex that underlies decision-making. Noradrenaline release in the cerebellum is known to be important for motor plasticity but less is known about plasticity of the cerebellar noradrenergic (NA) system, itself. We characterized plasticity of dopamine β-hydroxylase-immunoreactive NA fibers in the cerebellum of adolescent female rats that are evoked by voluntary wheel running, food restriction (FR) or by both, in combination. When 8 days of wheel access was combined with FR during the last 4 days, some responded with excessive exercise, choosing to run even during the hours of food access: this exacerbated weight loss beyond that due to FR alone. In the vermis, exercise, with or without FR, shortened the inter-varicosity intervals and increased varicosity density along NA fibers, while excessive exercise, due to FR, also shortened NA fibers. In contrast, the hemisphere required the FR-evoked excessive exercise to evoke shortened inter-varicosity intervals along NA fibers and this change was exhibited more strongly by rats that suppressed the FR-evoked excessive exercise, a behavior that minimized weight loss. Presuming that shortened inter-varicosity intervals translate to enhanced NA release and synthesis of norepinephrine, this enhancement in the cerebellar hemisphere may contribute towards protection of individuals from the life-threatening activity-based anorexia via relays with higher-order cortical areas that mediate the animal's decision to suppress the innate FR-evoked hyperactivity.

  11. Noradrenergic signaling in the medial prefrontal cortex and amygdala differentially regulates vicarious trial-and-error in a spatial decision-making task.

    PubMed

    Amemiya, Seiichiro; Kubota, Natsuko; Umeyama, Nao; Nishijima, Takeshi; Kita, Ichiro

    2016-01-15

    In uncertain choice situations, we deliberately search and evaluate possible options before taking an action. Once we form a preference regarding the current situation, we take an action more automatically and with less deliberation. In rats, the deliberation process can be seen in vicarious trial-and-error behavior (VTE), which is a head-orienting behavior toward options at a choice point. Recent neurophysiological findings suggest that VTE reflects the rat's thinking about future options as deliberation, expectation, and planning when rats feel conflict. VTE occurs depending on the demand: an increase occurs during initial learning, and a decrease occurs with progression in learning. However, the brain circuit underlying the regulation of VTE has not been thoroughly examined. In situations in which VTE often appears, the medial prefrontal cortex (mPFC) and the amygdala (AMY) are crucial for learning and decision making. Our previous study reported that noradrenaline regulates VTE. Here, to investigate whether the mPFC and AMY are involved in regulation of VTE, we examined the effects of local injection of clonidine, an alpha2 adrenergic autoreceptor agonist, into either region in rats during VTE and choice behavior during a T-maze choice task. Injection of clonidine into either region impaired selection of the advantageous choice in the task. Furthermore, clonidine injection into the mPFC suppressed occurrence of VTE in the early phase of the task, whereas injection into the AMY inhibited the decrease in VTE in the later phase and thus maintained a high level of VTE throughout the task. These results suggest that the mPFC and AMY play a role in the increase and decrease in VTE, respectively, and that noradrenergic mechanisms mediate the dynamic regulation of VTE over experiences. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Effects of atomoxetine on attention and impulsivity in the five-choice serial reaction time task in rats with lesions of dorsal noradrenergic ascending bundle.

    PubMed

    Liu, Yia-Ping; Huang, Teng-Shun; Tung, Che-Se; Lin, Chen-Cheng

    2015-01-02

    Atomoxetine, a noradrenaline reuptake inhibitor (NRI), which is a non-stimulating medicine that is used for the treatment of patients with attention deficit hyperactivity disorder (ADHD), has been found to be effective in reducing behavioral impulsivity in rodents, but its efficacy in a dorsal noradrenergic ascending bundle (DNAB)-lesioned condition has not been examined. The present study aimed to investigate the effects of DNAB lesions on attention and impulsive control in the five-choice serial reaction time task (5-CSRTT) in rats treated with atomoxetine. The drug-induced changes in noradrenaline efflux in the medial prefrontal cortex were also measured. 5-CSRTT-trained rats were included in one of the following groups: N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)/Atomoxetine, Sham/Atomoxetine, DSP-4/Saline, or Sham/Saline. Acute atomoxetine (0.3 mg/kg) was administered 14 days after the DSP-4 regime. The behavioral testing included manipulations of the inter-trial interval (ITI), stimulation duration and food satiety. In vivo microdialysis of the noradrenaline efflux in the medial prefrontal cortex and the expression of the noradrenaline transporter (NAT) in the DNAB areas were examined. Atomoxetine reduced impulsivity and perseveration in the long-ITI condition with no effects on any other variables. This phenomenon was not influenced by DSP-4 pre-treatment. The DNAB-lesioned rats had lower noradrenaline efflux in the medial prefrontal cortex. DSP-4 caused no change in NAT expression in the DNAB areas. These findings suggested that noradrenaline reuptake may not be exclusively responsible for the atomoxetine effects in adjusting impulsivity. The role of DNAB should also be considered, particularly in conditions requiring greater behavioral inhibition. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Effects of levomilnacipran ER on noradrenergic symptoms, anxiety symptoms, and functional impairment in adults with major depressive disorder: Post hoc analysis of 5 clinical trials.

    PubMed

    Blier, Pierre; Gommoll, Carl; Chen, Changzheng; Kramer, Kenneth

    2017-03-01

    To evaluate the effects of levomilnacipran extended-release (LVM-ER; 40-120mg/day) on noradrenergic (NA) and anxiety-related symptoms in adults with major depressive disorder (MDD) and explore the relationship between these symptoms and functional impairment. Data were pooled from 5 randomized, double-blind, placebo-controlled trials (N=2598). Anxiety and NA Cluster scores were developed by adding selected item scores from the Montgomery-Åsberg Depression Rating Scale (MADRS) and 17-item Hamilton Depression Rating Scale (HAMD 17 ). A path analysis was conducted to estimate the direct effects of LVM-ER on functional impairment (Sheehan Disability Scale [SDS] total score) and the indirect effects through changes in NA and Anxiety Cluster scores. Mean improvements from baseline in NA and Anxiety Cluster scores were significantly greater with LVM-ER versus placebo (both P<0.001), as were the response rates (≥50% score improvement): NA Cluster (44% vs 34%; odds ratio=1.56; P<0.0001); Anxiety Cluster (39% vs 36%; odds ratio=1.19; P=0.041). Mean improvement in SDS total score was also significantly greater with LVM-ER versus placebo (-7.3 vs -5.6; P<0.0001). LVM-ER had an indirect effect on change in SDS total score that was mediated more strongly through NA Cluster score change (86%) than Anxiety Cluster score change (18%); the direct effect was negligible. NA and Anxiety Cluster scores, developed based on the face validity of individual MADRS and HAMD 17 items, were not predefined as efficacy outcomes in any of the studies. In adults with MDD, LVM-ER indirectly improved functional impairment mainly through improvements in NA symptoms and less so via anxiety symptoms. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  14. Neuron-specific splicing.

    PubMed

    Hakim, Nor Hakimah Ab; Majlis, Burhanuddin Yeop; Suzuki, Hitoshi; Tsukahara, Toshifumi

    2017-03-22

    During pre-mRNA splicing events, introns are removed from the pre-mRNA, and the remaining exons are connected together to form a single continuous molecule. Alternative splicing is a common mechanism for the regulation of gene expression in eukaryotes. More than 90% of human genes are known to undergo alternative splicing. The most common type of alternative splicing is exon skipping, which is also known as cassette exon. Other known alternative splicing events include alternative 5' splice sites, alternative 3' splice sites, intron retention, and mutually exclusive exons. Alternative splicing events are controlled by regulatory proteins responsible for both positive and negative regulation. In this review, we focus on neuronal splicing regulators and discuss several notable regulators in depth. In addition, we have also included an example of splicing regulation mediated by the RBFox protein family. Lastly, as previous studies have shown that a number of splicing factors are associated with neuronal diseases such as Alzheime's disease (AD) and Autism spectrum disorder (ASD), here we consider their importance in neuronal diseases wherein the underlying mechanisms have yet to be elucidated.

  15. Blueberries and neuronal aging.

    PubMed

    Shukitt-Hale, Barbara

    2012-01-01

    As the population of people in the United States over the age of 65 years continues to increase, so too will the incidence of age-related pathologies, including decreases in cognitive and motor function. In cases of severe deficits in memory or motor function, hospitalization and/or custodial care would be a likely outcome. This means that unless some way is found to reduce these age-related decrements in neuronal function, health care costs will continue to rise exponentially. Evidence is accumulating that consumption of blueberries may be one strategy to forestall or even reverse age-related neuronal deficits, as well as their subsequent behavioral manifestations, in order to increase healthy aging. Research suggests that the polyphenolic compounds found in blueberries exert their beneficial effects either through their ability to lower oxidative stress and inflammation or directly by altering the signaling involved in neuronal communication. These interventions, in turn, may protect against age-related deficits in cognitive and motor function. Appropriately, the US Department of Agriculture has figured prominently in these discoveries, through the efforts of two USDA researchers who worked for the department 100 years apart. Copyright © 2012 S. Karger AG, Basel.

  16. Stress- and diet-induced fat gain is controlled by NPY in catecholaminergic neurons.

    PubMed

    Zhang, Lei; Lee, I-Chieh J; Enriquez, Rondaldo F; Lau, Jackie; Vähätalo, Laura H; Baldock, Paul A; Savontaus, Eriika; Herzog, Herbert

    2014-08-01

    Neuropeptide Y (NPY) and noradrenaline are commonly co-expressed in sympathetic neurons. Both are key regulators of energy homeostasis and critical for stress-coping. However, little is known about the specific function of NPY in the catecholaminergic system in these regulations. Here we show that mice with NPY expression only in the noradrenergic and adrenergic cells of the catecholaminergic system (catNPY) exhibited exacerbated diet-induced obesity, lower body and brown adipose tissue temperatures compared to WT and NPY(-/-) mice under a HFD. Furthermore, chronic stress increased adiposity and serum corticosterone level in WT but not NPY(-/-) mice. Re-introducing NPY specifically to the catecholaminergic system in catNPY mice restored stress responsiveness associated with increased respiratory exchange ratio and decreased liver pACC to tACC ratio. These results demonstrate catecholaminergic NPY signalling is critical in mediating diet- and chronic stress-induced fat gain via effects on diet-induced thermogenesis and stress-induced increases in corticosterone levels and lipogenic capacity.

  17. Stress- and diet-induced fat gain is controlled by NPY in catecholaminergic neurons

    PubMed Central

    Zhang, Lei; Lee, I-Chieh J.; Enriquez, Rondaldo F.; Lau, Jackie; Vähätalo, Laura H.; Baldock, Paul A.; Savontaus, Eriika; Herzog, Herbert

    2014-01-01

    Neuropeptide Y (NPY) and noradrenaline are commonly co-expressed in sympathetic neurons. Both are key regulators of energy homeostasis and critical for stress-coping. However, little is known about the specific function of NPY in the catecholaminergic system in these regulations. Here we show that mice with NPY expression only in the noradrenergic and adrenergic cells of the catecholaminergic system (catNPY) exhibited exacerbated diet-induced obesity, lower body and brown adipose tissue temperatures compared to WT and NPY−/− mice under a HFD. Furthermore, chronic stress increased adiposity and serum corticosterone level in WT but not NPY−/− mice. Re-introducing NPY specifically to the catecholaminergic system in catNPY mice restored stress responsiveness associated with increased respiratory exchange ratio and decreased liver pACC to tACC ratio. These results demonstrate catecholaminergic NPY signalling is critical in mediating diet- and chronic stress-induced fat gain via effects on diet-induced thermogenesis and stress-induced increases in corticosterone levels and lipogenic capacity. PMID:25061562

  18. Norepinephrine alters the expression of genes involved in neuronal sprouting and differentiation: relevance for major depression and antidepressant mechanisms.

    PubMed

    Laifenfeld, Daphna; Klein, Ehud; Ben-Shachar, Dorit

    2002-12-01

    Recent research into depression has focused on the involvement of long-term intracellular processes, leading to abnormal neuronal plasticity in brains of depressed patients, and reversed by antidepressant treatment. Given a suggested decrease in noradrenergic transmission in depression, and an antidepressant induced increase in norepinephrine (NE) level, a possible role for NE in mediating alterations in neuronal morphology and plasticity was examined. Human neuroblastoma SH-SY5Y cells treated with 10-5 m NE presented an elongated granule-rich cell-body and increased number of neurites, when compared with non-treated cells. Moreover, cell survival was enhanced in the presence of NE, while proliferation was inhibited. The above effects suggest a role for NE in cell differentiation. Indeed similar effects on cell survival and neurite outgrowth were induced in SH-SY5Y cells by retinoic acid (RA), an established differentiating agent. Finally, NE treatment resulted in a progressive decrease in the pluripotent marker Oct4 and an increase in the neuronal growth cone marker, growth-associated-protein 43 (GAP-43). Alongside these effects, NE-treated cells presented alterations in the expression of 44 genes as observed in a neurobiology cDNA microarray. Among the altered genes, an increase in the expression level of two neurite-outgrowth promoting genes, neural cell adhesion molecule L1 and laminin, was confirmed by RT-PCR. Taken together, the results support a role for NE in processes of synaptic connectivity, and may point to a role for this neurotransmitter in mediating the suggested neuronal plasticity in depression and in antidepressant treatment.

  19. Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus

    PubMed Central

    Hernández, Vivian M.; Hegeman, Daniel J.; Cui, Qiaoling; Kelver, Daniel A.; Fiske, Michael P.; Glajch, Kelly E.; Pitt, Jason E.; Huang, Tina Y.; Justice, Nicholas J.

    2015-01-01

    Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. SIGNIFICANCE STATEMENT Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping

  20. Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus.

    PubMed

    Hernández, Vivian M; Hegeman, Daniel J; Cui, Qiaoling; Kelver, Daniel A; Fiske, Michael P; Glajch, Kelly E; Pitt, Jason E; Huang, Tina Y; Justice, Nicholas J; Chan, C Savio

    2015-08-26

    Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping expression of the

  1. NEURONAL MECHANISMS OF VISUAL STABILITY

    PubMed Central

    Wurtz, Robert H.

    2008-01-01

    Human vision is stable and continuous in spite of the incessant interruptions produced by saccadic eye movements. These rapid eye movements serve vision by directing the high resolution fovea rapidly from one part of the visual scene to another. They should detract from vision because they generate two major problems: displacement of the retinal image with each saccade and blurring of the image during the saccade. This review considers the substantial advances in understanding the neuronal mechanisms underlying this visual stability derived primarily from neuronal recording and inactivation studies in the monkey, an excellent model for systems in the human brain. For the first problem, saccadic displacement, two neuronal candidates are salient. First are the neurons in frontal and parietal cortex with shifting receptive fields that provide anticipatory activity with each saccade and are driven by a corollary discharge. These could provide the mechanism for a retinotopic hypothesis of visual stability and possibly for a transsaccadic memory hypothesis, The second neuronal mechanism is provided by neurons whose visual response is modulated by eye position (gain field neurons) or are largely independent of eye position (real position neurons), and these neurons could provide the basis for a spatiotopic hypothesis. For the second problem, saccadic suppression, visual masking and corollary discharge are well established mechanisms, and possible neuronal correlates have been identified for each. PMID:18513781

  2. In vivo observation of a non-noradrenergic regulation of arylalkylamine N-acetyltransferase gene expression in the rat pineal complex.

    PubMed

    Garidou, M L; Bartol, I; Calgari, C; Pévet, P; Simonneaux, V

    2001-01-01

    The rodent pineal gland is the end point of several peripheral and central fibers innervating the superficial and deep parts of the gland. Up to now, only the sympathetic transmitter norepinephrine is thought to regulate melatonin synthesis, although numerous biochemical experiments have reported in vitro effects of various transmitters on melatonin synthesis. To find out whether there is non-noradrenergic regulation of in vivo pineal metabolism, the mRNA encoding the enzyme arylalkylamine N-acetyltransferase was studied using the highly sensitive technique of in situ hybridization. The existence of a marked nocturnal increase of arylalkylamine N-acetyltransferase mRNA in the superficial pineal gland was confirmed. Interestingly and for the first time, a similar daily variation was observed in the deep pineal. After removal of superior cervical ganglia, the daily rhythm in arylalkylamine N-acetyltransferase mRNA was abolished in both the superficial and deep pineal indicating that the rhythm is driven by sympathetic input in the entire pineal complex. Interestingly, the remaining arylalkylamine N-acetyltransferase mRNA level in the pineal of day- and night-time ganglionectomized rats was significantly higher than in the pineal of day-time intact animals. These data reveal a sympathetic-dependent day-time inhibition of arylalkylamine N-acetyltransferase gene expression. In addition, the day-time pineal arylalkylamine N-acetyltransferase mRNA expression in ganglionectomized rats persisted after adrenal gland removal but was reduced by 50% after propranolol injection. These results indicate that arylalkylamine N-acetyltransferase mRNA in ganglionectomized rats is not induced by circulating catecholamines and may be caused by both a centrally originated norepinephrine, as already suggested, and other non-adrenergic transmitter(s). In conclusion, this work shows that norepinephrine drives the nocturnal increase of arylalkylamine N-acetyltransferase gene expression both

  3. Light deprivation damages monoamine neurons and produces a depressive behavioral phenotype in rats.

    PubMed

    Gonzalez, M M C; Aston-Jones, G

    2008-03-25

    Light is an important environmental factor for regulation of mood. There is a high frequency of seasonal affective disorder in high latitudes where light exposure is limited, and bright light therapy is a successful antidepressant treatment. We recently showed that rats kept for 6 weeks in constant darkness (DD) have anatomical and behavioral features similar to depressed patients, including dysregulation of circadian sleep-waking rhythms and impairment of the noradrenergic (NA)-locus coeruleus (LC) system. Here, we analyzed the cell viability of neural systems related to the pathophysiology of depression after DD, including NA-LC, serotoninergic-raphe nuclei and dopaminergic-ventral tegmental area neurons, and evaluated the depressive behavioral profile of light-deprived rats. We found increased apoptosis in the three aminergic systems analyzed when compared with animals maintained for 6 weeks in 12:12 light-dark conditions. The most apoptosis was observed in NA-LC neurons, associated with a significant decrease in the number of cortical NA boutons. Behaviorally, DD induced a depression-like condition as measured by increased immobility in a forced swim test (FST). DD did not appear to be stressful (no effect on adrenal or body weights) but may have sensitized responses to subsequent stressors (increased fecal number during the FST). We also found that the antidepressant desipramine decreases these neural and behavioral effects of light deprivation. These findings indicate that DD induces neural damage in monoamine brain systems and this damage is associated with a depressive behavioral phenotype. Our results suggest a mechanism whereby prolonged limited light intensity could negatively impact mood.

  4. Is realistic neuronal modeling realistic?

    PubMed Central

    Almog, Mara

    2016-01-01

    Scientific models are abstractions that aim to explain natural phenomena. A successful model shows how a complex phenomenon arises from relatively simple principles while preserving major physical or biological rules and predicting novel experiments. A model should not be a facsimile of reality; it is an aid for understanding it. Contrary to this basic premise, with the 21st century has come a surge in computational efforts to model biological processes in great detail. Here we discuss the oxymoronic, realistic modeling of single neurons. This rapidly advancing field is driven by the discovery that some neurons don't merely sum their inputs and fire if the sum exceeds some threshold. Thus researchers have asked what are the computational abilities of single neurons and attempted to give answers using realistic models. We briefly review the state of the art of compartmental modeling highlighting recent progress and intrinsic flaws. We then attempt to address two fundamental questions. Practically, can we realistically model single neurons? Philosophically, should we realistically model single neurons? We use layer 5 neocortical pyramidal neurons as a test case to examine these issues. We subject three publically available models of layer 5 pyramidal neurons to three simple computational challenges. Based on their performance and a partial survey of published models, we conclude that current compartmental models are ad hoc, unrealistic models functioning poorly once they are stretched beyond the specific problems for which they were designed. We then attempt to plot possible paths for generating realistic single neuron models. PMID:27535372

  5. The Neuronal Ceroid-Lipofuscinoses

    ERIC Educational Resources Information Center

    Bennett, Michael J.; Rakheja, Dinesh

    2013-01-01

    The neuronal ceroid-lipofuscinoses (NCL's, Batten disease) represent a group of severe neurodegenerative diseases, which mostly present in childhood. The phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in…

  6. Neuronal avalanches and coherence potentials

    NASA Astrophysics Data System (ADS)

    Plenz, D.

    2012-05-01

    The mammalian cortex consists of a vast network of weakly interacting excitable cells called neurons. Neurons must synchronize their activities in order to trigger activity in neighboring neurons. Moreover, interactions must be carefully regulated to remain weak (but not too weak) such that cascades of active neuronal groups avoid explosive growth yet allow for activity propagation over long-distances. Such a balance is robustly realized for neuronal avalanches, which are defined as cortical activity cascades that follow precise power laws. In experiments, scale-invariant neuronal avalanche dynamics have been observed during spontaneous cortical activity in isolated preparations in vitro as well as in the ongoing cortical activity of awake animals and in humans. Theory, models, and experiments suggest that neuronal avalanches are the signature of brain function near criticality at which the cortex optimally responds to inputs and maximizes its information capacity. Importantly, avalanche dynamics allow for the emergence of a subset of avalanches, the coherence potentials. They emerge when the synchronization of a local neuronal group exceeds a local threshold, at which the system spawns replicas of the local group activity at distant network sites. The functional importance of coherence potentials will be discussed in the context of propagating structures, such as gliders in balanced cellular automata. Gliders constitute local population dynamics that replicate in space after a finite number of generations and are thought to provide cellular automata with universal computation. Avalanches and coherence potentials are proposed to constitute a modern framework of cortical synchronization dynamics that underlies brain function.

  7. Synchronization by elastic neuronal latencies.

    PubMed

    Vardi, Roni; Timor, Reut; Marom, Shimon; Abeles, Moshe; Kanter, Ido

    2013-01-01

    Psychological and physiological considerations entail that formation and functionality of neuronal cell assemblies depend upon synchronized repeated activation such as zero-lag synchronization. Several mechanisms for the emergence of this phenomenon have been suggested, including the global network quantity, the greatest common divisor of neuronal circuit delay loops. However, they require strict biological prerequisites such as precisely matched delays and connectivity, and synchronization is represented as a stationary mode of activity instead of a transient phenomenon. Here we show that the unavoidable increase in neuronal response latency to ongoing stimulation serves as a nonuniform gradual stretching of neuronal circuit delay loops. This apparent nuisance is revealed to be an essential mechanism in various types of neuronal time controllers, where synchronization emerges as a transient phenomenon and without predefined precisely matched synaptic delays. These findings are described in an experimental procedure where conditioned stimulations were enforced on a circuit of neurons embedded within a large-scale network of cortical cells in vitro, and are corroborated and extended by simulations of circuits composed of Hodgkin-Huxley neurons with time-dependent latencies. These findings announce a cortical time scale for time controllers based on tens of microseconds stretching of neuronal circuit delay loops per spike. They call for a reexamination of the role of the temporal periodic mode in brain functionality using advanced in vitro and in vivo experiments.

  8. Noradrenaline Modulates the Membrane Potential and Holding Current of Medial Prefrontal Cortex Pyramidal Neurons via β1-Adrenergic Receptors and HCN Channels

    PubMed Central

    Grzelka, Katarzyna; Kurowski, Przemysław; Gawlak, Maciej; Szulczyk, Paweł

    2017-01-01

    The medial prefrontal cortex (mPFC) receives dense noradrenergic projections from the locus coeruleus. Adrenergic innervation of mPFC pyramidal neurons plays an essential role in both physiology (control of memory formation, attention, working memory, and cognitive behavior) and pathophysiology (attention deficit hyperactivity disorder, posttraumatic stress disorder, cognitive deterioration after traumatic brain injury, behavioral changes related to addiction, Alzheimer’s disease and depression). The aim of this study was to elucidate the mechanism responsible for adrenergic receptor-mediated control of the resting membrane potential in layer V mPFC pyramidal neurons. The membrane potential or holding current of synaptically isolated layer V mPFC pyramidal neurons was recorded in perforated-patch and classical whole-cell configurations in slices from young rats. Application of noradrenaline (NA), a neurotransmitter with affinity for all types of adrenergic receptors, evoked depolarization or inward current in the tested neurons irrespective of whether the recordings were performed in the perforated-patch or classical whole-cell configuration. The effect of noradrenaline depended on β1- and not α1- or α2-adrenergic receptor stimulation. Activation of β1-adrenergic receptors led to an increase in inward Na+ current through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which carry a mixed Na+/K+ current. The protein kinase A- and C-, glycogen synthase kinase-3β- and tyrosine kinase-linked signaling pathways were not involved in the signal transduction between β1-adrenergic receptors and HCN channels. The transduction system operated in a membrane-delimited fashion and involved the βγ subunit of G-protein. Thus, noradrenaline controls the resting membrane potential and holding current in mPFC pyramidal neurons through β1-adrenergic receptors, which in turn activate HCN channels via a signaling pathway involving the βγ subunit. PMID

  9. Consciousness from neurons.

    PubMed

    Doty, R W

    1975-01-01

    Consciousness derives from a neural process that requires unceasing metabolic support, and probably involves only a select population of neocortical elements. The essential process must operate for roughly more than 100 ms for sensorial registration (Libet). It is highly unlikely that the essence of the process lies in its computational logic and hence it can never be produced by inanimate machines. Since the process is thus unique to neurons, and since the consciousness of the left hemisphere normally communicates with that of the right (and probably vice versa) via the forebrain cornmissures, at least some portion of the nerve impulse traffic across the commissures must possess a wholly mysterious property enabling its transcendent compilation into a unified conscious experience. Comprehending the nature of this property which couples ionic fluxions into mentality is the quintessential problem of science. The forebrain commissures may ultimately provide the clues for its solution.

  10. [Neurons and values].

    PubMed

    Camps, Victoria

    2013-09-01

    This article examines the advances made by neuroscience in the attempt to find an answer to the question regarding the origin and foundation of moral judgements and of human behaviour in compliance with them. The conception of the brain as something dynamic and capable of adapting to the social and cultural surroundings is seen to be an important point for philosophy. At the same time, the complexity of ethical issues that cannot be reduced to observations based strictly on neurons alone also becomes quite apparent. Nevertheless, scientists and philosophers should get together and communicate with one another so as to be able to pose their questions with greater rigour and take advantage of each other's respective knowledge.

  11. Motor neurone disease

    PubMed Central

    Talbot, K

    2002-01-01

    Motor neurone disease (MND), or amyotrophic lateral sclerosis (ALS), is a neurodegenerative disorder of unknown aetiology. Progressive motor weakness and bulbar dysfunction lead to premature death, usually from respiratory failure. Confirming the diagnosis may initially be difficult until the full clinical features are manifest. For all forms of the disease there is a significant differential diagnosis to consider, including treatable conditions, and therefore specialist neurological opinion should always be sought. Clear genetic inheritance has been demonstrated in a minority of patients with familial ALS but elucidation of the biological basis of genetic subtypes is also providing important information which may lead to treatments for sporadic forms of the disease. In the absence of curative or disease modifying therapy, management is supportive and requires a multidisciplinary approach. If, as seems likely, complex inherited and environmental factors contribute to the pathogenesis of MND, future treatment may involve a combination of molecular based treatments or restoration of cellular integrity using stem cell grafts. PMID:12357010

  12. Neuron's function revealed

    SciTech Connect

    None

    2009-01-01

    There's a new way to explore biologys secrets. With a flash of light, scientists from the U.S. Department of Energys Lawrence Berkeley National Laboratory and the University of California, Berkeley zeroed in on the type of neural cell that controls swimming in larval zebrafish. Using innovative light-activated proteins and gene expression techniques, the scientists zapped several zebrafish with a pulse of light, and initiated a swimming action in a subset of fish that was traced back to the type of neuron that drives the side-to-side motion of their tail fins. The technique behind this needle-in-haystack search for the neural rootsmore » of a specific behavior could become a powerful way to learn how any biological system works. http://newscenter.lbl.gov/press-releases/2009/09/16/light-activated-protein/« less

  13. Orexin Neurons Receive Glycinergic Innervations

    PubMed Central

    Watanabe, Masahiko; Sakurai, Takeshi

    2011-01-01

    Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM) sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2)-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation. PMID:21949857

  14. Postmitotic Specification of Drosophila Insulinergic Neurons from Pioneer Neurons

    PubMed Central

    Miguel-Aliaga, Irene; Thor, Stefan; Gould, Alex P

    2008-01-01

    Insulin and related peptides play important and conserved functions in growth and metabolism. Although Drosophila has proved useful for the genetic analysis of insulin functions, little is known about the transcription factors and cell lineages involved in insulin production. Within the embryonic central nervous system, the MP2 neuroblast divides once to generate a dMP2 neuron that initially functions as a pioneer, guiding the axons of other later-born embryonic neurons. Later during development, dMP2 neurons in anterior segments undergo apoptosis but their posterior counterparts persist. We show here that surviving posterior dMP2 neurons no longer function in axonal scaffolding but differentiate into neuroendocrine cells that express insulin-like peptide 7 (Ilp7) and innervate the hindgut. We find that the postmitotic transition from pioneer to insulin-producing neuron is a multistep process requiring retrograde bone morphogenetic protein (BMP) signalling and four transcription factors: Abdominal-B, Hb9, Fork Head, and Dimmed. These five inputs contribute in a partially overlapping manner to combinatorial codes for dMP2 apoptosis, survival, and insulinergic differentiation. Ectopic reconstitution of this code is sufficient to activate Ilp7 expression in other postmitotic neurons. These studies reveal striking similarities between the transcription factors regulating insulin expression in insect neurons and mammalian pancreatic β-cells. PMID:18336071

  15. Object detecting neurons in Drosophila

    PubMed Central

    Keleş, Mehmet F.; Frye, Mark A.

    2017-01-01

    SUMMARY Many animals rely on vision to detect objects such as conspecifics, predators, and prey. Hypercomplex cells found in feline cortex and small target motion detectors found in dragonfly and hoverfly optic lobes demonstrate robust tuning for small objects with weak or no response to larger objects or movement of the visual panorama [1–3]. However, the relationship between anatomical, molecular, and functional properties of object detection circuitry is not understood. Here, we characterize a specialized object detector in Drosophila, the lobula columnar neuron LC11 [4]. By imaging calcium dynamics with two-photon excitation microscopy we show that LC11 responds to the omni-directional movement of a small object darker than the background, with little or no responses to static flicker, vertically elongated bars, or panoramic gratings. LC11 dendrites innervate multiple layers of the lobula, and each dendrite spans enough columns to sample 75-degrees of visual space, yet the area that evokes calcium responses is only 20-degrees wide, and shows robust responses to a 2.2-degree object spanning less than half of one facet of the compound eye. The dendrites of neighboring LC11s encode object motion retinotopically, but the axon terminals fuse into a glomerular structure in the central brain where retinotopy is lost. Blocking inhibitory ionic currents abolishes small object sensitivity and facilitates responses to elongated bars and gratings. Our results reveal high acuity object motion detection in the Drosophila optic lobe. PMID:28190726

  16. Shaping the Output of Lumbar Flexor Motoneurons by Sacral Neuronal Networks.

    PubMed

    Cherniak, Meir; Anglister, Lili; Lev-Tov, Aharon

    2017-02-01

    The ability to improve motor function in spinal cord injury patients by reactivating spinal central pattern generators (CPGs) requires the elucidation of neurons and pathways involved in activation and modulation of spinal networks in accessible experimental models. Previously we reported on adrenoceptor-dependent sacral control of lumbar flexor motoneuron firing in newborn rats. The current work focuses on clarification of the circuitry and connectivity involved in this unique modulation and its potential use. Using surgical manipulations of the spinal gray and white matter, electrophysiological recordings, and confocal microscopy mapping, we found that methoxamine (METH) activation of sacral networks within the ventral aspect of S2 segments was sufficient to produce alternating rhythmic bursting (0.15-1 Hz) in lumbar flexor motoneurons. This lumbar rhythm depended on continuity of the ventral funiculus (VF) along the S2-L2 segments. Interrupting the VF abolished the rhythm and replaced it by slow unstable bursting. Calcium imaging of S1-S2 neurons, back-labeled via the VF, revealed that ∼40% responded to METH, mostly by rhythmic firing. All uncrossed projecting METH responders and ∼70% of crossed projecting METH responders fired with the concurrent ipsilateral motor output, while the rest (∼30%) fired with the contralateral motor output. We suggest that METH-activated sacral CPGs excite ventral clusters of sacral VF neurons to deliver the ascending drive required for direct rhythmic activation of lumbar flexor motoneurons. The capacity of noradrenergic-activated sacral CPGs to modulate the activity of lumbar networks via sacral VF neurons provides a novel way to recruit rostral lumbar motoneurons and modulate the output required to execute various motor behaviors. Spinal central pattern generators (CPGs) produce the rhythmic output required for coordinating stepping and stabilizing the body axis during movements. Electrical stimulation and exogenous drugs

  17. Angiotensin II AT1 receptors mediate neuronal sensitization and sustained blood pressure response induced by a single injection of amphetamine.

    PubMed

    Marchese, N A; Paz, M C; Caeiro, X; Dadam, F M; Baiardi, G; Perez, M F; Bregonzio, C

    2017-01-06

    A single exposure to amphetamine induces neurochemical sensitization in striatal areas. The neuropeptide angiotensin II, through AT 1 receptors (AT 1 -R) activation, is involved in these responses. However, amphetamine-induced alterations can be extended to extra-striatal areas involved in blood pressure control and their physiological outcomes. Our aim for the present study was to analyze the possible role for AT 1 -R in these events using a two-injection protocol and to further characterize the proposed AT 1 -R antagonism protocol. Central effect of orally administered AT 1 -R blocker (Candesartan, 3mg/kg p.o.×5days) in male Wistar rats was analyzed by spontaneous activity of neurons within locus coeruleus. In another group of animals pretreated with the AT 1 -R blocker or vehicle, sensitization was achieved by a single administration of amphetamine (5mg/kg i.p. - day 6) followed by a 3-week period off drug. On day 27, after receiving an amphetamine challenge (0.5mg/kg i.p.), we evaluated: (1) the sensitized c-Fos expression in locus coeruleus (LC), nucleus of the solitary tract (NTS), caudal ventrolateral medulla (A1) and central amygdala (CeAmy); and (2) the blood pressure response. AT 1 -R blockade decreased LC neurons' spontaneous firing rate. Moreover, sensitized c-Fos immunoreactivity in TH+neurons was found in LC and NTS; and both responses were blunted by the AT 1 -R blocker pretreatment. Meanwhile, no differences were found neither in CeAmy nor A1. Sensitized blood pressure response was observed as sustained changes in mean arterial pressure and was effectively prevented by AT 1 -R blockade. Our results extend AT 1 -R role in amphetamine-induced sensitization over noradrenergic nuclei and their cardiovascular output. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Stochastic models of neuronal dynamics.

    PubMed

    Harrison, L M; David, O; Friston, K J

    2005-05-29

    Cortical activity is the product of interactions among neuronal populations. Macroscopic electrophysiological phenomena are generated by these interactions. In principle, the mechanisms of these interactions afford constraints on biologically plausible models of electrophysiological responses. In other words, the macroscopic features of cortical activity can be modelled in terms of the microscopic behaviour of neurons. An evoked response potential (ERP) is the mean electrical potential measured from an electrode on the scalp, in response to some event. The purpose of this paper is to outline a population density approach to modelling ERPs. We propose a biologically plausible model of neuronal activity that enables the estimation of physiologically meaningful parameters from electrophysiological data. The model encompasses four basic characteristics of neuronal activity and organization: (i) neurons are dynamic units, (ii) driven by stochastic forces, (iii) organized into populations with similar biophysical properties and response characteristics and (iv) multiple populations interact to form functional networks. This leads to a formulation of population dynamics in terms of the Fokker-Planck equation. The solution of this equation is the temporal evolution of a probability density over state-space, representing the distribution of an ensemble of trajectories. Each trajectory corresponds to the changing state of a neuron. Measurements can be modelled by taking expectations over this density, e.g. mean membrane potential, firing rate or energy consumption per neuron. The key motivation behind our approach is that ERPs represent an average response over many neurons. This means it is sufficient to model the probability density over neurons, because this implicitly models their average state. Although the dynamics of each neuron can be highly stochastic, the dynamics of the density is not. This means we can use Bayesian inference and estimation tools that have already

  19. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

    PubMed

    Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

    2017-03-01

    The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers

  20. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases

    PubMed Central

    Kaifer, Kevin A.; Osman, Erkan Y.; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L.

    2017-01-01

    The term “motor neuron disease” encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic

  1. Towards Automatic Classification of Neurons

    PubMed Central

    Armañanzas, Rubén; Ascoli, Giorgio A.

    2015-01-01

    The classification of neurons into types has been much debated since the inception of modern neuroscience. Recent experimental advances are accelerating the pace of data collection. The resulting information growth of morphological, physiological, and molecular properties encourages efforts to automate neuronal classification by powerful machine learning techniques. We review state-of-the-art analysis approaches and availability of suitable data and resources, highlighting prominent challenges and opportunities. The effective solution of the neuronal classification problem will require continuous development of computational methods, high-throughput data production, and systematic metadata organization to enable cross-lab integration. PMID:25765323

  2. Evidence of involvement of neurone-glia/neurone-neurone communications via gap junctions in synchronised activity of KNDy neurones.

    PubMed

    Ikegami, K; Minabe, S; Ieda, N; Goto, T; Sugimoto, A; Nakamura, S; Inoue, N; Oishi, S; Maturana, A D; Sanbo, M; Hirabayashi, M; Maeda, K-I; Tsukamura, H; Uenoyama, Y

    2017-06-01

    Pulsatile secretion of gonadotrophin-releasing hormone (GnRH)/luteinising hormone is indispensable for the onset of puberty and reproductive activities at adulthood in mammalian species. A cohort of neurones expressing three neuropeptides, namely kisspeptin, encoded by the Kiss1 gene, neurokinin B (NKB) and dynorphin A, localised in the hypothalamic arcuate nucleus (ARC), so-called KNDy neurones, comprises a putative intrinsic source of the GnRH pulse generator. Synchronous activity among KNDy neurones is considered to be required for pulsatile GnRH secretion. It has been reported that gap junctions play a key role in synchronising electrical activity in the central nervous system. Thus, we hypothesised that gap junctions are involved in the synchronised activities of KNDy neurones, which is induced by NKB-NK3R signalling. We determined the role of NKB-NK3R signalling in Ca 2+ oscillation (an indicator of neuronal activities) of KNDy neurones and its synchronisation mechanism among KNDy neurones. Senktide, a selective agonist for NK3R, increased the frequency of Ca 2+ oscillations in cultured Kiss1-GFP cells collected from the mediobasal hypothalamus of the foetal Kiss1-green fluorescent protein (GFP) mice. The senktide-induced Ca 2+ oscillations were synchronised in the Kiss1-GFP and neighbouring glial cells. Confocal microscopy analysis of these cells, which have shown synchronised Ca 2+ oscillations, revealed close contacts between Kiss1-GFP cells, as well as between Kiss1-GFP cells and glial cells. Dye coupling experiments suggest cell-to-cell communication through gap junctions between Kiss1-GFP cells and neighbouring glial cells. Connexin-26 and -37 mRNA were found in isolated ARC Kiss1 cells taken from adult female Kiss1-GFP transgenic mice. Furthermore, 18β-glycyrrhetinic acids and mefloquine, which are gap junction inhibitors, attenuated senktide-induced Ca 2+ oscillations in Kiss1-GFP cells. Taken together, these results suggest that NKB-NK3R signalling

  3. A fish on the hunt, observed neuron by neuron

    SciTech Connect

    None

    2010-01-01

    This three-dimensional microscopy image reveals an output neuron of the optic tectum lighting up in response to visual information from the retina. The scientists used this state-of-the-art imaging technology to learn how neurons in the optic tectum take visual information and convert it into an output that drives action. More information: http://newscenter.lbl.gov/feature-stories/2010/10/29/zebrafish-vision/

  4. Power gain exhibited by motile mechanosensory neurons in Drosophila ears

    NASA Astrophysics Data System (ADS)

    Göpfert, M. C.; Humphris, A. D. L.; Albert, J. T.; Robert, D.; Hendrich, O.

    2005-01-01

    In insects and vertebrates alike, hearing is assisted by the motility of mechanosensory cells. Much like pushing a swing augments its swing, this cellular motility is thought to actively augment vibrations inside the ear, thus amplifying the ear's mechanical input. Power gain is the hallmark of such active amplification, yet whether and how much energy motile mechanosensory cells contribute within intact auditory systems has remained uncertain. Here, we assess the mechanical energy provided by motile mechanosensory neurons in the antennal hearing organs of Drosophila melanogaster by analyzing the fluctuations of the sound receiver to which these neurons connect. By using dead WT flies and live mutants (tilB2, btv5P1, and nompA2) with defective neurons as a background, we show that the intact, motile neurons do exhibit power gain. In WT flies, the neurons lift the receiver's mean total energy by 19 zJ, which corresponds to 4.6 times the energy of the receiver's Brownian motion. Larger energy contributions (200 zJ) associate with self-sustained oscillations, suggesting that the neurons adjust their energy expenditure to optimize the receiver's sensitivity to sound. We conclude that motile mechanosensory cells provide active amplification; in Drosophila, mechanical energy contributed by these cells boosts the vibrations that enter the ear. cochlear amplifier | hearing | auditory mechanics | cell mobility | hair cell

  5. Power gain exhibited by motile mechanosensory neurons in Drosophila ears

    PubMed Central

    Göpfert, M. C.; Humphris, A. D. L.; Albert, J. T.; Robert, D.; Hendrich, O.

    2005-01-01

    In insects and vertebrates alike, hearing is assisted by the motility of mechanosensory cells. Much like pushing a swing augments its swing, this cellular motility is thought to actively augment vibrations inside the ear, thus amplifying the ear's mechanical input. Power gain is the hallmark of such active amplification, yet whether and how much energy motile mechanosensory cells contribute within intact auditory systems has remained uncertain. Here, we assess the mechanical energy provided by motile mechanosensory neurons in the antennal hearing organs of Drosophila melanogaster by analyzing the fluctuations of the sound receiver to which these neurons connect. By using dead WT flies and live mutants (tilB2, btv5P1, and nompA2) with defective neurons as a background, we show that the intact, motile neurons do exhibit power gain. In WT flies, the neurons lift the receiver's mean total energy by 19 zJ, which corresponds to 4.6 times the energy of the receiver's Brownian motion. Larger energy contributions (200 zJ) associate with self-sustained oscillations, suggesting that the neurons adjust their energy expenditure to optimize the receiver's sensitivity to sound. We conclude that motile mechanosensory cells provide active amplification; in Drosophila, mechanical energy contributed by these cells boosts the vibrations that enter the ear. PMID:15623551

  6. Tinbergen on mirror neurons

    PubMed Central

    Heyes, Cecilia

    2014-01-01

    Fifty years ago, Niko Tinbergen defined the scope of behavioural biology with his four problems: causation, ontogeny, survival value and evolution. About 20 years ago, there was another highly significant development in behavioural biology—the discovery of mirror neurons (MNs). Here, I use Tinbergen's original four problems (rather than the list that appears in textbooks) to highlight the differences between two prominent accounts of MNs, the genetic and associative accounts; to suggest that the latter provides the defeasible ‘best explanation’ for current data on the causation and ontogeny of MNs; and to argue that functional analysis, of the kind that Tinbergen identified somewhat misleadingly with studies of ‘survival value’, should be a high priority for future research. In this kind of functional analysis, system-level theories would assign MNs a small, but potentially important, role in the achievement of action understanding—or another social cognitive function—by a production line of interacting component processes. These theories would be tested by experimental intervention in human and non-human animal samples with carefully documented and controlled developmental histories. PMID:24778376

  7. Tinbergen on mirror neurons.

    PubMed

    Heyes, Cecilia

    2014-01-01

    Fifty years ago, Niko Tinbergen defined the scope of behavioural biology with his four problems: causation, ontogeny, survival value and evolution. About 20 years ago, there was another highly significant development in behavioural biology-the discovery of mirror neurons (MNs). Here, I use Tinbergen's original four problems (rather than the list that appears in textbooks) to highlight the differences between two prominent accounts of MNs, the genetic and associative accounts; to suggest that the latter provides the defeasible 'best explanation' for current data on the causation and ontogeny of MNs; and to argue that functional analysis, of the kind that Tinbergen identified somewhat misleadingly with studies of 'survival value', should be a high priority for future research. In this kind of functional analysis, system-level theories would assign MNs a small, but potentially important, role in the achievement of action understanding-or another social cognitive function-by a production line of interacting component processes. These theories would be tested by experimental intervention in human and non-human animal samples with carefully documented and controlled developmental histories.

  8. Neuronal boost to evolutionary dynamics

    PubMed Central

    de Vladar, Harold P.; Szathmáry, Eörs

    2015-01-01

    Standard evolutionary dynamics is limited by the constraints of the genetic system. A central message of evolutionary neurodynamics is that evolutionary dynamics in the brain can happen in a neuronal niche in real time, despite the fact that neurons do not reproduce. We show that Hebbian learning and structural synaptic plasticity broaden the capacity for informational replication and guided variability provided a neuronally plausible mechanism of replication is in place. The synergy between learning and selection is more efficient than the equivalent search by mutation selection. We also consider asymmetric landscapes and show that the learning weights become correlated with the fitness gradient. That is, the neuronal complexes learn the local properties of the fitness landscape, resulting in the generation of variability directed towards the direction of fitness increase, as if mutations in a genetic pool were drawn such that they would increase reproductive success. Evolution might thus be more efficient within evolved brains than among organisms out in the wild. PMID:26640653

  9. Noradrenergic β-receptor antagonism in the basolateral amygdala impairs reconsolidation, but not extinction, of alcohol self-administration: Intra-BLA propranolol impairs reconsolidation of alcohol self-administration.

    PubMed

    Chesworth, Rose; Corbit, Laura H

    2018-04-09

    A critical barrier to recovery from alcohol addiction is relapse propensity. Alcohol cues can trigger relapse, and pharmacologically facilitating processes such as extinction, which decreases cue associations, may help prevent relapse. The noradrenergic system mediates extinction learning for alcohol; however, the neural locus of this effect is unknown. This study sought to determine whether the basolateral amygdala (BLA), a region critical for fear extinction, also mediates extinction of alcohol seeking. Hooded Wistar rats (N = 12-15 per experiment) were implanted with bilateral cannula targeting the BLA and trained to lever press for 10% ethanol during auditory or visual cues. Infusions of the β-receptor antagonist propranolol (2 µg/side) were administered prior to extinction (Experiment 1), and rats assessed for relapse-like behaviour two weeks later, thus allowing for spontaneous recovery. We expected intra-BLA propranolol to impair extinction learning; however, propranolol-treated rats exhibited reduced responding in the test of spontaneous recovery, suggesting enhanced extinction. We investigated this unexpected result by determining if propranolol treatment affected memory processes other than extinction. In a subsequent experiment, rats were infused with propranolol immediately after extinction to target consolidation of extinction (Experiment 2a), and assessed for spontaneous recovery. Propranolol was also infused after self-administration to target reconsolidation of the original learning (Experiment 2b). Propranolol treatment had no effect on consolidation of extinction learning, but impaired reconsolidation of self-administration. Propranolol administered prior to a self-administration session did not affect reinforced responding (Experiment 2c). Extinction and reconsolidation are opposing processes triggered by specific test conditions. We suggest our test conditions induced reconsolidation of self-administration memory by propranolol, rather

  10. 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.

  11. Long latency of evoked quantal transmitter release from somata of locus coeruleus neurons in rat pontine slices

    PubMed Central

    Huang, H.-P.; Wang, S.-R.; Yao, W.; Zhang, C.; Zhou, Y.; Chen, X.-W.; Zhang, B.; Xiong, W.; Wang, L.-Y.; Zheng, L.-H.; Landry, M.; Hökfelt, T.; Xu, Z.-Q. D.; Zhou, Z.

    2007-01-01

    The locus coeruleus (LC) harbors a compact group of noradrenergic cell bodies projecting to virtually all parts of the central nervous system. By using combined measurements of amperometry and patch-clamp, quantal vesicle release of noradrenaline (NA) was detected as amperometric spikes, after depolarization of the LC neurons. After a pulse depolarization, the average latency of amperometric spikes was 1,870 ms, whereas the latency of glutamate-mediated excitatory postsynaptic currents was 1.6 ms. A substantial fraction of the depolarization-induced amperometric spikes originated from the somata. In contrast to glutamate-mediated excitatory postsynaptic currents, NA secretion was strongly modulated by the action potential frequency (0.5–50 Hz). Somatodendritic NA release from LC upon enhanced cell activity produced autoinhibition of firing and of NA release. We conclude that, in contrast to classic synaptic transmission, quantal NA release from LC somata is characterized by a number of distinct properties, including long latency and high sensitivity to action potential frequency. PMID:17227848

  12. Exposure to Advertisement Calls of Reproductive Competitors Activates Vocal-Acoustic and Catecholaminergic Neurons in the Plainfin Midshipman Fish, Porichthys notatus

    PubMed Central

    Petersen, Christopher L.; Timothy, Miky; Kim, D. Spencer; Bhandiwad, Ashwin A.; Mohr, Robert A.; Sisneros, Joseph A.; Forlano, Paul M.

    2013-01-01

    While the neural circuitry and physiology of the auditory system is well studied among vertebrates, far less is known about how the auditory system interacts with other neural substrates to mediate behavioral responses to social acoustic signals. One species that has been the subject of intensive neuroethological investigation with regard to the production and perception of social acoustic signals is the plainfin midshipman fish, Porichthys notatus, in part because acoustic communication is essential to their reproductive behavior. Nesting male midshipman vocally court females by producing a long duration advertisement call. Females localize males by their advertisement call, spawn and deposit all their eggs in their mate’s nest. As multiple courting males establish nests in close proximity to one another, the perception of another male’s call may modulate individual calling behavior in competition for females. We tested the hypothesis that nesting males exposed to advertisement calls of other males would show elevated neural activity in auditory and vocal-acoustic brain centers as well as differential activation of catecholaminergic neurons compared to males exposed only to ambient noise. Experimental brains were then double labeled by immunofluorescence (-ir) for tyrosine hydroxylase (TH), an enzyme necessary for catecholamine synthesis, and cFos, an immediate-early gene product used as a marker for neural activation. Males exposed to other advertisement calls showed a significantly greater percentage of TH-ir cells colocalized with cFos-ir in the noradrenergic locus coeruleus and the dopaminergic periventricular posterior tuberculum, as well as increased numbers of cFos-ir neurons in several levels of the auditory and vocal-acoustic pathway. Increased activation of catecholaminergic neurons may serve to coordinate appropriate behavioral responses to male competitors. Additionally, these results implicate a role for specific catecholaminergic neuronal groups

  13. (-)Deprenyl and (-)1-phenyl-2-propylaminopentane, [(-)PPAP], act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons.

    PubMed

    Knoll, J; Miklya, I; Knoll, B; Markó, R; Kelemen, K

    1996-01-01

    The activity of the catecholaminergic neurons in the rat brain is enhanced significantly 30 min after the subcutaneous injection of very small doses of (-)deprenyl (threshold doses: 0.01 mg/kg for noradrenergic neurons and 0.025 mg/kg for dopaminergic neurons). As a catecholaminergic activity enhancer (CAE) substance (-)deprenyl is about ten times more potent than its parent compound, (-)methamphetamine. While the (+)methamphetamine is 3-5 times more potent than (-)methamphetammine in releasing catecholamines, the (-)methamphetamine is the more potent CAE substance. The mechanism of the CAE effect of (-)deprenyl and (-)PPAP, a deprenyl-derived substance devoid of MAO inhibitory potency, was studied in rats by measuring: a) the release of catecholamines from striatum, substantia nigra, tuberculum olfactorium and locus coeruleus; b) the stimulation induced release of 3H-noradrenaline from the isolated brain stem; and c) the antagonistic effect against tetrabenazine-induced depression of learning in the shuttle box. The CAE effect was found to be unrelated: a) to the inhibition of MAO activity; b) to the inhibition of presynaptic catecholamine receptors; c) to the inhibition of the uptake of catecholamines; and d) to the release of catecholamines. It was concluded that (-)deprenyl and (-)PPAP act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons of the brain. We show that both (-)deprenyl and (-)PPAP enhance the inward Ca2+ current in sino-auricular fibers of the frog heart. (-)PPAP was much more potent than either (+)PPAP or (-)deprenyl in this test.

  14. Exposure to advertisement calls of reproductive competitors activates vocal-acoustic and catecholaminergic neurons in the plainfin midshipman fish, Porichthys notatus.

    PubMed

    Petersen, Christopher L; Timothy, Miky; Kim, D Spencer; Bhandiwad, Ashwin A; Mohr, Robert A; Sisneros, Joseph A; Forlano, Paul M

    2013-01-01

    While the neural circuitry and physiology of the auditory system is well studied among vertebrates, far less is known about how the auditory system interacts with other neural substrates to mediate behavioral responses to social acoustic signals. One species that has been the subject of intensive neuroethological investigation with regard to the production and perception of social acoustic signals is the plainfin midshipman fish, Porichthys notatus, in part because acoustic communication is essential to their reproductive behavior. Nesting male midshipman vocally court females by producing a long duration advertisement call. Females localize males by their advertisement call, spawn and deposit all their eggs in their mate's nest. As multiple courting males establish nests in close proximity to one another, the perception of another male's call may modulate individual calling behavior in competition for females. We tested the hypothesis that nesting males exposed to advertisement calls of other males would show elevated neural activity in auditory and vocal-acoustic brain centers as well as differential activation of catecholaminergic neurons compared to males exposed only to ambient noise. Experimental brains were then double labeled by immunofluorescence (-ir) for tyrosine hydroxylase (TH), an enzyme necessary for catecholamine synthesis, and cFos, an immediate-early gene product used as a marker for neural activation. Males exposed to other advertisement calls showed a significantly greater percentage of TH-ir cells colocalized with cFos-ir in the noradrenergic locus coeruleus and the dopaminergic periventricular posterior tuberculum, as well as increased numbers of cFos-ir neurons in several levels of the auditory and vocal-acoustic pathway. Increased activation of catecholaminergic neurons may serve to coordinate appropriate behavioral responses to male competitors. Additionally, these results implicate a role for specific catecholaminergic neuronal groups in

  15. Dendritic architecture of the von Economo neurons.

    PubMed

    Watson, K K; Jones, T K; Allman, J M

    2006-09-01

    The von Economo neurons are one of the few known specializations to hominoid cortical microcircuitry. Here, using a Golgi preparation of a human postmortem brain, we describe the dendritic architecture of this unique population of neurons. We have found that, in contrast to layer 5 pyramidal neurons, the von Economo neurons have sparse dendritic trees and symmetric apical and basal components. This result provides the first detailed anatomical description of a neuron type unique to great apes and humans.

  16. Mitochondria, motor neurons and aging.

    PubMed

    García, M L; Fernández, A; Solas, M T

    2013-07-15

    While the role of mitochondria in aging has been well characterized, their involvement in motor neuron aging remains poorly understood. Thus, we performed an exhaustive ultrastructural study of mitochondria in motor neurons from aged rats that revealed dramatic alterations in the mitochondria of axon terminals at neuromuscular junctions, characterized by swelling, mitochondrial fusion and the presence of megamitochondria. These alterations were not observed in ventral horn motor neurons in the spinal cord of aged rats, which were only altered by the appearance of electron-dense bodies in the dilated matrix cristae. Using X-ray microanalytical techniques we demonstrated the presence of calcium in these bodies, suggesting Ca(2+) overload. Moreover, in motor neurons from aged rats, cytochrome c and activated caspase 3 were detected in the cytoplasm of axon terminals at neuromuscular junctions, factors implicated in the apoptosis. Active caspase 3 was also found in the nucleus, soma and axons of aged alpha motor neuron neurons, where it mainly associated with microtubules. The colocalization of dynein and cleaved caspase 3 in neuromuscular junctions is strongly suggestive of the retrograde transport of apoptotic factors to the soma. These results are consistent with the early stages of degeneration in neuromuscular junctions during aging, which is followed by dying back. Given that aging is a key risk factor for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), the identification of age-related motor neuron degeneration initiated at the distal end of the axon may provide a new therapeutic target for early intervention. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Neuronal SUMOylation: Mechanisms, Physiology, and Roles in Neuronal Dysfunction

    PubMed Central

    Henley, Jeremy M.; Craig, Tim J.; Wilkinson, Kevin A.

    2014-01-01

    Protein SUMOylation is a critically important posttranslational protein modification that participates in nearly all aspects of cellular physiology. In the nearly 20 years since its discovery, SUMOylation has emerged as a major regulator of nuclear function, and more recently, it has become clear that SUMOylation has key roles in the regulation of protein trafficking and function outside of the nucleus. In neurons, SUMOylation participates in cellular processes ranging from neuronal differentiation and control of synapse formation to regulation of synaptic transmission and cell survival. It is a highly dynamic and usually transient modification that enhances or hinders interactions between proteins, and its consequences are extremely diverse. Hundreds of different proteins are SUMO substrates, and dysfunction of protein SUMOylation is implicated in a many different diseases. Here we briefly outline core aspects of the SUMO system and provide a detailed overview of the current understanding of the roles of SUMOylation in healthy and diseased neurons. PMID:25287864

  18. Stochastic phase-change neurons.

    PubMed

    Tuma, Tomas; Pantazi, Angeliki; Le Gallo, Manuel; Sebastian, Abu; Eleftheriou, Evangelos

    2016-08-01

    Artificial neuromorphic systems based on populations of spiking neurons are an indispensable tool in understanding the human brain and in constructing neuromimetic computational systems. To reach areal and power efficiencies comparable to those seen in biological systems, electroionics-based and phase-change-based memristive devices have been explored as nanoscale counterparts of synapses. However, progress on scalable realizations of neurons has so far been limited. Here, we show that chalcogenide-based phase-change materials can be used to create an artificial neuron in which the membrane potential is represented by the phase configuration of the nanoscale phase-change device. By exploiting the physics of reversible amorphous-to-crystal phase transitions, we show that the temporal integration of postsynaptic potentials can be achieved on a nanosecond timescale. Moreover, we show that this is inherently stochastic because of the melt-quench-induced reconfiguration of the atomic structure occurring when the neuron is reset. We demonstrate the use of these phase-change neurons, and their populations, in the detection of temporal correlations in parallel data streams and in sub-Nyquist representation of high-bandwidth signals.

  19. More questions for mirror neurons.

    PubMed

    Borg, Emma

    2013-09-01

    The mirror neuron system is widely held to provide direct access to the motor goals of others. This paper critically investigates this idea, focusing on the so-called 'intentional worry'. I explore two answers to the intentional worry: first that the worry is premised on too limited an understanding of mirror neuron behaviour (Sections 2 and 3), second that the appeal made to mirror neurons can be refined in such a way as to avoid the worry (Section 4). I argue that the first response requires an account of the mechanism by which small-scale gestures are supposedly mapped to larger chains of actions but that none of the extant accounts of this mechanism are plausible. Section 4 then briefly examines refinements of the mirror neuron-mindreading hypothesis which avoid the intentional worry. I conclude that these refinements may well be plausible but that they undermine many of the claims standardly made for mirror neurons. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Brain Neurons as Quantum Computers:

    NASA Astrophysics Data System (ADS)

    Bershadskii, A.; Dremencov, E.; Bershadskii, J.; Yadid, G.

    The question: whether quantum coherent states can sustain decoherence, heating and dissipation over time scales comparable to the dynamical timescales of brain neurons, has been actively discussed in the last years. A positive answer on this question is crucial, in particular, for consideration of brain neurons as quantum computers. This discussion was mainly based on theoretical arguments. In the present paper nonlinear statistical properties of the Ventral Tegmental Area (VTA) of genetically depressive limbic brain are studied in vivo on the Flinders Sensitive Line of rats (FSL). VTA plays a key role in the generation of pleasure and in the development of psychological drug addiction. We found that the FSL VTA (dopaminergic) neuron signals exhibit multifractal properties for interspike frequencies on the scales where healthy VTA dopaminergic neurons exhibit bursting activity. For high moments the observed multifractal (generalized dimensions) spectrum coincides with the generalized dimensions spectrum calculated for a spectral measure of a quantum system (so-called kicked Harper model, actively used as a model of quantum chaos). This observation can be considered as a first experimental (in vivo) indication in the favor of the quantum (at least partially) nature of brain neurons activity.

  1. Neuronal factors determining high intelligence.

    PubMed

    Dicke, Ursula; Roth, Gerhard

    2016-01-05

    Many attempts have been made to correlate degrees of both animal and human intelligence with brain properties. With respect to mammals, a much-discussed trait concerns absolute and relative brain size, either uncorrected or corrected for body size. However, the correlation of both with degrees of intelligence yields large inconsistencies, because although they are regarded as the most intelligent mammals, monkeys and apes, including humans, have neither the absolutely nor the relatively largest brains. The best fit between brain traits and degrees of intelligence among mammals is reached by a combination of the number of cortical neurons, neuron packing density, interneuronal distance and axonal conduction velocity--factors that determine general information processing capacity (IPC), as reflected by general intelligence. The highest IPC is found in humans, followed by the great apes, Old World and New World monkeys. The IPC of cetaceans and elephants is much lower because of a thin cortex, low neuron packing density and low axonal conduction velocity. By contrast, corvid and psittacid birds have very small and densely packed pallial neurons and relatively many neurons, which, despite very small brain volumes, might explain their high intelligence. The evolution of a syntactical and grammatical language in humans most probably has served as an additional intelligence amplifier, which may have happened in songbirds and psittacids in a convergent manner. © 2015 The Author(s).

  2. Neuronal factors determining high intelligence

    PubMed Central

    Dicke, Ursula; Roth, Gerhard

    2016-01-01

    Many attempts have been made to correlate degrees of both animal and human intelligence with brain properties. With respect to mammals, a much-discussed trait concerns absolute and relative brain size, either uncorrected or corrected for body size. However, the correlation of both with degrees of intelligence yields large inconsistencies, because although they are regarded as the most intelligent mammals, monkeys and apes, including humans, have neither the absolutely nor the relatively largest brains. The best fit between brain traits and degrees of intelligence among mammals is reached by a combination of the number of cortical neurons, neuron packing density, interneuronal distance and axonal conduction velocity—factors that determine general information processing capacity (IPC), as reflected by general intelligence. The highest IPC is found in humans, followed by the great apes, Old World and New World monkeys. The IPC of cetaceans and elephants is much lower because of a thin cortex, low neuron packing density and low axonal conduction velocity. By contrast, corvid and psittacid birds have very small and densely packed pallial neurons and relatively many neurons, which, despite very small brain volumes, might explain their high intelligence. The evolution of a syntactical and grammatical language in humans most probably has served as an additional intelligence amplifier, which may have happened in songbirds and psittacids in a convergent manner. PMID:26598734

  3. Towards a Neuronal Gauge Theory

    PubMed Central

    Sengupta, Biswa; Tozzi, Arturo; Cooray, Gerald K.; Douglas, Pamela K.; Friston, Karl J.

    2016-01-01

    Given the amount of knowledge and data accruing in the neurosciences, is it time to formulate a general principle for neuronal dynamics that holds at evolutionary, developmental, and perceptual timescales? In this paper, we propose that the brain (and other self-organised biological systems) can be characterised via the mathematical apparatus of a gauge theory. The picture that emerges from this approach suggests that any biological system (from a neuron to an organism) can be cast as resolving uncertainty about its external milieu, either by changing its internal states or its relationship to the environment. Using formal arguments, we show that a gauge theory for neuronal dynamics—based on approximate Bayesian inference—has the potential to shed new light on phenomena that have thus far eluded a formal description, such as attention and the link between action and perception. PMID:26953636

  4. Neuronal oscillations in Parkinson's disease.

    PubMed

    Witcher, Mark; Moran, Rosalyn; Tatter, Stephen B; Laxton, Adrian W

    2014-06-01

    Parkinson's Disease (PD), characterized by tremor, rigidity, and bradykinesia, is one of the most prevalent neurodegenerative disorders in the world. The pathological hallmark of PD is the loss of dopaminergic cells in the substantia nigra and other brain regions. The pathophysiological mechanisms by which dopaminergic cell loss leads to the motor manifestations of PD are yet to be fully elucidated. A growing body of evidence has revealed abnormal neuronal oscillations within and between multiple brain regions in PD. Unique oscillatory patterns are associated with specific motor abnormalities in PD. Therapies, such as dopaminergic medication and deep brain stimulation that disrupt these abnormal neuronal oscillatory patterns produce symptomatic improvement in PD patients. These findings emphasize the importance of abnormal neuronal oscillations in the pathophysiology of PD, making the disruption of these oscillatory patterns a promising target in the development of effective PD treatments.

  5. Changes in chemical coding of sympathetic chain ganglia (SChG) neurons supplying porcine urinary bladder after botulinum toxin (BTX) treatment.

    PubMed

    Lepiarczyk, E; Bossowska, A; Majewski, M

    2015-05-01

    Botulinum toxin (BTX) is a neurotoxin used in medicine as an effective drug in experimental therapy of neurogenic urinary bladder disorders. We have investigated the influence of BTX on the chemical coding of sympathetic chain ganglia (SChG) neurons supplying the porcine urinary bladder. The toxin was injected into the wall of the bladder. SChG neurons were visualized by a retrograde tracing method with fluorescent tracer fast blue (FB) and their chemical coding was investigated by double-labelling immunohistochemistry with antibodies against dopamine β-hydroxylase (DβH; a marker of noradrenergic neurons), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), galanin (GAL), Leu(5)-enkephalin (L-ENK) and neuronal nitric oxide synthase (nNOS). In both the control (n = 5) and BTX-treated pigs (n = 5), the vast majority (91 ± 2.3 % and 89.8 ± 2.5 %, respectively) of FB-positive (FB+) nerve cells were DβH+. BTX injections caused a decrease in the number of FB+/DβH+ neurons that were immunopositive to NPY (39.5 ± 4.5 % vs 74.5 ± 11.9 %), VIP (8.9 ± 5.3 % vs 22.3 ± 8.8 %), SOM (5.8 ± 2.3 % vs 17.4 ± 3.7 %) or GAL (0.9 ± 1.2 % vs 5.4 ± 4.4 %) and a distinct increase in the number of FB+/DβH+ neurons that were immunoreactive to L-ENK (3.7 ± 2.9 % vs 1.1 % ± 0.8 %) or nNOS (7.7 ± 3.5 % vs 0.8 ± 0.6 %). Our study provides novel evidence that the therapeutic effects of BTX on the mammalian urinary bladder are partly mediated by SChG neurons.

  6. Calcium signals in olfactory neurons.

    PubMed

    Tareilus, E; Noé, J; Breer, H

    1995-11-09

    Laser scanning confocal microscopy in combination with the fluorescent calcium indicators Fluo-3 and Fura-Red was employed to estimate the intracellular concentration of free calcium ions in individual olfactory receptor neurons and to monitor temporal and spatial changes in the Ca(2+)-level upon stimulation. The chemosensory cells responded to odorants with a significant increase in the calcium concentration, preferentially in the dendritic knob. Applying various stimulation paradigma, it was found that in a population of isolated cells, subsets of receptor neurons display distinct patterns of responsiveness.

  7. Neuronal Transcriptome of Aplysia: Neuronal Compartments and Circuitry

    PubMed Central

    Moroz, Leonid L.; Edwards, John R.; Puthanveettil, Sathyanarayanan V.; Kohn, Andrea B.; Ha, Thomas; Heyland, Andreas; Knudsen, Bjarne; Sahni, Anuj; Yu, Fahong; Liu, Li; Jezzini, Sami; Lovell, Peter; Iannucculli, William; Chen, Minchen; Nguyen, Tuan; Sheng, Huitao; Shaw, Regina; Kalachikov, Sergey; Panchin, Yuri V.; Farmerie, William; Russo, James J.; Ju, Jingyue; Kandel, Eric R.

    2014-01-01

    SUMMARY Molecular analyses of Aplysia, a well-established model organism for cellular and systems neural science, have been seriously handicapped by a lack of adequate genomic information. By sequencing cDNA libraries from the central nervous system (CNS), we have identified over 175,000 expressed sequence tags (ESTs), of which 19,814 are unique neuronal gene products and represent 50%–70% of the total Aplysia neuronal transcriptome. We have characterized the transcriptome at three levels: (1) the central nervous system, (2) the elementary components of a simple behavior: the gill-withdrawal reflex—by analyzing sensory, motor, and serotonergic modulatory neurons, and (3) processes of individual neurons. In addition to increasing the amount of available gene sequences of Aplysia by two orders of magnitude, this collection represents the largest database available for any member of the Lophotrochozoa and therefore provides additional insights into evolutionary strategies used by this highly successful diversified lineage, one of the three proposed super-clades of bilateral animals. PMID:17190607

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

    PubMed

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

    2015-08-01

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

  9. [What mirror neurons have revealed: revisited].

    PubMed

    Murata, Akira; Maeda, Kazutaka

    2014-06-01

    The first paper on mirror neurons was published in 1992. In the span of over two decades since then, much knowledge about the relationship between social cognitive function and the motor control system has been accumulated. Direct matching of visual actions and their corresponding motor representations is the most important functional property of mirror neuron. Many studies have emphasized intrinsic simulation as a core concept for mirror neurons. Mirror neurons are thought to play a role in social cognitive function. However, the function of mirror neurons in the macaque remains unclear, because such cognitive functions are limited or lacking in macaque monkeys. It is therefore important to discuss these neurons in the context of motor function. Rizzolatti and colleagues have stressed that the most important function of mirror neurons in macaques is recognition of actions performed by other individuals. I suggest that mirror neurons in the Macaque inferior pariental lobule might be correlated with body schema. In the parieto-premotor network, matching of corollary discharge and actual sensory feedback is an essential neuronal operation. Recently, neurons showing mirror properties were found in some cortical areas outside the mirror neuron system. The current work would revisit the outcomes of mirror neuron studies to discuss the function of mirror neurons in the monkey.

  10. Slow waves in mutually inhibitory neuronal networks

    NASA Astrophysics Data System (ADS)

    Jalics, Jozsi

    2004-05-01

    A variety of experimental and modeling studies have been performed to investigate wave propagation in networks of thalamic neurons and their relationship to spindle sleep rhythms. It is believed that spindle oscillations result from the reciprocal interaction between thalamocortical (TC) and thalamic reticular (RE) neurons. We consider a network of TC and RE cells reduced to a one-layer network model and represented by a system of singularly perturbed integral-differential equations. Geometric singular perturbation methods are used to prove the existence of a locally unique slow wave pulse that propagates along the network. By seeking a slow pulse solution, we reformulate the problem to finding a heteroclinic orbit in a 3D system of ODEs with two additional constraints on the location of the orbit at two distinct points in time. In proving the persistence of the singular heteroclinic orbit, difficulties arising from the solution passing near points where normal hyperbolicity is lost on a 2D critical manifold are overcome by employing results by Wechselberger [Singularly perturbed folds and canards in R3, Thesis, TU-Wien, 1998].

  11. [Nucleotide receptors in learning and neuronal plasticity].

    PubMed

    Czajkowski, Rafał

    2014-01-01

    Nucleotide signalling plays an important role in neuronal plasticity and learning. Nucleotides are released at the synaptic terminals and may act pre- and postsynaptically by activating Pland P2 receptors. The A1 receptor, activated tonically by resting concentration of adenosine regulates basal neurotransmission. The A2A receptor is activated by increased adenosine levels and participates in plastic changes. ATP may act as an independent neurotransmitter on the P2X1 receptor, or via P2X3 subtype as a neuromodulator that affects NMDA receptor signalling. The G protein coupled P2Y receptors also evoke neuromodulatory effect on the neuronal plasticity, inhibiting LTD in prefrontal cortex. P2X7 receptor is responsible for communication between astrocytes and for synchronizing their activity. ATP and adenosine released by astrocytes act as neuromodulators both at the release site and heterosynaptically. Taken together, these multiple actions of nucleotides constitute a mechanism regulating homeostatic processes that are necessary for proper brain functioning: synaptic scaling and metaplasticity.

  12. GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex.

    PubMed

    Kaushal, R; Taylor, B K; Jamal, A B; Zhang, L; Ma, F; Donahue, R; Westlund, K N

    2016-10-15

    Trigeminal neuropathic pain is described as constant excruciating facial pain. The study goal was to investigate the role of nucleus locus coeruleus (LC) in a model of chronic orofacial neuropathic pain (CCI-ION). The study examines LC's relationship to both the medullary dorsal horn receiving trigeminal nerve sensory innervation and the medial prefrontal cortex (mPFC). LC is a major source of CNS noradrenaline (NA) and a primary nucleus involved in pain modulation. Although descending inhibition of acute pain by LC is well established, contribution of the LC to facilitation of chronic neuropathic pain is also reported. In the present study, a rat orofacial pain model of trigeminal neuropathy was induced by chronic constrictive injury of the infraorbital nerve (CCI-ION). Orofacial neuropathic pain was indicated by development of whisker pad mechanical hypersensitivity. Hypersensitivity was alleviated by selective elimination of NA neurons, including LC (A6 cell group), with the neurotoxin anti-dopamine-β-hydroxylase saporin (anti-DβH-saporin) microinjected either intracerebroventricularly (i.c.v.) or into trigeminal spinal nucleus caudalis (spVc). The GABA A receptor antagonist, bicuculline, administered directly into LC (week 8) inhibited hypersensitivity. This indicates a valence shift in which increased GABA A signaling ongoing in LC after trigeminal nerve injury paradoxically produces excitatory facilitation of the chronic pain state. Microinjection of NAα1 receptor antagonist, benoxathian, into mPFC attenuated whisker pad hypersensitivity, while NAα2 receptor antagonist, idazoxan, was ineffective. Thus, GABA A -mediated activation of NA neurons during CCI-ION can facilitate hypersensitivity through NAα1 receptors in the mPFC. These data indicate LC is a chronic pain generator. Published by Elsevier Ltd.

  13. Bifurcating neuron: computation and learning.

    PubMed

    Lysetskiy, Mykola; Zurada, Jacek M

    2004-03-01

    The ability of bifurcating processing units and their networks to rapidly switch between different dynamic modes has been used in recent research efforts to model new computational properties of neural systems. In this spirit, we devise a bifurcating neuron based on control of chaos collapsing to a period-3 orbit in the dynamics of a quadratic logistic map (QLM). Proposed QLM3 neuron is constructed with the third iterate of QLM and uses an external input, which governs its dynamics. The input shifts the neuron's dynamics from chaos to one of the stable fixed points. This way the inputs from certain ranges (clusters) are mapped to stable fixed points, while the rest of the inputs is mapped to chaotic or periodic output dynamics. It has been shown that QLM3 neuron is able to learn a specific mapping by adaptively adjusting its bifurcation parameter, the idea of which is based on the principles of parametric control of logistic maps [Proceedings of the International Symposium on Nonlinear Theory and its Applications (NOLTA'97), Honolulu, HI, 1997; Proceedings of SPIE, 2000]. Learning algorithm for the bifurcation parameter is proposed, which employs the error gradient descent method.

  14. Biomechanics of Single Cortical Neurons

    PubMed Central

    Bernick, Kristin B.; Prevost, Thibault P.; Suresh, Subra; Socrate, Simona

    2011-01-01

    This study presents experimental results and computational analysis of the large strain dynamic behavior of single neurons in vitro with the objective of formulating a novel quantitative framework for the biomechanics of cortical neurons. Relying on the atomic force microscopy (AFM) technique, novel testing protocols are developed to enable the characterization of neural soma deformability over a range of indentation rates spanning three orders of magnitude – 10, 1, and 0.1 μm/s. Modified spherical AFM probes were utilized to compress the cell bodies of neonatal rat cortical neurons in load, unload, reload and relaxation conditions. The cell response showed marked hysteretic features, strong non-linearities, and substantial time/rate dependencies. The rheological data were complemented with geometrical measurements of cell body morphology, i.e. cross-diameter and height estimates. A constitutive model, validated by the present experiments, is proposed to quantify the mechanical behavior of cortical neurons. The model aimed to correlate empirical findings with measurable degrees of (hyper-) elastic resilience and viscosity at the cell level. The proposed formulation, predicated upon previous constitutive model developments undertaken at the cortical tissue level, was implemented into a three-dimensional finite element framework. The simulated cell response was calibrated to the experimental measurements under the selected test conditions, providing a novel single cell model that could form the basis for further refinements. PMID:20971217

  15. Biomechanics of single cortical neurons.

    PubMed

    Bernick, Kristin B; Prevost, Thibault P; Suresh, Subra; Socrate, Simona

    2011-03-01

    This study presents experimental results and computational analysis of the large strain dynamic behavior of single neurons in vitro with the objective of formulating a novel quantitative framework for the biomechanics of cortical neurons. Relying on the atomic force microscopy (AFM) technique, novel testing protocols are developed to enable the characterization of neural soma deformability over a range of indentation rates spanning three orders of magnitude, 10, 1, and 0.1 μm s(-1). Modified spherical AFM probes were utilized to compress the cell bodies of neonatal rat cortical neurons in load, unload, reload and relaxation conditions. The cell response showed marked hysteretic features, strong non-linearities, and substantial time/rate dependencies. The rheological data were complemented with geometrical measurements of cell body morphology, i.e. cross-diameter and height estimates. A constitutive model, validated by the present experiments, is proposed to quantify the mechanical behavior of cortical neurons. The model aimed to correlate empirical findings with measurable degrees of (hyper)elastic resilience and viscosity at the cell level. The proposed formulation, predicated upon previous constitutive model developments undertaken at the cortical tissue level, was implemented in a three-dimensional finite element framework. The simulated cell response was calibrated to the experimental measurements under the selected test conditions, providing a novel single cell model that could form the basis for further refinements. Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  16. Optimal compensation for neuron loss

    PubMed Central

    Barrett, David GT; Denève, Sophie; Machens, Christian K

    2016-01-01

    The brain has an impressive ability to withstand neural damage. Diseases that kill neurons can go unnoticed for years, and incomplete brain lesions or silencing of neurons often fail to produce any behavioral effect. How does the brain compensate for such damage, and what are the limits of this compensation? We propose that neural circuits instantly compensate for neuron loss, thereby preserving their function as much as possible. We show that this compensation can explain changes in tuning curves induced by neuron silencing across a variety of systems, including the primary visual cortex. We find that compensatory mechanisms can be implemented through the dynamics of networks with a tight balance of excitation and inhibition, without requiring synaptic plasticity. The limits of this compensatory mechanism are reached when excitation and inhibition become unbalanced, thereby demarcating a recovery boundary, where signal representation fails and where diseases may become symptomatic. DOI: http://dx.doi.org/10.7554/eLife.12454.001 PMID:27935480

  17. Optical control of neuronal growth

    NASA Astrophysics Data System (ADS)

    Koch, Daniel; Betz, Timo; Ehrlicher, Allen; Gogler, Michael; Stuhrmann, Bjorn; Kas, Josef

    2004-10-01

    Understanding and controlling neuronal growth are basic objectives in neuroscience, biology, biophysics, and biomedicine, and are vital for the formation of neural circuits in vitro, as well as for nerve regeneration in vivo. All molecular stimuli for neuronal growth eventually address the polymeric cytoskeleton, which advances a neurite's leading edge also known as the growth cone. We have shown that optical forces of a highly focused infrared laser beam influence the motility of a growth cone by biasing the polymerization-driven intracellular machinery. In actively extending growth cones, a laser spot placed at specific areas of the neurite's leading edge affects the growth speed, the direction taken by a growth cone, and the splitting of a growth cone. This novel optical tool manipulates a natural biological process, the cytoskeleton driven morphological changes in growth cones, with potential applications in the formation of neuronal networks and in understanding growth cone motility. The current apparatus combines optical tweezers, phase contrast and fluorescence imaging, and real-time shape detection. Automated and dynamically readjusted irradiation of the growth cone is used to examine and to influence structural and morphological changes of neuronal growth.

  18. Analgesic Effects of Bee Venom Derived Phospholipase A(2) in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain.

    PubMed

    Li, Dongxing; Lee, Younju; Kim, Woojin; Lee, Kyungjin; Bae, Hyunsu; Kim, Sun Kwang

    2015-06-29

    A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A2 (bvPLA2) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA2, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA2-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA2 treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system.

  19. Anion transport mechanisms in neurons.

    PubMed

    Russell, J M

    1980-01-01

    Evidence has been presented and reviewed to show that chloride is often not in electrochemical equilibrium across neuronal cell membranes. An ATP- and sodium-dependent uptake mechanism has been described for the squid giant axon. Finally, the role of chloride in the maintenance of pH1 has been discussed. Present evidence favors a net chloride extrusion being involved in the acid extrusion process. Measurements of free, ionized chloride levels in several neuronal cells have suggested that the transmembrane distribution of chloride does not conform to thermodynamic equilibrium conditions. Net extrusion of Cl- against its electrochemical gradient has been measured in the giant neuron of the Aplysia abdominal ganglion. In the squid giant axon, cellular Cl- levels are higher than predicted from passive thermodynamic considerations. An ATP requirement as well as a dependence upon extracellular sodium has been demonstrated for chloride influx. Similarly, there is an ATP-, external Cl-dependent, Na+ influx. Thus, an ATP-requiring Na-Cl cotransport mechanism appears to account for the high cellular chloride content of the squid giant axon. Chloride efflux from several neurons appears to be involved in the regulation of intracellular pH (pHI). When pHi is made acidic, chloride efflux from the squid giant axon increases and this stimulation requires cellular ATP and external HCO3-. When pHi is measured following an acid load, it is found that pHi recovery toward normal values requires cellular Cl-, ATP and external HCO3-. Thus, an exchange process between cellular Cl- and extracellular HCO3- appears to play an important role in pH1 regulation. Such a process appears to be responsible for the lower-than-equilibrium levels of chloride found in certain neuronal cells.

  20. Spiking neuron network Helmholtz machine

    PubMed Central

    Sountsov, Pavel; Miller, Paul

    2015-01-01

    An increasing amount of behavioral and neurophysiological data suggests that the brain performs optimal (or near-optimal) probabilistic inference and learning during perception and other tasks. Although many machine learning algorithms exist that perform inference and learning in an optimal way, the complete description of how one of those algorithms (or a novel algorithm) can be implemented in the brain is currently incomplete. There have been many proposed solutions that address how neurons can perform optimal inference but the question of how synaptic plasticity can implement optimal learning is rarely addressed. This paper aims to unify the two fields of probabilistic inference and synaptic plasticity by using a neuronal network of realistic model spiking neurons to implement a well-studied computational model called the Helmholtz Machine. The Helmholtz Machine is amenable to neural implementation as the algorithm it uses to learn its parameters, called the wake-sleep algorithm, uses a local delta learning rule. Our spiking-neuron network implements both the delta rule and a small example of a Helmholtz machine. This neuronal network can learn an internal model of continuous-valued training data sets without supervision. The network can also perform inference on the learned internal models. We show how various biophysical features of the neural implementation constrain the parameters of the wake-sleep algorithm, such as the duration of the wake and sleep phases of learning and the minimal sample duration. We examine the deviations from optimal performance and tie them to the properties of the synaptic plasticity rule. PMID:25954191

  1. Neuronal migration on laminin in vitro.

    PubMed

    Liang, S; Crutcher, K A

    1992-03-20

    Chick sympathetic (E-9) or telencephalic (E-7) neurons were cultured at low density on poly-DL-ornithine (PORN), poly-L-lysine (POLS), laminin or laminin-covered PORN or POLS and monitored with time-lapse videomicroscopy. Neurons migrated on laminin, or laminin-covered PORN or POLS, but not on PORN or POLS alone. Neuronal migration did not involve interactions with other cells indicating that neurons are capable of independent migration when exposed to a laminin substrate.

  2. BlastNeuron for Automated Comparison, Retrieval and Clustering of 3D Neuron Morphologies.

    PubMed

    Wan, Yinan; Long, Fuhui; Qu, Lei; Xiao, Hang; Hawrylycz, Michael; Myers, Eugene W; Peng, Hanchuan

    2015-10-01

    Characterizing the identity and types of neurons in the brain, as well as their associated function, requires a means of quantifying and comparing 3D neuron morphology. Presently, neuron comparison methods are based on statistics from neuronal morphology such as size and number of branches, which are not fully suitable for detecting local similarities and differences in the detailed structure. We developed BlastNeuron to compare neurons in terms of their global appearance, detailed arborization patterns, and topological similarity. BlastNeuron first compares and clusters 3D neuron reconstructions based on global morphology features and moment invariants, independent of their orientations, sizes, level of reconstruction and other variations. Subsequently, BlastNeuron performs local alignment between any pair of retrieved neurons via a tree-topology driven dynamic programming method. A 3D correspondence map can thus be generated at the resolution of single reconstruction nodes. We applied BlastNeuron to three datasets: (1) 10,000+ neuron reconstructions from a public morphology database, (2) 681 newly and manually reconstructed neurons, and (3) neurons reconstructions produced using several independent reconstruction methods. Our approach was able to accurately and efficiently retrieve morphologically and functionally similar neuron structures from large morphology database, identify the local common structures, and find clusters of neurons that share similarities in both morphology and molecular profiles.

  3. Region-dependent effects of diabetes and insulin-replacement on neuronal nitric oxide synthase- and heme oxygenase-immunoreactive submucous neurons.

    PubMed

    Bódi, Nikolett; Szalai, Zita; Chandrakumar, Lalitha; Bagyánszki, Mária

    2017-11-07

    To investigate the intestinal segment-specific effects of diabetes and insulin replacement on the density of different subpopulations of submucous neurons. Ten weeks after the onset of type 1 diabetes samples were taken from the duodenum, ileum and colon of streptozotocin-induce diabetic, insulin-treated diabetic and sex- and age-matched control rats. Whole-mount preparations of submucous plexus were prepared from the different gut segments for quantitative fluorescent immunohistochemistry. The following double-immunostainings were performed: neuronal nitric oxide synthase (nNOS) and HuC/D, heme oxygenase (HO) 1 and peripherin, as well as HO2 and peripherin. The density of nNOS-, HO1- and HO2-immunoreactive (IR) neurons was determined as a percentage of the total number of submucous neurons. The total number of submucous neurons and the proportion of nNOS-, HO1- and HO2-IR subpopulations were not affected in the duodenal ganglia of control, diabetic and insulin-treated rats. While the total neuronal number did not change in either the ileum or the colon, the density of nitrergic neurons exhibited a 2- and 3-fold increase in the diabetic ileum and colon, respectively, which was further enhanced after insulin replacement. The presence of HO1- and HO2-IR submucous neurons was robust in the colon of controls (38.4%-50.8%), whereas it was significantly lower in the small intestinal segments (0.0%-4.2%, P < 0.0001). Under pathophysiological conditions the only alteration detected was an increase in the ileum and a decrease in the colon of the proportion of HO-IR neurons in insulin-treated diabetic animals. Diabetes and immediate insulin replacement induce the most pronounced region-specific alterations of nNOS-, HO1- and HO2-IR submucous neuronal density in the distal parts of the gut.

  4. Region-dependent effects of diabetes and insulin-replacement on neuronal nitric oxide synthase- and heme oxygenase-immunoreactive submucous neurons

    PubMed Central

    Bódi, Nikolett; Szalai, Zita; Chandrakumar, Lalitha; Bagyánszki, Mária

    2017-01-01

    AIM To investigate the intestinal segment-specific effects of diabetes and insulin replacement on the density of different subpopulations of submucous neurons. METHODS Ten weeks after the onset of type 1 diabetes samples were taken from the duodenum, ileum and colon of streptozotocin-induce diabetic, insulin-treated diabetic and sex- and age-matched control rats. Whole-mount preparations of submucous plexus were prepared from the different gut segments for quantitative fluorescent immunohistochemistry. The following double-immunostainings were performed: neuronal nitric oxide synthase (nNOS) and HuC/D, heme oxygenase (HO) 1 and peripherin, as well as HO2 and peripherin. The density of nNOS-, HO1- and HO2-immunoreactive (IR) neurons was determined as a percentage of the total number of submucous neurons. RESULTS The total number of submucous neurons and the proportion of nNOS-, HO1- and HO2-IR subpopulations were not affected in the duodenal ganglia of control, diabetic and insulin-treated rats. While the total neuronal number did not change in either the ileum or the colon, the density of nitrergic neurons exhibited a 2- and 3-fold increase in the diabetic ileum and colon, respectively, which was further enhanced after insulin replacement. The presence of HO1- and HO2-IR submucous neurons was robust in the colon of controls (38.4%-50.8%), whereas it was significantly lower in the small intestinal segments (0.0%-4.2%, P < 0.0001). Under pathophysiological conditions the only alteration detected was an increase in the ileum and a decrease in the colon of the proportion of HO-IR neurons in insulin-treated diabetic animals. CONCLUSION Diabetes and immediate insulin replacement induce the most pronounced region-specific alterations of nNOS-, HO1- and HO2-IR submucous neuronal density in the distal parts of the gut. PMID:29151690

  5. Neurons from the adult human dentate nucleus: neural networks in the neuron classification.

    PubMed

    Grbatinić, Ivan; Marić, Dušica L; Milošević, Nebojša T

    2015-04-07

    Topological (central vs. border neuron type) and morphological classification of adult human dentate nucleus neurons according to their quantified histomorphological properties using neural networks on real and virtual neuron samples. In the real sample 53.1% and 14.1% of central and border neurons, respectively, are classified correctly with total of 32.8% of misclassified neurons. The most important result present 62.2% of misclassified neurons in border neurons group which is even greater than number of correctly classified neurons (37.8%) in that group, showing obvious failure of network to classify neurons correctly based on computational parameters used in our study. On the virtual sample 97.3% of misclassified neurons in border neurons group which is much greater than number of correctly classified neurons (2.7%) in that group, again confirms obvious failure of network to classify neurons correctly. Statistical analysis shows that there is no statistically significant difference in between central and border neurons for each measured parameter (p>0.05). Total of 96.74% neurons are morphologically classified correctly by neural networks and each one belongs to one of the four histomorphological types: (a) neurons with small soma and short dendrites, (b) neurons with small soma and long dendrites, (c) neuron with large soma and short dendrites, (d) neurons with large soma and long dendrites. Statistical analysis supports these results (p<0.05). Human dentate nucleus neurons can be classified in four neuron types according to their quantitative histomorphological properties. These neuron types consist of two neuron sets, small and large ones with respect to their perykarions with subtypes differing in dendrite length i.e. neurons with short vs. long dendrites. Besides confirmation of neuron classification on small and large ones, already shown in literature, we found two new subtypes i.e. neurons with small soma and long dendrites and with large soma and short

  6. Anti-dopamine beta-hydroxylase immunotoxin-induced sympathectomy in adult rats

    NASA Technical Reports Server (NTRS)

    Picklo, M. J.; Wiley, R. G.; Lonce, S.; Lappi, D. A.; Robertson, D.

    1995-01-01

    Anti-dopamine beta-hydroxylase immunotoxin (DHIT) is an antibody-targeted noradrenergic lesioning tool comprised of a monoclonal antibody against the noradrenergic enzyme, dopamine beta-hydroxylase, conjugated to saporin, a ribosome-inactivating protein. Noradrenergic-neuron specificity and completeness and functionality of sympathectomy were assessed. Adult, male Sprague-Dawley rats were given 28.5, 85.7, 142 or 285 micrograms/kg DHIT i.v. Three days after injection, a 6% to 73% decrease in the neurons was found in the superior cervical ganglia of the animals. No loss of sensory, nodose and dorsal root ganglia, neurons was observed at the highest dose of DHIT. In contrast, the immunotoxin, 192-saporin (142 micrograms/kg), lesioned all three ganglia. To assess the sympathectomy, 2 wk after treatment (285 micrograms/kg), rats were anesthetized with urethane (1 g/kg) and cannulated in the femoral artery and vein. DHIT-treated animals' basal systolic blood pressure and heart rate were significantly lower than controls. Basal plasma norepinephrine levels were 41% lower in DHIT-treated animals than controls. Tyramine-stimulated release of norepinephrine in DHIT-treated rats was 27% of controls. Plasma epinephrine levels of DHIT animals were not reduced. DHIT-treated animals exhibited a 2-fold hypersensitivity to the alpha-adrenergic agonist phenylephrine. We conclude that DHIT selectively delivered saporin to noradrenergic neurons resulting in destruction of these neurons. Anti-dopamine beta-hydroxylase immunotoxin administration produces a rapid, irreversible sympathectomy.

  7. What We Know Currently about Mirror Neurons

    PubMed Central

    Kilner, J.M.; Lemon, R.N.

    2013-01-01

    Mirror neurons were discovered over twenty years ago in the ventral premotor region F5 of the macaque monkey. Since their discovery much has been written about these neurons, both in the scientific literature and in the popular press. They have been proposed to be the neuronal substrate underlying a vast array of different functions. Indeed so much has been written about mirror neurons that last year they were referred to, rightly or wrongly, as “The most hyped concept in neuroscience”. Here we try to cut through some of this hyperbole and review what is currently known (and not known) about mirror neurons. PMID:24309286

  8. What we know currently about mirror neurons.

    PubMed

    Kilner, J M; Lemon, R N

    2013-12-02

    Mirror neurons were discovered over twenty years ago in the ventral premotor region F5 of the macaque monkey. Since their discovery much has been written about these neurons, both in the scientific literature and in the popular press. They have been proposed to be the neuronal substrate underlying a vast array of different functions. Indeed so much has been written about mirror neurons that last year they were referred to, rightly or wrongly, as "The most hyped concept in neuroscience". Here we try to cut through some of this hyperbole and review what is currently known (and not known) about mirror neurons. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Oscillatory integration windows in neurons

    PubMed Central

    Gupta, Nitin; Singh, Swikriti Saran; Stopfer, Mark

    2016-01-01

    Oscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly test this idea in the locust olfactory system. We find that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we show that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrate that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking. PMID:27976720

  10. Oscillatory integration windows in neurons.

    PubMed

    Gupta, Nitin; Singh, Swikriti Saran; Stopfer, Mark

    2016-12-15

    Oscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly test this idea in the locust olfactory system. We find that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we show that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrate that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking.

  11. CRTC1 mediates preferential transcription at neuronal activity-regulated CRE/TATA promoters.

    PubMed

    Parra-Damas, Arnaldo; Rubió-Ferrarons, Laura; Shen, Jie; Saura, Carlos A

    2017-12-21

    Gene expression mediated by the transcription factor cAMP-responsive element-binding protein (CREB) is essential for a wide range of brain processes. The transcriptional coactivartor CREB-regulated transcription coactivator-1 (CRTC1) is required for efficient induction of CREB target genes during neuronal activity. However, the mechanisms regulating induction of specific CREB/CRTC1-dependent genes during neuronal activity remain largely unclear. Here, we investigated the molecular mechanisms regulating activity-dependent gene transcription upon activation of the CREB/CRTC1 signaling pathway in neurons. Depolarization and cAMP signals induce preferential transcription of activity-dependent genes containing promoters with proximal CRE/TATA sequences, such as c-fos, Dusp1, Nr4a1, Nr4a2 and Ptgs2, but not genes with proximal CRE/TATA-less promoters (e.g. Nr4a3, Presenilin-1 and Presenilin-2). Notably, biochemical and chromatin immunoprecipitation analyses reveal constitutive binding of CREB to target gene promoters in the absence of neuronal activity, whereas recruitment of CRTC1 to proximal CRE/TATA promoters depends on neuronal activity. Neuronal activity induces rapid CRTC1 dephosphorylation, nuclear translocation and binding to endogenous CREB. These results indicate that neuronal activity induces a preferential binding of CRTC1 to the transcriptional complex in CRE/TATA-containing promoters to engage activity-dependent transcription in neurons.

  12. Recycling endosomes in neuronal membrane traffic.

    PubMed

    Schmidt, Michael R; Haucke, Volker

    2007-06-01

    Neurons are highly polarized cells with axonal and somatodendritic membrane surfaces that spatially separate signal-sending from signal-receiving membrane domains. As found in many other cell types, different populations of endosomes are involved in the sorting of synaptic and other membrane cargo in neurons. The exact source of the membrane for neurite extension and process remodelling during neuronal differentiation has remained uncertain, and we do not know exactly how polarized sorting of neuronal membrane proteins is achieved. In the present article, we will provide a brief overview of endosomes and their putative or proven functions in fibroblasts, epithelial cells and neurons. On the basis of insights from non-neuronal cell types and recent studies on the function of recycling endosomes during synaptic plasticity-induced membrane remodelling, we postulate a speculative model regarding the role of recycling endosomes in neuronal differentiation.

  13. Neuroglobin and neuronal cell survival.

    PubMed

    Fiocchetti, Marco; De Marinis, Elisabetta; Ascenzi, Paolo; Marino, Maria

    2013-09-01

    The balance between neuronal apoptosis and survival sculpts the developing brain and has an important role in neurodegenerative diseases. Thus, the individuation of signals that could modulate the cell death machinery as well as enhance survival in neurons promises to provide multiple points of therapeutic intervention in neurodegenerative diseases. Neuroglobin (NGB), the first nerve globin identified in neuronal tissues of humans, seems to possess a protective role in the brain only after up-regulation. Here, the NGB physiological role in the control of neuronal survival is reviewed. In vitro studies suggested that cytosolic NGB could react very rapidly with cytochrome c released from mitochondria, thus interfering with the intrinsic pathway of apoptosis. Although very suggestive, these data do not explain either the role of NGB up-regulation in neuroprotection or the recently reported NGB localization into mitochondria. Recently, we identified the steroid hormone 17β-estradiol (E2) as an endogenous modulator of NGB levels in neuroblastoma SK-N-BE cell line. Upon E2 stimulation, NGB reallocates mainly into mitochondria where the association with the mitochondrial cytochrome c occurs. Remarkably, E2 treatment before an apoptotic stimulus strongly enhances the NGB:cytochrome c association reducing cytochrome c release into the cytosol. As a consequence, a decrease of caspase-3 activation and, in turn, of the apoptotic cascade activation take place. Besides E2, other compounds have been reported to up-regulate the NGB expression highlighting the possibility to develop NGB-mediated therapeutic strategies against stroke damage and neurodegenerative diseases. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Guiding neuronal growth with light

    NASA Astrophysics Data System (ADS)

    Ehrlicher, A.; Betz, T.; Stuhrmann, B.; Koch, D.; Milner, V.; Raizen, M. G.; Käs, J.

    2002-12-01

    Control over neuronal growth is a fundamental objective in neuroscience, cell biology, developmental biology, biophysics, and biomedicine and is particularly important for the formation of neural circuits in vitro, as well as nerve regeneration in vivo [Zeck, G. & Fromherz, P. (2001) Proc. Natl. Acad. Sci. USA 98, 10457-10462]. We have shown experimentally that we can use weak optical forces to guide the direction taken by the leading edge, or growth cone, of a nerve cell. In actively extending growth cones, a laser spot is placed in front of a specific area of the nerve's leading edge, enhancing growth into the beam focus and resulting in guided neuronal turns as well as enhanced growth. The power of our laser is chosen so that the resulting gradient forces are sufficiently powerful to bias the actin polymerization-driven lamellipodia extension, but too weak to hold and move the growth cone. We are therefore using light to control a natural biological process, in sharp contrast to the established technique of optical tweezers [Ashkin, A. (1970) Phys. Rev. Lett. 24, 156-159; Ashkin, A. & Dziedzic, J. M. (1987) Science 235, 1517-1520], which uses large optical forces to manipulate entire structures. Our results therefore open an avenue to controlling neuronal growth in vitro and in vivo with a simple, noncontact technique.

  15. Consciousness from neurons and waves

    NASA Astrophysics Data System (ADS)

    John, E. R.

    2004-05-01

    This paper presents a theory of consciousness based on the following evidence: [1] Complex stimuli are decomposed by the exogenous system into attributes transmitted to synapses of pyramidal neurons in lower cortical layers, encoding fragments of sensations as nonrandom synchronization that increases local voltages; [2] Endogenous readouts from representational systems encoding memories in a mesolimbic system are transmitted to synapses of the pyramidal neurons in upper layers; [3] Excitability of pyramidal neurons receiving convergent exogenous and endogenous inputs is enhanced, converting fragments of sensations to fragments of perception and creating high voltage islands of non-random synchrony; [4] Local Field Potential (LFP) oscillations are homeostatically regulated, imposing dynamically maintained local voltage thresholds that define a "Ground State" [5] Deviations from these most probable levels constitute local perturbations of entropy; [6] Modulation of cortex by LFPs, facilitating coherent cortico-thalamic (C-T) volleys of cells with suprathreshold excitability, binds dispersed fragments of local perturbations of entropy; [7] The thalamic cells from which convergence arose respond to these volleys by coherent T-C-T-C reverberations; [8] Sustained reverberation establishes a resonating electromagnetic field of information, the vehicle sustaining unified perception; [9] The resonating field of information constitutes Global Negative and generates the content of consciousness; [10] Invariant reversible LFP changes occur upon loss of consciousness and persistent shifts accompany many clinical disorders.

  16. Guiding Neuronal Growth with Light

    NASA Astrophysics Data System (ADS)

    Ehrlicher, Allen; Betz, Timo; Stuhrmann, Björn; Koch, Daniel; Goegler, Michael; Käs, Josef; Schreck, Florian; Moore, Sam; Raizen, Mark

    2003-03-01

    Control over neuronal growth is a fundamental objective in neuroscience, cell biology, developmental biology, biophysics, and biomedicine, and is particularly important for the formation of neural circuits in vitro, as well as nerve regeneration in vivo [Zeck, G. & Fromherz, P. (2001) Proc. Natl. Acad. Sci. USA 98, 10457-10462]. We have shown experimentally that we can use weak optical forces to guide the direction taken by the leading edge, or growth cone, of a nerve cell. In actively extending growth cones, a laser spot is placed in front of a chosen area of the nerve's leading edge, promoting growth into the beam focus. This allows guided neuronal turns as well as enhanced growth. The power of our laser is chosen so that the resulting gradient forces are sufficiently powerful to bias the actin polymerization-driven lamellipodia extension, but too weak to hold and move the growth cone. We are therefore using light to control a natural biological process, in sharp contrast to the established technique of optical tweezers [Ashkin, A. (1970) Phys. Rev. Lett. 24, 156-159; Ashkin, A. & Dziedzic, J. M. (1987) Science 235, 1517-1520] which uses large optical forces to manipulate entire structures. Our results therefore open a new avenue to controlling neuronal growth in vitro and in vivo with a simple, non-contact technique.

  17. Neuronal regulation of tendon homoeostasis

    PubMed Central

    Ackermann, Paul W

    2013-01-01

    The regulation of tendon homoeostasis, including adaptation to loading, is still not fully understood. Accumulating data, however, demonstrates that in addition to afferent (sensory) functions, the nervous system, via efferent pathways which are associated with through specific neuronal mediators plays an active role in regulating pain, inflammation and tendon homeostasis. This neuronal regulation of intact-, healing- and tendinopathic tendons has been shown to be mediated by three major groups of molecules including opioid, autonomic and excitatory glutamatergic neuroregulators. In intact healthy tendons the neuromediators are found in the surrounding structures: paratenon, endotenon and epitenon, whereas the proper tendon itself is practically devoid of neurovascular supply. This neuroanatomy reflects that normal tendon homoeostasis is regulated from the tendon surroundings. After injury and during tendon repair, however, there is extensive nerve ingrowth into the tendon proper, followed by a time-dependent emergence of sensory, autonomic and glutamatergic mediators, which amplify and fine-tune inflammation and regulate tendon regeneration. In tendinopathic condition, excessive and protracted presence of sensory and glutamatergic neuromediators has been identified, suggesting involvement in inflammatory, nociceptive and hypertrophic (degenerative) tissue responses. Under experimental and clinical conditions of impaired (e.g. diabetes) as well as excessive (e.g. tendinopathy) neuromediator release, dysfunctional tendon homoeostasis develops resulting in chronic pain and gradual degeneration. Thus there is a prospect that in the future pharmacotherapy and tissue engineering approaches targeting neuronal mediators and their receptors may prove to be effective therapies for painful, degenerative and traumatic tendon disorders. PMID:23718724

  18. Population Encoding With Hodgkin–Huxley Neurons

    PubMed Central

    Lazar, Aurel A.

    2013-01-01

    The recovery of (weak) stimuli encoded with a population of Hodgkin–Huxley neurons is investigated. In the absence of a stimulus, the Hodgkin–Huxley neurons are assumed to be tonically spiking. The methodology employed calls for 1) finding an input–output (I/O) equivalent description of the Hodgkin–Huxley neuron and 2) devising a recovery algorithm for stimuli encoded with the I/O equivalent neuron(s). A Hodgkin–Huxley neuron with multiplicative coupling is I/O equivalent with an Integrate-and-Fire neuron with a variable threshold sequence. For bandlimited stimuli a perfect recovery of the stimulus can be achieved provided that a Nyquist-type rate condition is satisfied. A Hodgkin–Huxley neuron with additive coupling and deterministic conductances is first-order I/O equivalent with a Project-Integrate-and-Fire neuron that integrates a projection of the stimulus on the phase response curve. The stimulus recovery is formulated as a spline interpolation problem in the space of finite length bounded energy signals. A Hodgkin–Huxley neuron with additive coupling and stochastic conductances is shown to be first-order I/O equivalent with a Project-Integrate-and-Fire neuron with random thresholds. For stimuli modeled as elements of Sobolev spaces the reconstruction algorithm minimizes a regularized quadratic optimality criterion. Finally, all previous recovery results of stimuli encoded with Hodgkin–Huxley neurons with multiplicative and additive coupling, and deterministic and stochastic conductances are extended to stimuli encoded with a population of Hodgkin–Huxley neurons. PMID:24194625

  19. Glutamate neurons within the midbrain dopamine regions.

    PubMed

    Morales, M; Root, D H

    2014-12-12

    Midbrain dopamine systems play important roles in Parkinson's disease, schizophrenia, addiction, and depression. The participation of midbrain dopamine systems in diverse clinical contexts suggests these systems are highly complex. Midbrain dopamine regions contain at least three neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. Here, we review the locations, subtypes, and functions of glutamatergic neurons within midbrain dopamine regions. Vesicular glutamate transporter 2 (VGluT2) mRNA-expressing neurons are observed within each midbrain dopamine system. Within rat retrorubral field (RRF), large populations of VGluT2 neurons are observed throughout its anteroposterior extent. Within rat substantia nigra pars compacta (SNC), VGluT2 neurons are observed centrally and caudally, and are most dense within the laterodorsal subdivision. RRF and SNC rat VGluT2 neurons lack tyrosine hydroxylase (TH), making them an entirely distinct population of neurons from dopaminergic neurons. The rat ventral tegmental area (VTA) contains the most heterogeneous populations of VGluT2 neurons. VGluT2 neurons are found in each VTA subnucleus but are most dense within the anterior midline subnuclei. Some subpopulations of rat VGluT2 neurons co-express TH or glutamic acid decarboxylase (GAD), but most of the VGluT2 neurons lack TH or GAD. Different subsets of rat VGluT2-TH neurons exist based on the presence or absence of vesicular monoamine transporter 2, dopamine transporter, or D2 dopamine receptor. Thus, the capacity by which VGluT2-TH neurons may release dopamine will differ based on their capacity to accumulate vesicular dopamine, uptake extracellular dopamine, or be autoregulated by dopamine. Rat VTA VGluT2 neurons exhibit intrinsic VTA projections and extrinsic projections to the accumbens and to the prefrontal cortex. Mouse VTA VGluT2 neurons project to accumbens shell, prefrontal cortex, ventral pallidum, amygdala, and lateral habenula. Given their molecular

  20. Presynaptic inhibition of GABAergic synaptic transmission by adenosine in mouse hypothalamic hypocretin neurons.

    PubMed

    Xia, J X; Xiong, J X; Wang, H K; Duan, S M; Ye, J N; Hu, Z A

    2012-01-10

    Hypocretin neurons in the lateral hypothalamus, a new wakefulness-promoting center, have been recently regarded as an important target involved in endogenous adenosine-regulating sleep homeostasis. The GABAergic synaptic transmissions are the main inhibitory afferents to hypocretin neurons, which play an important role in the regulation of excitability of these neurons. The inhibitory effect of adenosine, a homeostatic sleep-promoting factor, on the excitatory glutamatergic synaptic transmissions in hypocretin neurons has been well documented, whether adenosine also modulates these inhibitory GABAergic synaptic transmissions in these neurons has not been investigated. In this study, the effect of adenosine on inhibitory postsynaptic currents (IPSCs) in hypocretin neurons was examined by using perforated patch-clamp recordings in the acute hypothalamic slices. The findings demonstrated that adenosine suppressed the amplitude of evoked IPSCs in a dose-dependent manner, which was completely abolished by 8-cyclopentyltheophylline (CPT), a selective antagonist of adenosine A1 receptor but not adenosine A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl) xanthine. A presynaptic origin was suggested as following: adenosine increased paired-pulse ratio as well as reduced GABAergic miniature IPSC frequency without affecting the miniature IPSC amplitude. Further findings demonstrated that when the frequency of electrical stimulation was raised to 10 Hz, but not 1 Hz, a time-dependent depression of evoked IPSC amplitude was detected in hypocretin neurons, which could be partially blocked by CPT. However, under a higher frequency at 100 Hz stimulation, CPT had no action on the depressed GABAergic synaptic transmission induced by such tetanic stimulation in these hypocretin neurons. These results suggest that endogenous adenosine generated under certain stronger activities of synaptic transmissions exerts an inhibitory effect on GABAergic synaptic transmission in hypocretin

  1. Dual transgene expression in murine cerebellar Purkinje neurons by viral transduction in vivo.

    PubMed

    Bosch, Marie K; Nerbonne, Jeanne M; Ornitz, David M

    2014-01-01

    Viral-vector mediated gene transfer to cerebellar Purkinje neurons in vivo is a promising avenue for gene therapy of cerebellar ataxias and for genetic manipulation in functional studies of animal models of cerebellar disease. Here, we report the results of experiments designed to identify efficient methods for viral transduction of adult murine Purkinje neurons in vivo. For these analyses, several lentiviral and an adeno-associated virus (AAV), serotype 1, vector with various promoter combinations were generated and compared for in situ transduction efficiency, assayed by fluorescent reporter protein expression in Purkinje neurons. Additional experiments were also conducted to identify the optimal experimental strategy for co-expression of two proteins in individual Purkinje neurons. Of the viruses tested, AAV1 with a CAG promoter exhibited the highest specificity for Purkinje neurons. To deliver two proteins to the same Purkinje neuron, several methods were tested, including: an internal ribosome entry site (IRES), a 2A sequence, a dual promoter vector, and co-injection of two viruses. Efficient expression of both proteins in the same Purkinje neuron was only achieved by co-injecting two AAV1-CAG viruses. We found that use of an AAV1-CAG virus outperformed similar lentivirus vectors and that co-injection of two AAV1-CAG viruses could be used to efficiently deliver two proteins to the same Purkinje neuron in adult mice. AAV1 with a CAG promoter is highly efficient and selective at transducing adult cerebellar Purkinje neurons and two AAV-CAG viruses can be used to efficiently express two proteins in the same neuron in vivo.

  2. Luteinizing hormone receptors are expressed in rat myenteric neurons and mediate neuronal loss.

    PubMed

    Sand, Elin; Voss, Ulrikke; Ohlsson, Bodil; Ekblad, Eva

    2015-12-01

    Clinical observations have suggested repeated gonadotropin-releasing hormone (GnRH) exposure to cause intestinal dysfunction and loss of enteric neurons. This has been further studied and confirmed in a rat in vivo model involving iterated GnRH treatments. Mechanisms behind are enigmatic since no GnRH receptors are found to be expressed in enteric neurons neither in man nor rat. Both species, however, harbor substantial subpopulations of luteinizing hormone (LH) receptor-immunoreactive myenteric neurons which suggests that intestinal GnRH-induced neuropathy may be mediated by LH release. To reveal if exposures of GnRH or LH to rat myenteric neurons in vitro cause neuronal loss. Primary cultured adult rat myenteric neurons were exposed to single or repeated treatments of the GnRH analog buserelin or the LH analog lutrotropin alpha, and neuronal survival was determined by cell counting. Possible presence of GnRH- or LH receptor -immunoreactive neurons was determined by immunocytochemistry. Exposure to the LH, but not the GnRH, analog caused significantly reduced neuronal survival. LH, but not GnRH, receptors were found to be expressed on cultured myenteric neurons. Myenteric neurons express LH receptors in vitro and LH exposure causes reduced neuronal survival. This suggests that GnRH-induced enteric neuropathy in vivo is mediated by way of LH release and activation of enteric neuronal LH receptors.

  3. Timing Mechanisms in Neuronal Pathfinding, Synaptic Reorganization, and Neuronal Regeneration

    PubMed Central

    Ivakhnitskaia, Evguenia; Hamada, Kana; Chang, Chieh

    2015-01-01

    Precise temporal control of neuro-differentiation and postdifferentiation events is necessary for the creation of appropriate wiring diagram in the brain. To make advances in the treatment of neurodevelopmental and neurodegenerative disorders, and traumatic brain injury, it is important to understand these mechanisms. Caenorhabditis elegans has emerged as a revolutionary tool for the study of neural circuits due to its genetic homology to vertebrates and ease of genetic manipulation. microRNA (miRNA), a ubiquitous class of small non-coding RNA, that inhibits the expression of target genes, has emerged as an important timing control molecule through research conducted on C. elegans. This review will focus on the temporal control of neurodifferentiation and post-differentiation events exerted by the two conserved miRNAs, lin-4 and let-7. We summarize recent findings on the role of lin-4 as a timing regulator controlling transition of sequential events in neuronal pathfinding and synaptic remodeling, and the role of let-7 as a timing regulator that limits the regeneration potential of post-differentiated AVM neurons as they age. PMID:26748770

  4. Nasal neuron PET imaging quantifies neuron generation and degeneration

    PubMed Central

    Van de Bittner, Genevieve C.; Riley, Misha M.; Cao, Luxiang; Herrick, Scott P.; Ricq, Emily L.; O’Neill, Michael J.; Ahmed, Zeshan; Murray, Tracey K.; Smith, Jaclyn E.; Wang, Changning; Schroeder, Frederick A.; Albers, Mark W.; Hooker, Jacob M.

    2017-01-01

    Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics. PMID:28112682

  5. Neuronal Networks on Nanocellulose Scaffolds.

    PubMed

    Jonsson, Malin; Brackmann, Christian; Puchades, Maja; Brattås, Karoline; Ewing, Andrew; Gatenholm, Paul; Enejder, Annika

    2015-11-01

    Proliferation, integration, and neurite extension of PC12 cells, a widely used culture model for cholinergic neurons, were studied in nanocellulose scaffolds biosynthesized by Gluconacetobacter xylinus to allow a three-dimensional (3D) extension of neurites better mimicking neuronal networks in tissue. The interaction with control scaffolds was compared with cationized nanocellulose (trimethyl ammonium betahydroxy propyl [TMAHP] cellulose) to investigate the impact of surface charges on the cell interaction mechanisms. Furthermore, coatings with extracellular matrix proteins (collagen, fibronectin, and laminin) were investigated to determine the importance of integrin-mediated cell attachment. Cell proliferation was evaluated by a cellular proliferation assay, while cell integration and neurite propagation were studied by simultaneous label-free Coherent anti-Stokes Raman Scattering and second harmonic generation microscopy, providing 3D images of PC12 cells and arrangement of nanocellulose fibrils, respectively. Cell attachment and proliferation were enhanced by TMAHP modification, but not by protein coating. Protein coating instead promoted active interaction between the cells and the scaffold, hence lateral cell migration and integration. Irrespective of surface modification, deepest cell integration measured was one to two cell layers, whereas neurites have a capacity to integrate deeper than the cell bodies in the scaffold due to their fine dimensions and amoeba-like migration pattern. Neurites with lengths of >50 μm were observed, successfully connecting individual cells and cell clusters. In conclusion, TMAHP-modified nanocellulose scaffolds promote initial cellular scaffold adhesion, which combined with additional cell-scaffold treatments enables further formation of 3D neuronal networks.

  6. Neuronal regulation of tendon homoeostasis.

    PubMed

    Ackermann, Paul W

    2013-08-01

    The regulation of tendon homoeostasis, including adaptation to loading, is still not fully understood. Accumulating data, however, demonstrates that in addition to afferent (sensory) functions, the nervous system, via efferent pathways which are associated with through specific neuronal mediators plays an active role in regulating pain, inflammation and tendon homeostasis. This neuronal regulation of intact-, healing- and tendinopathic tendons has been shown to be mediated by three major groups of molecules including opioid, autonomic and excitatory glutamatergic neuroregulators. In intact healthy tendons the neuromediators are found in the surrounding structures: paratenon, endotenon and epitenon, whereas the proper tendon itself is practically devoid of neurovascular supply. This neuroanatomy reflects that normal tendon homoeostasis is regulated from the tendon surroundings. After injury and during tendon repair, however, there is extensive nerve ingrowth into the tendon proper, followed by a time-dependent emergence of sensory, autonomic and glutamatergic mediators, which amplify and fine-tune inflammation and regulate tendon regeneration. In tendinopathic condition, excessive and protracted presence of sensory and glutamatergic neuromediators has been identified, suggesting involvement in inflammatory, nociceptive and hypertrophic (degenerative) tissue responses. Under experimental and clinical conditions of impaired (e.g. diabetes) as well as excessive (e.g. tendinopathy) neuromediator release, dysfunctional tendon homoeostasis develops resulting in chronic pain and gradual degeneration. Thus there is a prospect that in the future pharmacotherapy and tissue engineering approaches targeting neuronal mediators and their receptors may prove to be effective therapies for painful, degenerative and traumatic tendon disorders. © 2013 The Authors. International Journal of Experimental Pathology © 2013 International Journal of Experimental Pathology.

  7. Mini Review: Biomaterials for Enhancing Neuronal Repair

    NASA Astrophysics Data System (ADS)

    Cangellaris, Olivia V.; Gillette, Martha U.

    2018-04-01

    As they differentiate from neuroblasts, nascent neurons become highly polarized and elongate. Neurons extend and elaborate fine and fragile cellular extensions that form circuits enabling long-distance communication and signal integration within the body. While other organ systems are developing, projections of differentiating neurons find paths to distant targets. Subsequent post-developmental neuronal damage is catastrophic because the cues for reinnervation are no longer active. Advances in biomaterials are enabling fabrication of micro-environments that encourage neuronal regrowth and restoration of function by recreating these developmental cues. This mini-review considers new materials that employ topographical, chemical, electrical, and/or mechanical cues for use in neuronal repair. Manipulating and integrating these elements in different combinations will generate new technologies to enhance neural repair.

  8. Morphological Neuron Classification Using Machine Learning

    PubMed Central

    Vasques, Xavier; Vanel, Laurent; Villette, Guillaume; Cif, Laura

    2016-01-01

    Classification and quantitative characterization of neuronal morphologies from histological neuronal reconstruction is challenging since it is still unclear how to delineate a neuronal cell class and which are the best features to define them by. The morphological neuron characterization represents a primary source to address anatomical comparisons, morphometric analysis of cells, or brain modeling. The objectives of this paper are (i) to develop and integrate a pipeline that goes from morphological feature extraction to classification and (ii) to assess and compare the accuracy of machine learning algorithms to classify neuron morphologies. The algorithms were trained on 430 digitally reconstructed neurons subjectively classified into layers and/or m-types using young and/or adult development state population of the somatosensory cortex in rats. For supervised algorithms, linear discriminant analysis provided better classification results in comparison with others. For unsupervised algorithms, the affinity propagation and the Ward algorithms provided slightly better results. PMID:27847467

  9. New Insights into Neuron-Glia Communication

    NASA Astrophysics Data System (ADS)

    Fields, R. Douglas; Stevens-Graham, Beth

    2002-10-01

    Two-way communication between neurons and nonneural cells called glia is essential for axonal conduction, synaptic transmission, and information processing and thus is required for normal functioning of the nervous system during development and throughout adult life. The signals between neurons and glia include ion fluxes, neurotransmitters, cell adhesion molecules, and specialized signaling molecules released from synaptic and nonsynaptic regions of the neuron. In contrast to the serial flow of information along chains of neurons, glia communicate with other glial cells through intracellular waves of calcium and via intercellular diffusion of chemical messengers. By releasing neurotransmitters and other extracellular signaling molecules, glia can affect neuronal excitability and synaptic transmission and perhaps coordinate activity across networks of neurons.

  10. MRI of neuronal plasticity in rodent models.

    PubMed

    Pelled, Galit

    2011-01-01

    Modifications in the behavior and architecture of neuronal networks are well documented to occur in association with learning and memory, as well as following injury. These plasticity mechanisms are crucial to ensure adequate processing of stimuli, and they also dictate the degree of recovery following peripheral or central nervous system injury. Nevertheless, the underlying neuronal mechanisms that determine the degree of plasticity of neuronal pathways are not fully understood. Recent developments in animal-dedicated magnetic resonance imaging (MRI) scanners and related hardware afford a high spatial and temporal resolution, making functional MRI and manganese-enhanced MRI emerging tools for studying reorganization of neuronal pathways in rodent models. Many of the observed changes in neuronal functions in rodent's brains following injury discussed here agree with clinical human fMRI findings. This demonstrates that animal model imaging can have a significant clinical impact in the neuronal plasticity and rehabilitation arenas.

  11. A chimeric path to neuronal synchronization

    SciTech Connect

    Essaki Arumugam, Easwara Moorthy; Spano, Mark L.

    2015-01-15

    Synchronization of neuronal activity is associated with neurological disorders such as epilepsy. This process of neuronal synchronization is not fully understood. To further our understanding, we have experimentally studied the progression of this synchronization from normal neuronal firing to full synchronization. We implemented nine FitzHugh-Nagumo neurons (a simplified Hodgkin-Huxley model) via discrete electronics. For different coupling parameters (synaptic strengths), the neurons in the ring were either unsynchronized or completely synchronized when locally coupled in a ring. When a single long-range connection (nonlocal coupling) was introduced, an intermediate state known as a chimera appeared. The results indicate that (1) epilepsy ismore » likely not only a dynamical disease but also a topological disease, strongly tied to the connectivity of the underlying network of neurons, and (2) the synchronization process in epilepsy may not be an “all or none” phenomenon, but can pass through an intermediate stage (chimera)« less

  12. A chimeric path to neuronal synchronization

    NASA Astrophysics Data System (ADS)

    Essaki Arumugam, Easwara Moorthy; Spano, Mark L.

    2015-01-01

    Synchronization of neuronal activity is associated with neurological disorders such as epilepsy. This process of neuronal synchronization is not fully understood. To further our understanding, we have experimentally studied the progression of this synchronization from normal neuronal firing to full synchronization. We implemented nine FitzHugh-Nagumo neurons (a simplified Hodgkin-Huxley model) via discrete electronics. For different coupling parameters (synaptic strengths), the neurons in the ring were either unsynchronized or completely synchronized when locally coupled in a ring. When a single long-range connection (nonlocal coupling) was introduced, an intermediate state known as a chimera appeared. The results indicate that (1) epilepsy is likely not only a dynamical disease but also a topological disease, strongly tied to the connectivity of the underlying network of neurons, and (2) the synchronization process in epilepsy may not be an "all or none" phenomenon, but can pass through an intermediate stage (chimera).

  13. Arc - An endogenous neuronal retrovirus?

    PubMed

    Shepherd, Jason D

    2018-05-01

    The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain and has been implicated in various neurological disorders. However, little is known about Arc's evolutionary origins. Recent studies suggest that mammalian Arc originated from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestral to retroviruses. In particular, Arc contains homology to the Gag polyprotein that forms the viral capsid and is essential for viral infectivity. This surprising connection raises the intriguing possibility that Arc may share molecular characteristics of retroviruses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Neurosemantics, neurons and system theory.

    PubMed

    Breidbach, Olaf

    2007-08-01

    Following the concept of internal representations, signal processing in a neuronal system has to be evaluated exclusively based on internal system characteristics. Thus, this approach omits the external observer as a control function for sensory integration. Instead, the configuration of the system and its computational performance are the effects of endogenous factors. Such self-referential operation is due to a strictly local computation in a network and, thereby, computations follow a set of rules that constitute the emergent behaviour of the system. These rules can be shown to correspond to a "logic" that is intrinsic to the system, an idea which provides the basis for neurosemantics.

  15. dHb9 expressing larval motor neurons persist through metamorphosis to innervate adult-specific muscle targets and function in Drosophila eclosion

    PubMed Central

    Banerjee, Soumya; Toral, Marcus; Siefert, Matthew; Conway, David; Dorr, Meredith

    2016-01-01

    The Drosophila larval nervous system is radically restructured during metamorphosis to produce adult specific neural circuits and behaviors. Genesis of new neurons, death of larval neurons and remodeling of those neurons that persistent collectively act to shape the adult nervous system. Here we examine the fate of a subset of larval motor neurons during this restructuring process. We used a dHb9 reporter, in combination with the FLP/FRT system to individually identify abdominal motor neurons in the larval to adult transition using a combination of relative cell body (CB) location, axonal position and muscle targets. We found that segment specific cell death of some dHb9 expressing motor neurons occurs throughout the metamorphosis period and continues into the post-eclosion period. Many dHb9>GFP expressing neurons however persist in the two anterior hemisegments, A1 and A2, which have segment specific muscles required for eclosion while a smaller proportion also persist in A2–A5. Consistent with a functional requirement for these neurons, ablating them during the pupal period produces defects in adult eclosion. In adults, subsequent to the execution of eclosion behaviors, the NMJs of some of these neurons were found to be dismantled and their muscle targets degenerate. Our studies demonstrate a critical continuity of some larval motor neurons into adults and reveal that multiple aspects of motor neuron remodeling and plasticity that are essential adult motor behaviors. PMID:27168166

  16. Mechanisms of Neuronal Apoptosis In Vivo

    DTIC Science & Technology

    2004-02-01

    neurons display compartmental was prominent during the first 15 days and then synap- changes in the localization of synucleins during matura- tic ...cells that can modify neuronal re- neuronal viability, effective restorative and therapeu- sponses directly or indirectly, confounding the inter- tic ...characteris- room air (SaO2 65%), and then 7 min of airway ocdu- tics (Portera-Cailliau et al., 1997ab). Some studies have sion (SaO2 5%), resulting in

  17. High-Degree Neurons Feed Cortical Computations

    PubMed Central

    Timme, Nicholas M.; Ito, Shinya; Shimono, Masanori; Yeh, Fang-Chin; Litke, Alan M.; Beggs, John M.

    2016-01-01

    Recent work has shown that functional connectivity among cortical neurons is highly varied, with a small percentage of neurons having many more connections than others. Also, recent theoretical developments now make it possible to quantify how neurons modify information from the connections they receive. Therefore, it is now possible to investigate how information modification, or computation, depends on the number of connections a neuron receives (in-degree) or sends out (out-degree). To do this, we recorded the simultaneous spiking activity of hundreds of neurons in cortico-hippocampal slice cultures using a high-density 512-electrode array. This preparation and recording method combination produced large numbers of neurons recorded at temporal and spatial resolutions that are not currently available in any in vivo recording system. We utilized transfer entropy (a well-established method for detecting linear and nonlinear interactions in time series) and the partial information decomposition (a powerful, recently developed tool for dissecting multivariate information processing into distinct parts) to quantify computation between neurons where information flows converged. We found that computations did not occur equally in all neurons throughout the networks. Surprisingly, neurons that computed large amounts of information tended to receive connections from high out-degree neurons. However, the in-degree of a neuron was not related to the amount of information it computed. To gain insight into these findings, we developed a simple feedforward network model. We found that a degree-modified Hebbian wiring rule best reproduced the pattern of computation and degree correlation results seen in the real data. Interestingly, this rule also maximized signal propagation in the presence of network-wide correlations, suggesting a mechanism by which cortex could deal with common random background input. These are the first results to show that the extent to which a neuron

  18. Distribution of orexin-1 receptor-green fluorescent protein- (OX1-GFP) expressing neurons in the mouse brain stem and pons: Co-localization with tyrosine hydroxylase and neuronal nitric oxide synthase.

    PubMed

    Darwinkel, A; Stanić, D; Booth, L C; May, C N; Lawrence, A J; Yao, S T

    2014-10-10

    We used a reporter mouse line in which green fluorescent protein (GFP) was inserted into the orexin-1 receptor (OX1) locus to systematically map the neuroanatomical distribution of the OX1 receptor in the mouse brainstem and pons. Here, we show that the OX1 receptor is expressed in a select subset of medullary and pontine nuclei. In the medulla, we observed OX1-GFP expression in the cuneate, gracile, dorsal motor nucleus of the vagus (10N), nucleus of the solitary tract and medullary raphe areas. In the pons, the greatest expression was found in the locus coeruleus (LC) and dorsal raphe nucleus (DRN). High to moderate expression was found in the pedunculopontine tegmental nucleus (PPTg), laterodorsal tegmental nucleus, A5 noradrenergic cell group (A5) and the periaqueductal gray. Double-labeling with neuronal nitric oxide synthase (NOS1) revealed extensive co-localization in cell bodies and fibers of the 10N, A5 cell group and the PPTg. Double-staining with tyrosine hydroxylase revealed extensive co-expression in the LC, DRN and the lateral paragigantocellularis cell group in the ventral medulla. Our findings faithfully recapitulate the findings of OX1 mRNA expression previously reported. This is the first study to systematically map the neuroanatomical distribution of OX1 receptors within the mouse hindbrain and suggest that this OX1-GFP transgenic reporter mouse line might be a useful tool with which to study the neuroanatomy and physiology of OX1 receptor-expressing cells. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. The VD1/RPD2 neuronal system in the central nervous system of the pond snail Lymnaea stagnalis studied by in situ hybridization and immunocytochemistry.

    PubMed

    Kerkhoven, R M; Croll, R P; Ramkema, M D; Van Minnen, J; Bogerd, J; Boer, H H

    1992-03-01

    VD1 and RPD2 are two giant neuropeptidergic neurons in the central nervous system (CNS) of the pond snail Lymnaea stagnalis. We wished to determine whether other central neurons in the CNS of L. stagnalis express the VD1/RPD2 gene. To this end, in situ hybridization with the cDNA probe of the VD1/RPD2 gene and immunocytochemistry with antisera specific to VD1 and RPD2 (the alpha 1-antiserum, Mab4H5 and ALMA 6) and to R15 (the alpha 1 and 16-mer antisera) were performed on alternate tissue sections. A VD1/RPD2 neuronal system comprising three classes of neurons (A1-A3) was found. All neurons of the system express the gene. Division into classes is based on immunocytochemical characteristics. Class A1 neurons (VD1 and RPD2) immunoreact with the alpha 1-antiserum, Mab4H5 and ALMA 6. Class A2 neurons (1-5 small and 1-5 medium sized neurons in the visceral and right parietal ganglion, and two clusters of small neurons and 5 medium-sized neurons in the cerebral ganglia) immunoreact with the alpha 1-antiserum and Mab4H5, but not with ALMA 6. Class A3 neurons (3-4 medium-sized neurons and a cluster of 4-5 small neurons located in the pedal ganglion) immunoreact with the alpha 1-antiserum only. All neurons of the system are immunonegative to the R15 antisera. The observations suggest that the neurons of the VD1/RPD2 system produce different sets of neuropeptides. A group of approximately 15 neurons (class B), scattered in the ganglia, immunostained with one or more of the antisera, but did not react with the cDNA probe in in situ hybridization.

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

    PubMed

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

    2016-03-16

    Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    PubMed Central

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

    2017-01-01

    SUMMARY Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery. PMID:26948889

  2. Shaping Neuronal Network Activity by Presynaptic Mechanisms

    PubMed Central

    Ashery, Uri

    2015-01-01

    Neuronal microcircuits generate oscillatory activity, which has been linked to basic functions such as sleep, learning and sensorimotor gating. Although synaptic release processes are well known for their ability to shape the interaction between neurons in microcircuits, most computational models do not simulate the synaptic transmission process directly and hence cannot explain how changes in synaptic parameters alter neuronal network activity. In this paper, we present a novel neuronal network model that incorporates presynaptic release mechanisms, such as vesicle pool dynamics and calcium-dependent release probability, to model the spontaneous activity of neuronal networks. The model, which is based on modified leaky integrate-and-fire neurons, generates spontaneous network activity patterns, which are similar to experimental data and robust under changes in the model's primary gain parameters such as excitatory postsynaptic potential and connectivity ratio. Furthermore, it reliably recreates experimental findings and provides mechanistic explanations for data obtained from microelectrode array recordings, such as network burst termination and the effects of pharmacological and genetic manipulations. The model demonstrates how elevated asynchronous release, but not spontaneous release, synchronizes neuronal network activity and reveals that asynchronous release enhances utilization of the recycling vesicle pool to induce the network effect. The model further predicts a positive correlation between vesicle priming at the single-neuron level and burst frequency at the network level; this prediction is supported by experimental findings. Thus, the model is utilized to reveal how synaptic release processes at the neuronal level govern activity patterns and synchronization at the network level. PMID:26372048

  3. Brain state-dependent neuronal computation

    PubMed Central

    Quilichini, Pascale P.; Bernard, Christophe

    2012-01-01

    Neuronal firing pattern, which includes both the frequency and the timing of action potentials, is a key component of information processing in the brain. Although the relationship between neuronal output (the firing pattern) and function (during a task/behavior) is not fully understood, there is now considerable evidence that a given neuron can show very different firing patterns according to brain state. Thus, such neurons assembled into neuronal networks generate different rhythms (e.g., theta, gamma and sharp wave ripples), which sign specific brain states (e.g., learning, sleep). This implies that a given neuronal network, defined by its hard-wired physical connectivity, can support different brain state-dependent activities through the modulation of its functional connectivity. Here, we review data demonstrating that not only the firing pattern, but also the functional connections between neurons, can change dynamically. We then explore the possible mechanisms of such versatility, focusing on the intrinsic properties of neurons and the properties of the synapses they establish, and how they can be modified by neuromodulators, i.e., the different ways that neurons can use to switch from one mode of communication to the other. PMID:23060787

  4. Glutamate Mediated Astrocytic Filtering of Neuronal Activity

    PubMed Central

    Herzog, Nitzan; De Pittà, Maurizio; Jacob, Eshel Ben; Berry, Hugues; Hanein, Yael

    2014-01-01

    Neuron-astrocyte communication is an important regulatory mechanism in various brain functions but its complexity and role are yet to be fully understood. In particular, the temporal pattern of astrocyte response to neuronal firing has not been fully characterized. Here, we used neuron-astrocyte cultures on multi-electrode arrays coupled to Ca2+ imaging and explored the range of neuronal stimulation frequencies while keeping constant the amount of stimulation. Our results reveal that astrocytes specifically respond to the frequency of neuronal stimulation by intracellular Ca2+ transients, with a clear onset of astrocytic activation at neuron firing rates around 3-5 Hz. The cell-to-cell heterogeneity of the astrocyte Ca2+ response was however large and increasing with stimulation frequency. Astrocytic activation by neurons was abolished with antagonists of type I metabotropic glutamate receptor, validating the glutamate-dependence of this neuron-to-astrocyte pathway. Using a realistic biophysical model of glutamate-based intracellular calcium signaling in astrocytes, we suggest that the stepwise response is due to the supralinear dynamics of intracellular IP3 and that the heterogeneity of the responses may be due to the heterogeneity of the astrocyte-to-astrocyte couplings via gap junction channels. Therefore our results present astrocyte intracellular Ca2+ activity as a nonlinear integrator of glutamate-dependent neuronal activity. PMID:25521344

  5. Cortical Circuits of Callosal GABAergic Neurons.

    PubMed

    Rock, Crystal; Zurita, Hector; Lebby, Sharmon; Wilson, Charles J; Apicella, Alfonso Junior

    2018-04-01

    Anatomical studies have shown that the majority of callosal axons are glutamatergic. However, a small proportion of callosal axons are also immunoreactive for glutamic acid decarboxylase, an enzyme required for gamma-aminobutyric acid (GABA) synthesis and a specific marker for GABAergic neurons. Here, we test the hypothesis that corticocortical parvalbumin-expressing (CC-Parv) neurons connect the two hemispheres of multiple cortical areas, project through the corpus callosum, and are a functional part of the local cortical circuit. Our investigation of this hypothesis takes advantage of viral tracing and optogenetics to determine the anatomical and electrophysiological properties of CC-Parv neurons of the mouse auditory, visual, and motor cortices. We found a direct inhibitory pathway made up of parvalbumin-expressing (Parv) neurons which connects corresponding cortical areas (CC-Parv neurons → contralateral cortex). Like other Parv cortical neurons, these neurons provide local inhibition onto nearby pyramidal neurons and receive thalamocortical input. These results demonstrate a previously unknown long-range inhibitory circuit arising from a genetically defined type of GABAergic neuron that is engaged in interhemispheric communication.

  6. Drebrin in Neuronal Migration and Axonal Growth.

    PubMed

    Hanamura, Kenji

    2017-01-01

    During development, production of neurons from neural stem cells, migration of neurons from their birthplace to their final location, and extension of neurites, axons, and dendrites are important for the formation of functional neuronal circuits. The actin cytoskeleton has major roles in the morphological development of neurons. In this chapter, we focused on the distribution and function of the actin-binding protein, drebrin, to elucidate the importance of drebrin-bound F-actin in neurons during early developmental stages of neurons in embryonic, postnatal, and adult brains. There are three major isoforms of drebrin in the chicken brain (E1, E2, and A) and two major isoforms in the mammalian brain (E and A). Among these drebrin isoforms, drebrin E1 and E2 in chicken and drebrin E in the mammalian brain are involved in these neuronal stages. In migrating neurons of the developing and adult brain, drebrin is localized at the base of filopodia of leading processes, to regulate neuronal migration. In axonal growth cones, drebrin is localized in the transitional zone to regulate axonal growth by inhibiting actomyosin interactions and mediating the interactions between F-actin and microtubules. For axonal collateral branching, drebrin is localized at axonal actin patches and the base of filopodia, to accelerate the transition from actin patches to filopodia and stabilize the filopodia.

  7. Functional connectivity in in vitro neuronal assemblies

    PubMed Central

    Poli, Daniele; Pastore, Vito P.; Massobrio, Paolo

    2015-01-01

    Complex network topologies represent the necessary substrate to support complex brain functions. In this work, we reviewed in vitro neuronal networks coupled to Micro-Electrode Arrays (MEAs) as biological substrate. Networks of dissociated neurons developing in vitro and coupled to MEAs, represent a valid experimental model for studying the mechanisms governing the formation, organization and conservation of neuronal cell assemblies. In this review, we present some examples of the use of statistical Cluster Coefficients and Small World indices to infer topological rules underlying the dynamics exhibited by homogeneous and engineered neuronal networks. PMID:26500505

  8. Does diabetes mellitus target motor neurons?

    PubMed

    Ramji, Noor; Toth, Cory; Kennedy, James; Zochodne, Douglas W

    2007-05-01

    A pattern of peripheral neurodegeneration occurs in chronic diabetes mellitus in which an early, but selective retraction of distal axons may occur prior to any irretrievable neuronal loss. Clinical observations suggest that sensory systems undergo damage before those of motor neurons. In this work, we examined the fate of the spinal motor neuron in a long-term chronic model of experimental (streptozotocin-induced) diabetes already known to be associated with substantial loss of sensory neurons. The integrity, physiological function, and critical forms of protein expression of the full motor neuron tree was examined in mice exposed to 8 months of diabetes. Motor neurons developed progressive features of distal loss of axonal terminals but without perikaryal dropout, indicating distal axon retraction. While numbers and caliber of motor neuron perikarya and their nerve trunk axons were preserved, axons developed conduction velocity slowing, loss of motor units and neuromuscular junctions, and compensatory single motor unit action potential enlargement. Four critical proteins directly linked to diabetic complications were altered in motor neurons of diabetic mice: an elevated perikaryal expression of RAGE and PARP, molecules associated with cellular stress, along with concurrent rises in HSP-27 and pAKT, molecules alternatively identified with neuroprotective survival. Moreover, Akt mRNA was increased in diabetic lumbar spinal cords. Overall these findings indicate that although motor neurons are resistant to irretrievable dropout, they are targeted nonetheless by diabetes and gradually withdraw their terminals from distal innervation.

  9. Spiking Neurons for Analysis of Patterns

    NASA Technical Reports Server (NTRS)

    Huntsberger, Terrance

    2008-01-01

    Artificial neural networks comprising spiking neurons of a novel type have been conceived as improved pattern-analysis and pattern-recognition computational systems. These neurons are represented by a mathematical model denoted the state-variable model (SVM), which among other things, exploits a computational parallelism inherent in spiking-neuron geometry. Networks of SVM neurons offer advantages of speed and computational efficiency, relative to traditional artificial neural networks. The SVM also overcomes some of the limitations of prior spiking-neuron models. There are numerous potential pattern-recognition, tracking, and data-reduction (data preprocessing) applications for these SVM neural networks on Earth and in exploration of remote planets. Spiking neurons imitate biological neurons more closely than do the neurons of traditional artificial neural networks. A spiking neuron includes a central cell body (soma) surrounded by a tree-like interconnection network (dendrites). Spiking neurons are so named because they generate trains of output pulses (spikes) in response to inputs received from sensors or from other neurons. They gain their speed advantage over traditional neural networks by using the timing of individual spikes for computation, whereas traditional artificial neurons use averages of activity levels over time. Moreover, spiking neurons use the delays inherent in dendritic processing in order to efficiently encode the information content of incoming signals. Because traditional artificial neurons fail to capture this encoding, they have less processing capability, and so it is necessary to use more gates when implementing traditional artificial neurons in electronic circuitry. Such higher-order functions as dynamic tasking are effected by use of pools (collections) of spiking neurons interconnected by spike-transmitting fibers. The SVM includes adaptive thresholds and submodels of transport of ions (in imitation of such transport in biological

  10. Discrimination of communication vocalizations by single neurons and groups of neurons in the auditory midbrain.

    PubMed

    Schneider, David M; Woolley, Sarah M N

    2010-06-01

    Many social animals including songbirds use communication vocalizations for individual recognition. The perception of vocalizations depends on the encoding of complex sounds by neurons in the ascending auditory system, each of which is tuned to a particular subset of acoustic features. Here, we examined how well the responses of single auditory neurons could be used to discriminate among bird songs and we compared discriminability to spectrotemporal tuning. We then used biologically realistic models of pooled neural responses to test whether the responses of groups of neurons discriminated among songs better than the responses of single neurons and whether discrimination by groups of neurons was related to spectrotemporal tuning and trial-to-trial response variability. The responses of single auditory midbrain neurons could be used to discriminate among vocalizations with a wide range of abilities, ranging from chance to 100%. The ability to discriminate among songs using single neuron responses was not correlated with spectrotemporal tuning. Pooling the responses of pairs of neurons generally led to better discrimination than the average of the two inputs and the most discriminating input. Pooling the responses of three to five single neurons continued to improve neural discrimination. The increase in discriminability was largest for groups of neurons with similar spectrotemporal tuning. Further, we found that groups of neurons with correlated spike trains achieved the largest gains in discriminability. We simulated neurons with varying levels of temporal precision and measured the discriminability of responses from single simulated neurons and groups of simulated neurons. Simulated neurons with biologically observed levels of temporal precision benefited more from pooling correlated inputs than did neurons with highly precise or imprecise spike trains. These findings suggest that pooling correlated neural responses with the levels of precision observed in the

  11. [Infantile autism and mirror neurons].

    PubMed

    Cornelio-Nieto, J O

    2009-02-27

    Infantile autism is a disorder that is characterised by alterations affecting reciprocal social interactions, abnormal verbal and non-verbal communication, poor imaginative activity and a restricted repertoire of activities and interests. The causes of autism remain unknown, but there are a number of different approaches that attempt to explain the neurobiological causes of the syndrome. A recent theory that has been considered is that of a dysfunction in the mirror neuron system (MNS). The MNS is a neuronal complex, originally described in monkeys and also found in humans, that is related with our movements and which offers specific responses to the movements and intended movements of other subjects. This system is believed to underlie processes of imitation and our capacity to learn by imitation. It is also thought to play a role in language acquisition, in expressing the emotions, in understanding what is happening to others and in empathy. Because these functions are altered in children with autism, it has been suggested that there is some dysfunction present in the MNS of those with autism. Dysfunction of the MNS could account for the symptoms that are observed in children with autism.

  12. Advances in motor neurone disease.

    PubMed

    Bäumer, Dirk; Talbot, Kevin; Turner, Martin R

    2014-01-01

    Motor neurone disease (MND), the commonest clinical presentation of which is amyotrophic lateral sclerosis (ALS), is regarded as the most devastating of adult-onset neurodegenerative disorders. The last decade has seen major improvements in patient care, but also rapid scientific advances, so that rational therapies based on key pathogenic mechanisms now seem plausible. ALS is strikingly heterogeneous in both its presentation, with an average one-year delay from first symptoms to diagnosis, and subsequent rate of clinical progression. Although half of patients succumb within 3-4 years of symptom onset, typically through respiratory failure, a significant minority survives into a second decade. Although an apparently sporadic disorder for most patients, without clear environmental triggers, recent genetic studies have identified disease-causing mutations in genes in several seemingly disparate functional pathways, so that motor neuron degeneration may need to be understood as a common final pathway with a number of upstream causes. This apparent aetiological and clinical heterogeneity suggests that therapeutic studies should include detailed biomarker profiling, and consider genetic as well as clinical stratification. The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein degradation pathways in the core of ALS pathogenesis. A major gap remains in understanding how such fundamental processes appear to function without obvious deficit in the decades prior to symptom emergence, and the study of pre-symptomatic gene carriers is an important new initiative.

  13. Neurons, networks, and motor behavior.

    PubMed

    Katz, P S

    1996-02-01

    The field of motor pattern generation and motor control has progressed markedly in the last decade. There has been a revolutionary shift in thinking from hard-wired circuits to multifunctional networks. Yet, it is clear that we still have a long way to go before we understand how very large ensembles of neurons produce behaviors. The systems where we have made the most headway are those that have an orderly topography, such as the superior colliculus (Sparks) or motor cortex (Georgopoulos). However, even in these systems, although we understand how to interpret the combined activity of the neuronal population, it is not clear how this population activity is translated into a motor command. Similarly, the directional behavior produced in cockroach (Ritzmann) and fish escape (Eaton) systems can be predicted based on the activity of neurons, but the cellular mechanisms producing the turning responses in cockroaches and teleost fish are not completely understood. Undoubtedly, computational approaches, including new mathematical formalisms and computer simulations, will play a role in elucidating how very large ensembles of neurons produce their coordinated output. For now, the systems where motor pattern generation is best understood at the cellular level are those with small numbers of neurons (such as invertebrate circuits) or small numbers of cell types, such as lamprey and tadpole spinal circuits. These systems are thus valuable for pointing to potential mechanisms used in larger systems. (Note that I avoid using the term "simple" systems to describe invertebrates because it is quite clear that these systems are anything but simple.) However, "interphyletic awareness," as it was referred to at this conference, is not important just for what it can tell us about how mammals work. It is also important to learn of alternative ways in which organisms solve similar problems. This may prove to be particularly important for the future of robotics. Already, robots have

  14. Anatomical characterization of PDF-tri neurons and peptidergic neurons associated with eclosion behavior in Drosophila.

    PubMed

    Selcho, Mareike; Mühlbauer, Barbara; Hensgen, Ronja; Shiga, Sakiko; Wegener, Christian; Yasuyama, Kouji

    2018-06-01

    The peptidergic Pigment-dispersing factor (PDF)-Tri neurons are a group of non-clock neurons that appear transiently around the time of adult ecdysis (=eclosion) in the fruit fly Drosophila melanogaster. This specific developmental pattern points to a function of these neurons in eclosion or other processes that are active around pupal-adult transition. As a first step to understand the role of these neurons, we here characterize the anatomy of the PDF-Tri neurons. In addition, we describe a further set of peptidergic neurons that have been associated with eclosion behavior, eclosion hormone (EH), and crustacean cardioactive peptide (CCAP) neurons, to single cell level in the pharate adult brain. PDF-Tri neurons as well as CCAP neurons co-express a classical transmitter indicated by the occurrence of small clear vesicles in addition to dense-core vesicles containing the peptides. In the tritocerebrum, gnathal ganglion and the superior protocerebrum PDF-Tri neurites contain peptidergic varicosities and both pre- and postsynaptic sites, suggesting that the PDF-Tri neurons represent modulatory rather than pure interneurons that connect the subesophageal zone with the superior protocerebrum. The extensive overlap of PDF-Tri arborizations with neurites of CCAP- and EH-expressing neurons in distinct brain regions provides anatomical evidence for a possible function of the PDF-Tri neurons in eclosion behavior. © 2018 Wiley Periodicals, Inc.

  15. Essential roles of mitochondrial depolarization in neuron loss through microglial activation and attraction toward neurons.

    PubMed

    Nam, Min-Kyung; Shin, Hyun-Ah; Han, Ji-Hye; Park, Dae-Wook; Rhim, Hyangshuk

    2013-04-10

    As life spans increased, neurodegenerative disorders that affect aging populations have also increased. Progressive neuronal loss in specific brain regions is the most common cause of neurodegenerative disease; however, key determinants mediating neuron loss are not fully understood. Using a model of mitochondrial membrane potential (ΔΨm) loss, we found only 25% cell loss in SH-SY5Y (SH) neuronal mono-cultures, but interestingly, 85% neuronal loss occurred when neurons were co-cultured with BV2 microglia. SH neurons overexpressing uncoupling protein 2 exhibited an increase in neuron-microglia interactions, which represent an early step in microglial phagocytosis of neurons. This result indicates that ΔΨm loss in SH neurons is an important contributor to recruitment of BV2 microglia. Notably, we show that ΔΨm loss in BV2 microglia plays a crucial role in microglial activation and phagocytosis of damaged SH neurons. Thus, our study demonstrates that ΔΨm loss in both neurons and microglia is a critical determinant of neuron loss. These findings also offer new insights into neuroimmunological and bioenergetical aspects of neurodegenerative disease. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses.

    PubMed

    Sudhakar, Shyam Kumar; Torben-Nielsen, Benjamin; De Schutter, Erik

    2015-12-01

    Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it.

  17. Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses

    PubMed Central

    Sudhakar, Shyam Kumar; Torben-Nielsen, Benjamin; De Schutter, Erik

    2015-01-01

    Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it. PMID:26630202

  18. Multisite two-photon imaging of neurons on multielectrode arrays

    NASA Astrophysics Data System (ADS)

    Potter, Steve M.; Lukina, Natalia; Longmuir, Kenneth J.; Wu, Yan

    2001-04-01

    We wish to understand how neural systems store, recall, and process information. We are using cultured networks of cortical neurons grown on microelectrode arrays as a model system for studying the emergent properties of ensembles of living neurons. We have developed a 2-way communication interface between the cultured network and a computer- generated animal, the Neurally Controlled Animat. Neural activity is used to control the behavior of the Animat, and 2- photon time-lapse imaging is carried out in order to observe the morphological changes that might underlie changes in neural processing. The 2-photon microscope is ideal for repeated imaging over hours or days, with submicron resolution and little photodamage. We have designed a computer-controlled microscope stage that allows imaging several locations in sequence, in order to collect more image data. For the latest progress, see: http://www.caltech.edu/~pinelab/PotterGroup.htm.

  19. Interactive Exploration for Continuously Expanding Neuron Databases.

    PubMed

    Li, Zhongyu; Metaxas, Dimitris N; Lu, Aidong; Zhang, Shaoting

    2017-02-15

    This paper proposes a novel framework to help biologists explore and analyze neurons based on retrieval of data from neuron morphological databases. In recent years, the continuously expanding neuron databases provide a rich source of information to associate neuronal morphologies with their functional properties. We design a coarse-to-fine framework for efficient and effective data retrieval from large-scale neuron databases. In the coarse-level, for efficiency in large-scale, we employ a binary coding method to compress morphological features into binary codes of tens of bits. Short binary codes allow for real-time similarity searching in Hamming space. Because the neuron databases are continuously expanding, it is inefficient to re-train the binary coding model from scratch when adding new neurons. To solve this problem, we extend binary coding with online updating schemes, which only considers the newly added neurons and update the model on-the-fly, without accessing the whole neuron databases. In the fine-grained level, we introduce domain experts/users in the framework, which can give relevance feedback for the binary coding based retrieval results. This interactive strategy can improve the retrieval performance through re-ranking the above coarse results, where we design a new similarity measure and take the feedback into account. Our framework is validated on more than 17,000 neuron cells, showing promising retrieval accuracy and efficiency. Moreover, we demonstrate its use case in assisting biologists to identify and explore unknown neurons. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Neuron Morphology Influences Axon Initial Segment Plasticity.

    PubMed

    Gulledge, Allan T; Bravo, Jaime J

    2016-01-01

    In most vertebrate neurons, action potentials are initiated in the axon initial segment (AIS), a specialized region of the axon containing a high density of voltage-gated sodium and potassium channels. It has recently been proposed that neurons use plasticity of AIS length and/or location to regulate their intrinsic excitability. Here we quantify the impact of neuron morphology on AIS plasticity using computational models of simplified and realistic somatodendritic morphologies. In small neurons (e.g., dentate granule neurons), excitability was highest when the AIS was of intermediate length and located adjacent to the soma. Conversely, neurons having larger dendritic trees (e.g., pyramidal neurons) were most excitable when the AIS was longer and/or located away from the soma. For any given somatodendritic morphology, increasing dendritic membrane capacitance and/or conductance favored a longer and more distally located AIS. Overall, changes to AIS length, with corresponding changes in total sodium conductance, were far more effective in regulating neuron excitability than were changes in AIS location, while dendritic capacitance had a larger impact on AIS performance than did dendritic conductance. The somatodendritic influence on AIS performance reflects modest soma-to-AIS voltage attenuation combined with neuron size-dependent changes in AIS input resistance, effective membrane time constant, and isolation from somatodendritic capacitance. We conclude that the impact of AIS plasticity on neuron excitability will depend largely on somatodendritic morphology, and that, in some neurons, a shorter or more distally located AIS may promote, rather than limit, action potential generation.

  1. Motor neurons and the generation of spinal motor neuron diversity

    PubMed Central

    Stifani, Nicolas

    2014-01-01

    Motor neurons (MNs) are neuronal cells located in the central nervous system (CNS) controlling a variety of downstream targets. This function infers the existence of MN subtypes matching the identity of the targets they innervate. To illustrate the mechanism involved in the generation of cellular diversity and the acquisition of specific identity, this review will focus on spinal MNs (SpMNs) that have been the core of significant work and discoveries during the last decades. SpMNs are responsible for the contraction of effector muscles in the periphery. Humans possess more than 500 different skeletal muscles capable to work in a precise time and space coordination to generate complex movements such as walking or grasping. To ensure such refined coordination, SpMNs must retain the identity of the muscle they innervate. Within the last two decades, scientists around the world have produced considerable efforts to elucidate several critical steps of SpMNs differentiation. During development, SpMNs emerge from dividing progenitor cells located in the medial portion of the ventral neural tube. MN identities are established by patterning cues working in cooperation with intrinsic sets of transcription factors. As the embryo develop, MNs further differentiate in a stepwise manner to form compact anatomical groups termed pools connecting to a unique muscle target. MN pools are not homogeneous and comprise subtypes according to the muscle fibers they innervate. This article aims to provide a global view of MN classification as well as an up-to-date review of the molecular mechanisms involved in the generation of SpMN diversity. Remaining conundrums will be discussed since a complete understanding of those mechanisms constitutes the foundation required for the elaboration of prospective MN regeneration therapies. PMID:25346659

  2. Iron is essential for neuron development and memory function in mouse hippocampus.

    PubMed

    Carlson, Erik S; Tkac, Ivan; Magid, Rhamy; O'Connor, Michael B; Andrews, Nancy C; Schallert, Timothy; Gunshin, Hiromi; Georgieff, Michael K; Petryk, Anna

    2009-04-01

    Iron deficiency (ID) is the most prevalent micronutrient deficiency in the world and it affects neurobehavioral outcome. It is unclear whether the effect of dietary ID on the brain is due to the lack of neuronal iron or from other processes occurring in conjunction with ID (e.g. hypoxia due to anemia). We delineated the role of murine Slc11a2 [divalent metal ion transporter-1 (DMT-1)] in hippocampal neuronal iron uptake during development and memory formation. Camk2a gene promoter-driven cre recombinase (Cre) transgene (Camk2a-Cre) mice were mated with Slc11a2 flox/flox mice to obtain nonanemic Slc11a2(hipp/hipp) (double mutant, hippocampal neuron-specific knockout of Slc11a2(hipp/hipp)) mice, the first conditionally targeted model of iron uptake in the brain. Slc11a2(hipp/hipp) mice had lower hippocampal iron content; altered developmental expression of genes involved in iron homeostasis, energy metabolism, and dendrite morphogenesis; reductions in markers for energy metabolism and glutamatergic neurotransmission on magnetic resonance spectroscopy; and altered pyramidal neuron dendrite morphology in area 1 of Ammon's Horn in the hippocampus. Slc11a2(hipp/hipp) mice did not reach the criterion on a difficult spatial navigation test but were able to learn a spatial navigation task on an easier version of the Morris water maze (MWM). Learning of the visual cued task did not differ between the Slc11a2(WT/WT) and Slc11a2(hipp/hipp) mice. Slc11a2(WT/WT) mice had upregulation of genes involved in iron uptake and metabolism in response to MWM training, and Slc11a2(hipp/hipp) mice had differential expression of these genes compared with Slc11a2(WT/WT) mice. Neuronal iron uptake by DMT-1 is essential for normal hippocampal neuronal development and Slc11a2 expression is induced by spatial memory training. Deletion of Slc11a2 disrupts hippocampal neuronal development and spatial memory behavior.

  3. Glutamate differently modulates excitatory and inhibitory adenosine receptors in neuronal and glial cells.

    PubMed

    Castillo, Carlos Alberto; León, David Agustín; Ballesteros-Yáñez, Inmaculada; Albasanz, José Luis; Martín, Mairena

    2010-08-01

    Adenosine is a neuromodulator which acts through adenosine receptors regulating functions such as inhibition of glutamate release. Adenosine A(1) and A(2A) receptor activations most often regulate opposing actions. Primary rat cortical neurons and rat C6 cells, an astrocytic derived cell line, were exposed to 100muM l-glutamate, and cell viability and transduction pathways mediated by both A(1) and A(2A) receptors were analyzed. Glutamate-induced excitotoxic damage was found only in cortical neurons, with C6 cells preserved. In C6 cells, adenosine A(1) and A(2A) receptors were increased and decreased, respectively. Consequently, A(1)-mediated adenylyl cyclase inhibition and A(2A)-mediated adenylyl cyclase stimulation were, respectively, increased and decreased after glutamate exposure. In cortical neurons, glutamate treatment increased both A(1) and A(2A) receptors. Moreover, adenylyl cyclase responsiveness to A(1) or A(2A) receptor agonists was heightened in these cells, in which pharmacological activation of AC induced cell death. Finally, activation of A(1) receptor or blockade of A(2A) receptor during glutamate treatment partially prevented the glutamate-induced cell death detected in cultured cortical neurons. Results show that adenosine receptors are regulated by glutamate, and that this regulation is dependent on the cell type, suggesting that adenosine receptors might be promising targets in the therapy against excitotoxic cell death.

  4. Opioids inhibit visceral afferent activation of catecholamine neurons in the solitary tract nucleus

    PubMed Central

    Cui, Ran Ji; Roberts, Brandon L.; Zhao, Huan; Andresen, Michael C.; Appleyard, Suzanne M.

    2014-01-01

    Brainstem A2/C2 catecholamine (CA) neurons within the solitary tract nucleus (NTS) influence many homeostatic functions, including food intake, stress, respiratory and cardiovascular reflexes. They also play a role in both opioid reward and withdrawal. Injections of opioids into the NTS modulate many autonomic functions influenced by catecholamine neurons including food intake and cardiac function. We recently showed that NTS-CA neurons are directly activated by incoming visceral afferent inputs. Here we determined whether opioid agonists modulate afferent activation of NTS-CA neurons using transgenic mice with EGFP expressed under the control of the tyrosine hydroxylase promoter (TH-EGFP) to identify catecholamine neurons. The opioid agonist Met-enkephalin (Met-Enk) significantly attenuated solitary tract evoked EPSCs (ST-EPSCs) in NTS TH-EGFP neurons by 80%, an effect reversed by wash or the mu opioid receptor specific antagonist, CTOP. Met-Enk had a significantly greater effect to inhibit afferent inputs onto TH-EGFP positive neurons than EGFP negative neurons, which were only inhibited by 50%. The mu agonist, DAMGO, also inhibited the ST-EPSC in TH-EGFP neurons in a dose-dependent manner. In contrast, neither the delta agonist DPDPE, nor the kappa agonist, U69,593, consistently inhibited the ST-EPSC amplitude. Met-Enk and DAMGO increased the paired pulse ratio, decreased the frequency, but not amplitude, of mini-EPSCs and had no effect on holding current, input resistance or current-voltage relationships in TH-EGFP neurons, suggesting a presynaptic mechanism of action on afferent terminals. Met-Enk significantly reduced both the basal firing rate of NTS TH-EGFP neurons and the ability of afferent stimulation to evoke an action potential. These results suggest that opioids inhibit NTS-CA neurons by reducing an excitatory afferent drive onto these neurons through presynaptic inhibition of glutamate release and elucidate one potential mechanism by which opioids

  5. Opioids inhibit visceral afferent activation of catecholamine neurons in the solitary tract nucleus.

    PubMed

    Cui, R J; Roberts, B L; Zhao, H; Andresen, M C; Appleyard, S M

    2012-10-11

    Brainstem A2/C2 catecholamine (CA) neurons within the solitary tract nucleus (NTS) influence many homeostatic functions, including food intake, stress, respiratory and cardiovascular reflexes. They also play a role in both opioid reward and withdrawal. Injections of opioids into the NTS modulate many autonomic functions influenced by catecholamine neurons including food intake and cardiac function. We recently showed that NTS-CA neurons are directly activated by incoming visceral afferent inputs. Here we determined whether opioid agonists modulate afferent activation of NTS-CA neurons using transgenic mice with EGFP expressed under the control of the tyrosine hydroxylase promoter (TH-EGFP) to identify catecholamine neurons. The opioid agonist Met-enkephalin (Met-Enk) significantly attenuated solitary tract-evoked excitatory postsynaptic currents (ST-EPSCs) in NTS TH-EGFP neurons by 80%, an effect reversed by wash or the mu opioid receptor-specific antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP). Met-Enk had a significantly greater effect to inhibit afferent inputs onto TH-EGFP-positive neurons than EGFP-negative neurons, which were only inhibited by 50%. The mu agonist, DAMGO, also inhibited the ST-EPSC in TH-EGFP neurons in a dose-dependent manner. In contrast, neither the delta agonist DPDPE, nor the kappa agonist, U69,593, consistently inhibited the ST-EPSC amplitude. Met-Enk and DAMGO increased the paired pulse ratio, decreased the frequency, but not amplitude, of mini-EPSCs and had no effect on holding current, input resistance or current-voltage relationships in TH-EGFP neurons, suggesting a presynaptic mechanism of action on afferent terminals. Met-Enk significantly reduced both the basal firing rate of NTS TH-EGFP neurons and the ability of afferent stimulation to evoke an action potential. These results suggest that opioids inhibit NTS-CA neurons by reducing an excitatory afferent drive onto these neurons through presynaptic inhibition of

  6. Local and commissural IC neurons make axosomatic inputs on large GABAergic tectothalamic neurons.

    PubMed

    Ito, Tetsufumi; Oliver, Douglas L

    2014-10-15

    Large GABAergic (LG) neurons are a distinct type of neuron in the inferior colliculus (IC) identified by their dense vesicular glutamate transporter 2 (VGLUT2)-containing axosomatic synaptic terminals. Yet the sources of these terminals are unknown. Since IC glutamatergic neurons express VGLUT2, and IC neurons are known to have local collaterals, we tested the hypothesis that these excitatory, glutamatergic axosomatic inputs on LG neurons come from local axonal collaterals and commissural IC neurons. We injected a recombinant viral tracer into the IC which enabled Golgi-like green fluorescent protein (GFP) labeling in both dendrites and axons. In all cases, we found terminals positive for both GFP and VGLUT2 (GFP+/VGLUT2+) that made axosomatic contacts on LG neurons. One to six axosomatic contacts were made on a single LG cell body by a single axonal branch. The GFP-labeled neurons giving rise to the VGLUT2+ terminals on LG neurons were close by. The density of GFP+/VGLUT2+ terminals on the LG neurons was related to the number of nearby GFP-labeled cells. On the contralateral side, a smaller number of LG neurons received axosomatic contacts from GFP+/VGLUT2+ terminals. In cases with a single GFP-labeled glutamatergic neuron, the labeled axonal plexus was flat, oriented in parallel to the fibrodendritic laminae, and contacted 9-30 LG cell bodies within the plexus. Our data demonstrated that within the IC microcircuitry there is a convergence of inputs from local IC excitatory neurons on LG cell bodies. This suggests that LG neurons are heavily influenced by the activity of the nearby laminar glutamatergic neurons in the IC. © 2014 Wiley Periodicals, Inc.

  7. Local and Commissural IC Neurons Make Axosomatic Inputs on Large GABAergic Tectothalamic Neurons

    PubMed Central

    Ito, Tetsufumi; Oliver, Douglas L.

    2014-01-01

    Large GABAergic (LG) neurons are a distinct type of neuron in the inferior colliculus (IC) identified by their dense VGLUT2-containing axosomatic synaptic terminals. Yet, the sources of these terminals are unknown. Since IC glutamatergic neurons express VGLUT2, and IC neurons are known to have local collaterals, we tested the hypothesis that these excitatory, glutamatergic axosomatic inputs on LG neurons come from local axonal collaterals and commissural IC neurons. We injected a recombinant viral tracer into the IC which enabled Golgi-like GFP labeling in both dendrites and axons. In all cases, we found terminals positive for both GFP and VGLUT2 (GFP+/VGLUT2+) that made axosomatic contacts on LG neurons. One to six axosomatic contacts were made on a single LG cell body by a single axonal branch. The GFP-labeled neurons giving rise to the VGLUT2+ terminals on LG neurons were close by. The density of GFP+/VGLUT2+ terminals on the LG neurons was related to the number of nearby GFP-labeled cells. On the contralateral side, a smaller number of LG neurons received axosomatic contacts from GFP+/VGLUT2+ terminals. In cases with a single GFP-labeled glutamatergic neuron, the labeled axonal plexus was flat, oriented in parallel to the fibrodendritic laminae, and contacted 9–30 LG cell bodies within the plexus. Our data demonstrated that within the IC microcircuitry, there is a convergence of inputs from local IC excitatory neurons on LG cell bodies. This suggests that LG neurons are heavily influenced by the activity of the nearby laminar glutamatergic neurons in the IC. PMID:24796971

  8. Heavy metals in locus ceruleus and motor neurons in motor neuron disease

    PubMed Central

    2013-01-01

    Background The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Results Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Conclusions Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons. PMID:24330485

  9. Heavy metals in locus ceruleus and motor neurons in motor neuron disease.

    PubMed

    Pamphlett, Roger; Kum Jew, Stephen

    2013-12-12

    The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons.

  10. Taste responses of cortical neurons.

    PubMed

    Yamamoto, T

    1984-01-01

    Branches of the facial, glossopharyngeal and vagus nerves which synapse with the receptor cells in the taste buds convey taste messages to the rostral part of the nucleus of the solitary tract. The second relay nucleus for ascending taste input is the parabrachial nucleus of the pons. The third relay nucleus is the medial parvocellular component of the ventrobasal complex of the thalamus. This thalamic nucleus projects to the cortical taste area. Another ascending projection site of the parabrachial nucleus is to the lateral hypothalamus, amygdala and bed nucleus of the stria terminalis. In monkeys, neurons from the gustatory area of the solitary nucleus directly reach the thalamic taste area, bypassing the parabrachial nucleus. Taste-elicited reflex activities are based on a hedonic (acceptable or rejective) aspect of taste, and are basically determined in the brain stem without activation of cortical neurons. The cerebral cortical taste area is located dorsal to the rhinal sulcus in or near the insular cortex in different species of animals. Besides this taste area, taste inputs also project to the tongue tactile area of the SI in monkeys, cats and rats. Taste-responsive neurons in SI area are also responsive to light tactile stimulation of the tongue. Human clinical case reports suggest that discrimination or recognition of taste quality are processed in the cortical taste area. In animal experiments, it is difficult to determine the functional significance of this area. However, recent behavioral studies using the conditioned taste aversion technique in rats suggest that the cortical taste area plays an important role in cognitive (learning, memorial, associative and discriminative) processes of taste sensation. Summated cortical evoked potentials have been recorded in human and rats to electrical and taste stimulations applied to the tongue surface. Recording of gustatory primary evoked potentials is unsuccessful in human subjects. The responses to taste

  11. Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain-barrier and impairs iron-dependent hippocampal neuron dendrite development

    PubMed Central

    Bastian, Thomas W.; Duck, Kari A.; Michalopoulos, George C.; Chen, Michael J.; Liu, Zhi-Jian; Connor, James R.; Lanier, Lorene M.; Sola-Visner, Martha C.; Georgieff, Michael K.

    2017-01-01

    Background Thrombocytopenia is common in sick neonates. Thrombopoietin mimetics (e.g., eltrombopag (ELT)) might provide an alternative therapy for selected neonates with severe and prolonged thrombocytopenia, and for infants and young children with different varieties of thrombocytopenia. However, ELT chelates intracellular iron, which may adversely affect developing organs with high metabolic requirements. Iron deficiency (ID) is particularly deleterious during brain development, impairing neuronal myelination, dopamine signaling, and dendritic maturation and ultimately impairing long-term neurological function (e.g. hippocampal-dependent learning and memory). Objective Determine whether ELT crosses the blood-brain barrier (BBB), causes neuronal ID and impairs hippocampal neuron dendrite maturation. Methods ELT transport across the BBB was assessed using primary bovine brain microvascular endothelial cells. Embryonic mouse primary hippocampal neuron cultures were treated with ELT or deferoxamine (DFO, an iron chelator) from 7 days in vitro (DIV) through 14DIV and assessed for gene expression and neuronal dendrite complexity. Results ELT crossed the BBB in a time-dependent manner. 2 and 6 μM ELT increased Tfr1 and Slc11a2 (iron-responsive genes involved in neuronal iron uptake) mRNA levels, indicating neuronal ID. 6 μM ELT, but not 2 μM ELT, decreased BdnfVI, Camk2a, and Vamp1 mRNA levels, suggesting impaired neuronal development and synaptic function. Dendrite branch number and length was reduced in 6 μM ELT-treated neurons, resulting in blunted dendritic arbor complexity that was similar to DFO-treated neurons. Conclusions ELT treatment during development may impair neuronal structure due to neuronal ID. Pre-clinical in vivo studies are warranted to assess ELT safety during periods of rapid brain development. PMID:28005311

  12. Acid-sensing ion channels in mouse olfactory bulb M/T neurons

    PubMed Central

    Li, Ming-Hua; Liu, Selina Qiuying; Inoue, Koichi; Lan, Jinquan; Simon, Roger P.

    2014-01-01

    The olfactory bulb contains the first synaptic relay in the olfactory pathway, the sensory system in which odorants are detected enabling these chemical stimuli to be transformed into electrical signals and, ultimately, the perception of odor. Acid-sensing ion channels (ASICs), a family of proton-gated cation channels, are widely expressed in neurons of the central nervous system. However, no direct electrophysiological and pharmacological characterizations of ASICs in olfactory bulb neurons have been described. Using a combination of whole-cell patch-clamp recordings and biochemical and molecular biological analyses, we demonstrated that functional ASICs exist in mouse olfactory bulb mitral/tufted (M/T) neurons and mainly consist of homomeric ASIC1a and heteromeric ASIC1a/2a channels. ASIC activation depolarized cultured M/T neurons and increased their intracellular calcium concentration. Thus, ASIC activation may play an important role in normal olfactory function. PMID:24821964

  13. Mirror neurons: functions, mechanisms and models.

    PubMed

    Oztop, Erhan; Kawato, Mitsuo; Arbib, Michael A

    2013-04-12

    Mirror neurons for manipulation fire both when the animal manipulates an object in a specific way and when it sees another animal (or the experimenter) perform an action that is more or less similar. Such neurons were originally found in macaque monkeys, in the ventral premotor cortex, area F5 and later also in the inferior parietal lobule. Recent neuroimaging data indicate that the adult human brain is endowed with a "mirror neuron system," putatively containing mirror neurons and other neurons, for matching the observation and execution of actions. Mirror neurons may serve action recognition in monkeys as well as humans, whereas their putative role in imitation and language may be realized in human but not in monkey. This article shows the important role of computational models in providing sufficient and causal explanations for the observed phenomena involving mirror systems and the learning processes which form them, and underlines the need for additional circuitry to lift up the monkey mirror neuron circuit to sustain the posited cognitive functions attributed to the human mirror neuron system. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Do mirror neurons subserve action understanding?

    PubMed

    Hickok, Gregory

    2013-04-12

    Mirror neurons were once widely believed to support action understanding via motor simulation of the observed actions. Recent evidence regarding the functional properties of mirror neurons in monkeys as well as much neuropsychological evidence in humans has shown that this is not the case. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  15. The Mirror Neuron System and Action Recognition

    ERIC Educational Resources Information Center

    Buccino, Giovanni; Binkofski, Ferdinand; Riggio, Lucia

    2004-01-01

    Mirror neurons, first described in the rostral part of monkey ventral premotor cortex (area F5), discharge both when the animal performs a goal-directed hand action and when it observes another individual performing the same or a similar action. More recently, in the same area mirror neurons responding to the observation of mouth actions have been…

  16. Do Mirror Neurons Subserve Action Understanding?

    PubMed Central

    Hickok, Gregory

    2012-01-01

    Mirror neurons were once widely believed to support action understanding via motor simulation of the observed actions. Recent evidence regarding the functional properties of mirror neurons in monkeys as well as much neuropsychological evidence in humans has shown that this is not the case PMID:23147121

  17. Adaptive Neurons For Artificial Neural Networks

    NASA Technical Reports Server (NTRS)

    Tawel, Raoul

    1990-01-01

    Training time decreases dramatically. In improved mathematical model of neural-network processor, temperature of neurons (in addition to connection strengths, also called weights, of synapses) varied during supervised-learning phase of operation according to mathematical formalism and not heuristic rule. Evidence that biological neural networks also process information at neuronal level.

  18. Elongator bridges tubulin acetylation and neuronal migration.

    PubMed

    Wynshaw-Boris, Anthony

    2009-02-06

    Neuronal cell migration and maturation are crucial for the development of the mammalian cerebral cortex. In this issue, Creppe et al. (2009) now show that the multisubunit histone acetyltransferase Elongator may regulate migration and branch formation of cortical neurons in the developing mouse brain by acetylating alpha-tubulin.

  19. Parallel network simulations with NEURON.

    PubMed

    Migliore, M; Cannia, C; Lytton, W W; Markram, Henry; Hines, M L

    2006-10-01

    The NEURON simulation environment has been extended to support parallel network simulations. Each processor integrates the equations for its subnet over an interval equal to the minimum (interprocessor) presynaptic spike generation to postsynaptic spike delivery connection delay. The performance of three published network models with very different spike patterns exhibits superlinear speedup on Beowulf clusters and demonstrates that spike communication overhead is often less than the benefit of an increased fraction of the entire problem fitting into high speed cache. On the EPFL IBM Blue Gene, almost linear speedup was obtained up to 100 processors. Increasing one model from 500 to 40,000 realistic cells exhibited almost linear speedup on 2,000 processors, with an integration time of 9.8 seconds and communication time of 1.3 seconds. The potential for speed-ups of several orders of magnitude makes practical the running of large network simulations that could otherwise not be explored.

  20. Parallel Network Simulations with NEURON

    PubMed Central

    Migliore, M.; Cannia, C.; Lytton, W.W; Markram, Henry; Hines, M. L.

    2009-01-01

    The NEURON simulation environment has been extended to support parallel network simulations. Each processor integrates the equations for its subnet over an interval equal to the minimum (interprocessor) presynaptic spike generation to postsynaptic spike delivery connection delay. The performance of three published network models with very different spike patterns exhibits superlinear speedup on Beowulf clusters and demonstrates that spike communication overhead is often less than the benefit of an increased fraction of the entire problem fitting into high speed cache. On the EPFL IBM Blue Gene, almost linear speedup was obtained up to 100 processors. Increasing one model from 500 to 40,000 realistic cells exhibited almost linear speedup on 2000 processors, with an integration time of 9.8 seconds and communication time of 1.3 seconds. The potential for speed-ups of several orders of magnitude makes practical the running of large network simulations that could otherwise not be explored. PMID:16732488

  1. Neuronal migration, apoptosis and bipolar disorder.

    PubMed

    Uribe, Ezequiel; Wix, Richard

    2012-01-01

    Bipolar disorder, like the majority of psychiatric disorders, is considered a neurodevelopment disease of neurodevelopment. There is an increased rate of neuronal birth and death during this development period. In the particular case of the processes that determine neuronal death, it is known that those neurons that establish connections have to be removed from the central nervous system. There is a deficit of GABAergic interneurons in the cerebral cortex in bipolar disorder, accompanied by overexpression of proapoptic genes. There is also an alteration in the expression of molecules that mediate in the migration of these neurons and their inclusion in functional synapsis during the foetal stage. The role of these molecules in the neuronal death pathways by apoptosis will be reviewed here in an attempt to establish biological hypotheses of the genesis of bipolar disorder. Copyright © 2011 SEP y SEPB. Published by Elsevier Espana. All rights reserved.

  2. Mirror neurons through the lens of epigenetics.

    PubMed

    Ferrari, Pier F; Tramacere, Antonella; Simpson, Elizabeth A; Iriki, Atsushi

    2013-09-01

    The consensus view in mirror neuron research is that mirror neurons comprise a uniform, stable execution-observation matching system. In this opinion article, we argue that, in light of recent evidence, this is at best an incomplete and oversimplified view of mirror neurons, where activity is actually variable and more plastic than previously theorized. We propose an epigenetic account for understanding developmental changes in sensorimotor systems, including variations in mirror neuron activity. Although associative and genetic accounts fail to consider the complexity of genetic and nongenetic interactions, we propose a new evolutionary developmental biology (evo-devo) perspective, which predicts that environmental differences early in development should produce variations in mirror neuron response patterns, tuning them to the social environment. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Reflections on mirror neurons and speech perception

    PubMed Central

    Lotto, Andrew J.; Hickok, Gregory S.; Holt, Lori L.

    2010-01-01

    The discovery of mirror neurons, a class of neurons that respond when a monkey performs an action and also when the monkey observes others producing the same action, has promoted a renaissance for the Motor Theory (MT) of speech perception. This is because mirror neurons seem to accomplish the same kind of one to one mapping between perception and action that MT theorizes to be the basis of human speech communication. However, this seeming correspondence is superficial, and there are theoretical and empirical reasons to temper enthusiasm about the explanatory role mirror neurons might have for speech perception. In fact, rather than providing support for MT, mirror neurons are actually inconsistent with the central tenets of MT. PMID:19223222

  4. Mirror neurons: their implications for group psychotherapy.

    PubMed

    Schermer, Victor L

    2010-10-01

    Recently discovered mirror neurons in the motor cortex of the brain register the actions and intentions of both the organism and others in the environment. As such, they may play a significant role in social behavior and groups. This paper considers the potential implications of mirror neurons and related neural networks for group therapists, proposing that mirror neurons and mirror systems provide "hard-wired" support for the group therapist's belief in the centrality of relationships in the treatment process and exploring their value in accounting for group-as-a-whole phenomena. Mirror neurons further confirm the holistic, social nature of perception, action, and intention as distinct from a stimulus-response behaviorism. The implications of mirror neurons and mirroring processes for the group therapist role, interventions, and training are also discussed.

  5. Non-neuronal cholinergic airway epithelium biology.

    PubMed

    Kummer, Wolfgang; Krasteva-Christ, Gabriela

    2014-06-01

    Acetylcholine, a major regulator of airway function, is not solely produced by neurons but also by a variety of non-neurons cells including various airway epithelial cells utilizing a molecular machinery of acetylcholine synthesis and release that differs from that of neurons. While canonical neuronal cholinergic signaling pathways, for example, nerve driven bronchoconstriction, are still valid, new pathways of cholinergic communication have emerged which center around innate immunity. These include cholinergic luminal signaling via the airway lining fluid to reach receptors at the apical side of epithelial cells and on macrophages patrolling on the surface, and preneuronal cholinergic signaling where sensory neurons are the target of ACh released from a recently identified chemosensory cell that monitors the airway lining fluid for the presence of potentially hazardous compounds utilizing the classical taste transduction cascade. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. [Impact of opiates on dopaminergic neurons].

    PubMed

    Kaufling, Jennifer; Freund-Mercier, Marie-José; Barrot, Michel

    2016-01-01

    Since the work of Johnson and North, it is known that opiates increase the activity of dopaminergic neurons by a GABA neuron-mediated desinhibition. This model should however be updated based on recent advances. Thus, the neuroanatomical location of the GABA neurons responsible for this desinhibition has been recently detailed: they belong to a brain structure in continuity with the posterior part of the ventral tegmental area and discovered this past decade. Other data also highlighted the critical role played by glutamatergic transmission in the opioid regulation of dopaminergic neuron activity. During protracted opiate withdrawal, the inhibitory/excitatory balance exerted on dopaminergic neurons is altered. These results are now leading to propose an original hypothesis for explaining the impact of protracted opiate withdrawal on mood. © 2016 médecine/sciences – Inserm.

  7. Dressed neurons: modeling neural glial interactions

    NASA Astrophysics Data System (ADS)

    Nadkarni, Suhita; Jung, Peter

    2004-03-01

    Based on recent experimental data, we design a model for neuronal membrane potentials that incorporates the influence of the surrounding glia (dressed neurons). A neurotransmitter released into the synaptic cleft triggers a Ca2+ response in nearby glial cells that spreads as a Ca2+ wave and interacts with other synapses via the release of glutamate from astrocytes. We consider the simple case of a neuron glia circuit that consists of a single neuron that triggers a Ca2+ response in the glial cell which in turn feeds back into synapses of the same neuron. It is shown that persistent spiking can occur if the glutamate receptors on the astrocytes are overexpressed—a condition that has been reported from patients suffering from mesial-lobe epilepsy.

  8. Timing control by redundant inhibitory neuronal circuits

    SciTech Connect

    Tristan, I., E-mail: itristan@ucsd.edu; Rulkov, N. F.; Huerta, R.

    2014-03-15

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

  9. Targeting neurons and photons for optogenetics

    PubMed Central

    Packer, Adam M.; Roska, Botond; Häusser, Michael

    2016-01-01

    Optogenetic approaches promise to revolutionize neuroscience by using light to manipulate neural activity in genetically or functionally defined neurons with millisecond precision. Harnessing the full potential of optogenetic tools, however, requires light to be targeted to the right neurons at the right time. Here we discuss some barriers and potential solutions to this problem. We review methods for targeting the expression of light-activatable molecules to specific cell types, under genetic, viral or activity-dependent control. Next we explore new ways to target light to individual neurons to allow for their precise activation and inactivation. These techniques provide a level of precision in the temporal and spatial activation of neurons that was not achievable in previous experiments. In combination with simultaneous recording and imaging techniques, these strategies will allow us to mimic the natural activity patterns of neurons in vivo, enabling previously impossible ‘dream experiments’. PMID:23799473

  10. Multidisciplinary Interventions in Motor Neuron Disease

    PubMed Central

    Williams, U. E.; Philip-Ephraim, E. E.; Oparah, S. K.

    2014-01-01

    Motor neuron disease is a neurodegenerative disease characterized by loss of upper motor neuron in the motor cortex and lower motor neurons in the brain stem and spinal cord. Death occurs 2–4 years after the onset of the disease. A complex interplay of cellular processes such as mitochondrial dysfunction, oxidative stress, excitotoxicity, and impaired axonal transport are proposed pathogenetic processes underlying neuronal cell loss. Currently evidence exists for the use of riluzole as a disease modifying drug; multidisciplinary team care approach to patient management; noninvasive ventilation for respiratory management; botulinum toxin B for sialorrhoea treatment; palliative care throughout the course of the disease; and Modafinil use for fatigue treatment. Further research is needed in management of dysphagia, bronchial secretion, pseudobulbar affect, spasticity, cramps, insomnia, cognitive impairment, and communication in motor neuron disease. PMID:26317009

  11. A COMPUTATIONAL MODEL OF MOTOR NEURON DEGENERATION

    PubMed Central

    Le Masson, Gwendal; Przedborski, Serge; Abbott, L.F.

    2014-01-01

    SUMMARY To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. PMID:25088365

  12. An overview of the neuron ring model

    NASA Technical Reports Server (NTRS)

    Taber, Rod

    1991-01-01

    The Neuron Ring model employs an avalanche structure with two important distinctions at the neuron level. Each neuron has two memory latches; one traps maximum neuronal activation during pattern presentation, and the other records the time of latch content change. The latches filter short term memory. In the process, they preserve length 1 snapshots of activation theory history. The model finds utility in pattern classification. Its synaptic weights are first conditioned with sample spectra. The model then receives a test or unknown signal. The objective is to identify the sample closest to the test signal. Class decision follows complete presentation of the test data. The decision maker relies exclusively on the latch contents. Presented here is an overview of the Neuron Ring at the seminar level.

  13. Effects of surface asymmetry on neuronal growth

    NASA Astrophysics Data System (ADS)

    Staii, Cristian

    Understanding the brain is of tremendous fundamental importance, but it is immensely challenging because of the complexity of both its architecture and function. A growing body of evidence shows that physical stimuli (stiffness of the growth substrate, gradients of various molecular species, geometry of the surrounding environment, traction forces etc.) play a key role in the wiring up of the nervous system. I will present a systematic experimental and theoretical investigation of neuronal growth on substrates with asymmetric geometries and textures. The experimental results show unidirectional axonal growth on these substrates. We demonstrate that the unidirectional bias is imparted by the surface ratchet geometry and quantify the geometrical guidance cues that control neuronal growth. Our results provide new insight into the role played by physical cues in neuronal growth, and could lead to new methods for stimulating neuronal regeneration and the engineering of artificial neuronal tissue. We acknowledge support from NSF through CBET 1067093.

  14. Vestibular efferent neurons project to the flocculus

    NASA Technical Reports Server (NTRS)

    Shinder, M. E.; Purcell, I. M.; Kaufman, G. D.; Perachio, A. A.

    2001-01-01

    A bilateral projection from the vestibular efferent neurons, located dorsal to the genu of the facial nerve, to the cerebellar flocculus and ventral paraflocculus was demonstrated. Efferent neurons were double-labeled by the unilateral injections of separate retrograde tracers into the labyrinth and into the floccular and ventral parafloccular lobules. Efferent neurons were found with double retrograde tracer labeling both ipsilateral and contralateral to the sites of injection. No double labeling was found when using a fluorescent tracer with non-fluorescent tracers such as horseradish peroxidase (HRP) or biotinylated dextran amine (BDA), but large percentages of efferent neurons were found to be double labeled when using two fluorescent substances including: fluorogold, microruby dextran amine, or rhodamine labeled latex beads. These data suggest a potential role for vestibular efferent neurons in modulating the dynamics of the vestibulo-ocular reflex (VOR) during normal and adaptive conditions.

  15. Role of neuronal activity in regulating the structure and function of auditory neurons

    SciTech Connect

    Born, D.E.

    1986-01-01

    The role of afferent activity in maintaining neuronal structure and function was investigated in second order auditory neurons in nucleus magnocellularis (NM) of the chicken. The cochlea provides the major excitatory input to NM neurons via the eighth nerve. Removal of the cochlea causes dramatic changes in NM neurons. To determine if the elimination of neuronal activity is responsible for the changes in NM seen after cochlea removal, tetrodotoxin was used block action potentials in the cochlear ganglion cells. Tetrodotoxin injections into the perilymph reliably blocked neuronal activity in the cochlear nerve and NM. Far field recordings of sound-evoked potentialsmore » revealed that responses returned within 6 hours. Changes in amino acid incorporation in NM neurons were measured by giving intracardiac injections of /sup 3/H-leucine and preparing tissue for autoradiographic demonstration of incorporated amino acid. Grain counts over individual neurons revealed that a single injection of tetrodotoxin produced a 40% decrease in grain density in ipsilateral NM neurons. It is concluded that neuronal activity plays an important contribution to the maintenance of the normal properties of NM neurons.« less

  16. Neuron-derived IgG protects neurons from complement-dependent cytotoxicity.

    PubMed

    Zhang, Jie; Niu, Na; Li, Bingjie; McNutt, Michael A

    2013-12-01

    Passive immunity of the nervous system has traditionally been thought to be predominantly due to the blood-brain barrier. This concept must now be revisited based on the existence of neuron-derived IgG. The conventional concept is that IgG is produced solely by mature B lymphocytes, but it has now been found to be synthesized by murine and human neurons. However, the function of this endogenous IgG is poorly understood. In this study, we confirm IgG production by rat cortical neurons at the protein and mRNA levels, with 69.0 ± 5.8% of cortical neurons IgG-positive. Injury to primary-culture neurons was induced by complement leading to increases in IgG production. Blockage of neuron-derived IgG resulted in more neuronal death and early apoptosis in the presence of complement. In addition, FcγRI was found in microglia and astrocytes. Expression of FcγR I in microglia was increased by exposure to neuron-derived IgG. Release of NO from microglia triggered by complement was attenuated by neuron-derived IgG, and this attenuation could be reversed by IgG neutralization. These data demonstrate that neuron-derived IgG is protective of neurons against injury induced by complement and microglial activation. IgG appears to play an important role in maintaining the stability of the nervous system.

  17. A single-neuron tracing study of arkypallidal and prototypic neurons in healthy rats.

    PubMed

    Fujiyama, Fumino; Nakano, Takashi; Matsuda, Wakoto; Furuta, Takahiro; Udagawa, Jun; Kaneko, Takeshi

    2016-12-01

    The external globus pallidus (GP) is known as a relay nucleus of the indirect pathway of the basal ganglia. Recent studies in dopamine-depleted and healthy rats indicate that the GP comprises two main types of pallidofugal neurons: the so-called "prototypic" and "arkypallidal" neurons. However, the reconstruction of complete arkypallidal neurons in healthy rats has not been reported. Here we visualized the entire axonal arborization of four single arkypallidal neurons and six single prototypic neurons in rat brain using labeling with a viral vector expressing membrane-targeted green fluorescent protein and examined the distribution of axon boutons in the target nuclei. Results revealed that not only the arkypallidal neurons but nearly all of the prototypic neurons projected to the striatum with numerous axon varicosities. Thus, the striatum is a major target nucleus for pallidal neurons. Arkypallidal and prototypic GP neurons located in the calbindin-positive and calbindin-negative regions mainly projected to the corresponding positive and negative regions in the striatum. Because the GP and striatum calbindin staining patterns reflect the topographic organization of the striatopallidal projection, the striatal neurons in the sensorimotor and associative regions constitute the reciprocal connection with the GP neurons in the corresponding regions.

  18. Distinct Corticostriatal GABAergic Neurons Modulate Striatal Output Neurons and Motor Activity.

    PubMed

    Melzer, Sarah; Gil, Mariana; Koser, David E; Michael, Magdalena; Huang, Kee Wui; Monyer, Hannah

    2017-05-02

    The motor cortico-basal ganglion loop is critical for motor planning, execution, and learning. Balanced excitation and inhibition in this loop is crucial for proper motor output. Excitatory neurons have been thought to be the only source of motor cortical input to the striatum. Here, we identify long-range projecting GABAergic neurons in the primary (M1) and secondary (M2) motor cortex that target the dorsal striatum. This population of projecting GABAergic neurons comprises both somatostatin-positive (SOM + ) and parvalbumin-positive (PV + ) neurons that target direct and indirect pathway striatal output neurons as well as cholinergic interneurons differentially. Notably, optogenetic stimulation of M1 PV + and M2 SOM + projecting neurons reduced locomotion, whereas stimulation of M1 SOM + projecting neurons enhanced locomotion. Thus, corticostriatal GABAergic projections modulate striatal output and motor activity. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  19. Pathological Changes of von Economo Neuron and Fork Neuron in Neuropsychiatric Diseases.

    PubMed

    Liu, Jia; Wang, Lu-ning; Arzberger, Thomas; Zhu, Ming-wei

    2016-02-01

    von Economo neuron (VEN) is a bipolar neuron characterized by a large spindle-shaped soma. VEN is generally distributed in the layer V of anterior insular lobe and anterior cingulate cortex. Fork neuron is another featured bipolar neuron. In recent years,many studies have illustrated that VEN and fork neurons are correlated with complicated cognition such as self-consciousness and social emotion. Studies in the development and morpholigies of these two neurons as well as their pathological changes in various neurological and psychiatric disorders have found that the abnormal number and functions of VEN can cause corresponding dysfunctions in social recognition and emotions both during the neuro-developmental stages of childhood and during the nerve degeneration in old age stage. Therefore, more attentions should be paid on the research of VEN and fork neurons in neuropsychiatric diseases.

  20. Neurones in the ventrolateral pons are required for post-hypoxic frequency decline in rats.

    PubMed Central

    Coles, S K; Dick, T E

    1996-01-01

    1. The breathing pattern following acute hypoxia (arterial O2 pressure (Pa,O2), 27.4 +/- 7.7 mmHg) was measured in intact, anaesthetized and spontaneously breathing adult rats (n = 4) and in anaesthetized, vagotomized, paralysed and ventilated animals (n = 14). Measurements were made both before and after bilateral lesions or chemical inactivation of neurones in the lateral pons. Respiratory motor activity was recorded as an index of the respiratory cycle. We tested the hypothesis that the ventrolateral pons is required for expression of post-hypoxic frequency decline, defined as a decrease in respiratory frequency below steady-state baseline levels following brief exposures to hypoxia. 2. We identified an area in the ventrolateral pons where brief (1 ms) low current (< or = 20 microA) pulses evoked a short-latency inhibitor of phrenic nerve activity. At this site, bilateral electrical or chemical lesions (n = 3) were performed, or neural activity was inhibited by focal injections of 10 mM muscimol (n = 9). In six control animals, neural activity was inhibited by muscimol injections into the lateral pons, dorsal to the target site. 3. Prior to pontine intervention, respiratory frequency decreased below baseline levels following 20-110 s of 8% O2. The decrease in frequency resulted from a prolongation of expiration (up to 276%), which gradually returned to baseline levels (tau = 45 s). 4. Following lesions or inhibition of neural activity in the ventrolateral pons, baseline inspiratory (TI) and expiratory (TE) durations were altered, albeit minimally, in the animals with intact vagus nerves. Expiratory duration following hypoxia was not different from baseline levels either in vagotomized (P = 0.18) or intact (P > 0.05) animals. In contrast, injections of muscimol at more dorsal sites did not alter the decrease in frequency normally seen following hypoxia. 5. Histological examination revealed that effective lesion or injection sites were within the lateral pontine

  1. Neuronal Ensemble Synchrony during Human Focal Seizures

    PubMed Central

    Ahmed, Omar J.; Harrison, Matthew T.; Eskandar, Emad N.; Cosgrove, G. Rees; Madsen, Joseph R.; Blum, Andrew S.; Potter, N. Stevenson; Hochberg, Leigh R.; Cash, Sydney S.

    2014-01-01

    Seizures are classically characterized as the expression of hypersynchronous neural activity, yet the true degree of synchrony in neuronal spiking (action potentials) during human seizures remains a fundamental question. We quantified the temporal precision of spike synchrony in ensembles of neocortical neurons during seizures in people with pharmacologically intractable epilepsy. Two seizure types were analyzed: those characterized by sustained gamma (∼40–60 Hz) local field potential (LFP) oscillations or by spike-wave complexes (SWCs; ∼3 Hz). Fine (<10 ms) temporal synchrony was rarely present during gamma-band seizures, where neuronal spiking remained highly irregular and asynchronous. In SWC seizures, phase locking of neuronal spiking to the SWC spike phase induced synchrony at a coarse 50–100 ms level. In addition, transient fine synchrony occurred primarily during the initial ∼20 ms period of the SWC spike phase and varied across subjects and seizures. Sporadic coherence events between neuronal population spike counts and LFPs were observed during SWC seizures in high (∼80 Hz) gamma-band and during high-frequency oscillations (∼130 Hz). Maximum entropy models of the joint neuronal spiking probability, constrained only on single neurons' nonstationary coarse spiking rates and local network activation, explained most of the fine synchrony in both seizure types. Our findings indicate that fine neuronal ensemble synchrony occurs mostly during SWC, not gamma-band, seizures, and primarily during the initial phase of SWC spikes. Furthermore, these fine synchrony events result mostly from transient increases in overall neuronal network spiking rates, rather than changes in precise spiking correlations between specific pairs of neurons. PMID:25057195

  2. Mirror neurons: from origin to function.

    PubMed

    Cook, Richard; Bird, Geoffrey; Catmur, Caroline; Press, Clare; Heyes, Cecilia

    2014-04-01

    This article argues that mirror neurons originate in sensorimotor associative learning and therefore a new approach is needed to investigate their functions. Mirror neurons were discovered about 20 years ago in the monkey brain, and there is now evidence that they are also present in the human brain. The intriguing feature of many mirror neurons is that they fire not only when the animal is performing an action, such as grasping an object using a power grip, but also when the animal passively observes a similar action performed by another agent. It is widely believed that mirror neurons are a genetic adaptation for action understanding; that they were designed by evolution to fulfill a specific socio-cognitive function. In contrast, we argue that mirror neurons are forged by domain-general processes of associative learning in the course of individual development, and, although they may have psychological functions, they do not necessarily have a specific evolutionary purpose or adaptive function. The evidence supporting this view shows that (1) mirror neurons do not consistently encode action "goals"; (2) the contingency- and context-sensitive nature of associative learning explains the full range of mirror neuron properties; (3) human infants receive enough sensorimotor experience to support associative learning of mirror neurons ("wealth of the stimulus"); and (4) mirror neurons can be changed in radical ways by sensorimotor training. The associative account implies that reliable information about the function of mirror neurons can be obtained only by research based on developmental history, system-level theory, and careful experimentation.

  3. Object-Detecting Neurons in Drosophila.

    PubMed

    Keleş, Mehmet F; Frye, Mark A

    2017-03-06

    Many animals rely on vision to detect objects such as conspecifics, predators, and prey. Hypercomplex cells found in feline cortex and small target motion detectors found in dragonfly and hoverfly optic lobes demonstrate robust tuning for small objects, with weak or no response to larger objects or movement of the visual panorama [1-3]. However, the relationship among anatomical, molecular, and functional properties of object detection circuitry is not understood. Here we characterize a specialized object detector in Drosophila, the lobula columnar neuron LC11 [4]. By imaging calcium dynamics with two-photon excitation microscopy, we show that LC11 responds to the omni-directional movement of a small object darker than the background, with little or no responses to static flicker, vertically elongated bars, or panoramic gratings. LC11 dendrites innervate multiple layers of the lobula, and each dendrite spans enough columns to sample 75° of visual space, yet the area that evokes calcium responses is only 20° wide and shows robust responses to a 2.2° object spanning less than half of one facet of the compound eye. The dendrites of neighboring LC11s encode object motion retinotopically, but the axon terminals fuse into a glomerular structure in the central brain where retinotopy is lost. Blocking inhibitory ionic currents abolishes small object sensitivity and facilitates responses to elongated bars and gratings. Our results reveal high-acuity object motion detection in the Drosophila optic lobe. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting.

    PubMed

    Morozova, Ekaterina O; Myroshnychenko, Maxym; Zakharov, Denis; di Volo, Matteo; Gutkin, Boris; Lapish, Christopher C; Kuznetsov, Alexey

    2016-10-01

    In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca 2+ ) concentration, thus reducing the Ca 2+ -dependent potassium (K + ) current. In this way, the GABA-mediated hyperpolarization replaces Ca 2+ -dependent K + current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally. Copyright © 2016 the American Physiological Society.

  5. Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting

    PubMed Central

    Myroshnychenko, Maxym; Zakharov, Denis; di Volo, Matteo; Gutkin, Boris; Lapish, Christopher C.; Kuznetsov, Alexey

    2016-01-01

    In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca2+) concentration, thus reducing the Ca2+-dependent potassium (K+) current. In this way, the GABA-mediated hyperpolarization replaces Ca2+-dependent K+ current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally. PMID:27440240

  6. High frequency neurons determine effective connectivity in neuronal networks.

    PubMed

    Pariz, Aref; Esfahani, Zahra G; Parsi, Shervin S; Valizadeh, Alireza; Canals, Santiago; Mirasso, Claudio R

    2018-02-01

    The emergence of flexible information channels in brain networks is a fundamental question in neuroscience. Understanding the mechanisms of dynamic routing of information would have far-reaching implications in a number of disciplines ranging from biology and medicine to information technologies and engineering. In this work, we show that the presence of a node firing at a higher frequency in a network with local connections, leads to reliable transmission of signals and establishes a preferential direction of information flow. Thus, by raising the firing rate a low degree node can behave as a functional hub, spreading its activity patterns polysynaptically in the network. Therefore, in an otherwise homogeneous and undirected network, firing rate is a tunable parameter that introduces directionality and enhances the reliability of signal transmission. The intrinsic firing rate across neuronal populations may thus determine preferred routes for signal transmission that can be easily controlled by changing the firing rate in specific nodes. We show that the results are generic and the same mechanism works in the networks with more complex topology. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Differential regulation of amyloid-. beta. -protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease

    SciTech Connect

    Higgins, G.A.; Lewis, D.A.; Bahmanyar, S.

    1988-02-01

    The authors have mapped the neuroanatomical distribution of amyloid-..beta..-protein mRNA within neuronal subpopulations of the hippocampal formation in the cynomolgus monkey (Macaca fascicularis), normal aged human, and patients with Alzheimer disease. Amyloid-..beta..-protein mRNA appears to be expressed in all hippocampal neurons, but at different levels of abundance. In the central nervous system of monkey and normal aged human, image analysis shows that neurons of the dentate gyrus and cornu Ammonis fields contain a 2.5-times-greater hybridization signal than is present in neurons of the subiculum and entorhinal cortex. In contrast, in the Alzheimer disease hippocampal formation, the levels of amyloid-..beta..-protein mRNAmore » in the cornu Ammonis field 3 and parasubiculum are equivalent. These findings suggest that within certain neuronal subpopulations cell type-specific regulation of amyloid-..beta..-protein gene expression may be altered in Alzheimer disease.« less

  8. Firing dynamics of an autaptic neuron

    NASA Astrophysics Data System (ADS)

    Wang, Heng-Tong; Chen, Yong

    2015-12-01

    Autapses are synapses that connect a neuron to itself in the nervous system. Previously, both experimental and theoretical studies have demonstrated that autaptic connections in the nervous system have a significant physiological function. Autapses in nature provide self-delayed feedback, thus introducing an additional timescale to neuronal activities and causing many dynamic behaviors in neurons. Recently, theoretical studies have revealed that an autapse provides a control option for adjusting the response of a neuron: e.g., an autaptic connection can cause the electrical activities of the Hindmarsh-Rose neuron to switch between quiescent, periodic, and chaotic firing patterns; an autapse can enhance or suppress the mode-locking status of a neuron injected with sinusoidal current; and the firing frequency and interspike interval distributions of the response spike train can also be modified by the autapse. In this paper, we review recent studies that showed how an autapse affects the response of a single neuron. Project supported by the National Natural Science Foundation of China (Grant Nos. 11275084 and 11447027) and the Fundamental Research Funds for the Central Universities, China (Grant No. GK201503025).

  9. Motor neuron regeneration in adult zebrafish.

    PubMed

    Reimer, Michell M; Sörensen, Inga; Kuscha, Veronika; Frank, Rebecca E; Liu, Chong; Becker, Catherina G; Becker, Thomas

    2008-08-20

    The mammalian spinal cord does not regenerate motor neurons that are lost as a result of injury or disease. Here we demonstrate that adult zebrafish, which show functional spinal cord regeneration, are capable of motor neuron regeneration. After a spinal lesion, the ventricular zone shows a widespread increase in proliferation, including slowly proliferating olig2-positive (olig2+) ependymo-radial glial progenitor cells. Lineage tracing in olig2:green fluorescent protein transgenic fish indicates that these cells switch from a gliogenic phenotype to motor neuron production. Numbers of undifferentiated small HB9+ and islet-1+ motor neurons, which are double labeled with the proliferation marker 5-bromo-2-deoxyuridine (BrdU), are transiently strongly increased in the lesioned spinal cord. Large differentiated motor neurons, which are lost after a lesion, reappear at 6-8 weeks after lesion, and we detected ChAT+/BrdU+ motor neurons that were covered by contacts immunopositive for the synaptic marker SV2. These observations suggest that, after a lesion, plasticity of olig2+ progenitor cells may allow them to generate motor neurons, some of which exhibit markers for terminal differentiation and integration into the existing adult spinal circuitry.

  10. Adaptation of rat olfactory bulb neurones.

    PubMed Central

    Mair, R G

    1982-01-01

    1. Single-unit activity was recorded from olfactory bulb neurones driven by odorous stimuli. Neural responses were quantified as averaged peristimulus time histograms. 2. Successive presentations of the same stimulus evoked similar patterns of activity during each presentation. Some neurones exhibited increased and others decreased excitability in the adapted state. The occurrence of such facilitative or suppressive self-adaptation was not determined by odorant concentration or by the number of action potentials evoked by a given stimulus. Neurones driven by more than one odorant exhibited the same type of adaptation (facilitative or suppressive) for all effective stimuli. 3. When the first odorant differed from the second, the number but not the pattern of action potentials evoked by the second odorant differed from the non-adapted state. Some neurones exhibited increased and others decreased excitability in the cross-adaptation state. Neurones exhibiting suppressive self-adaptation did not exhibit facilitative cross-adaptation and those exhibiting facilitative self-adaptation did not exhibit suppressive cross-adaptation. Instances of asymmetrical cross-adaptation were noted in which two odorants differed in the extent to which they affected subsequent sensitivity to each other. The degree of symmetry for a given pair of odorants differed for different neurones. It is concluded that neurones in the olfactory bulb differ in both the type (suppressive or facilitative) and extent of adaptation evoked by a given odorant. PMID:7108800

  11. Sloppiness in Spontaneously Active Neuronal Networks

    PubMed Central

    Panas, Dagmara; Amin, Hayder; Maccione, Alessandro; Muthmann, Oliver; van Rossum, Mark; Berdondini, Luca

    2015-01-01

    Various plasticity mechanisms, including experience-dependent, spontaneous, as well as homeostatic ones, continuously remodel neural circuits. Yet, despite fluctuations in the properties of single neurons and synapses, the behavior and function of neuronal assemblies are generally found to be very stable over time. This raises the important question of how plasticity is coordinated across the network. To address this, we investigated the stability of network activity in cultured rat hippocampal neurons recorded with high-density multielectrode arrays over several days. We used parametric models to characterize multineuron activity patterns and analyzed their sensitivity to changes. We found that the models exhibited sloppiness, a property where the model behavior is insensitive to changes in many parameter combinations, but very sensitive to a few. The activity of neurons with sloppy parameters showed faster and larger fluctuations than the activity of a small subset of neurons associated with sensitive parameters. Furthermore, parameter sensitivity was highly correlated with firing rates. Finally, we tested our observations from cell cultures on an in vivo recording from monkey visual cortex and we confirm that spontaneous cortical activity also shows hallmarks of sloppy behavior and firing rate dependence. Our findings suggest that a small subnetwork of highly active and stable neurons supports group stability, and that this endows neuronal networks with the flexibility to continuously remodel without compromising stability and function. PMID:26041916

  12. Guiding neuronal growth with optical trap

    NASA Astrophysics Data System (ADS)

    Feng, Xiuzhou; Xia, Chunlin; Zhu, Tianchun; Li, Chunpeng; Wan, Minghui; Zhang, Ye

    2005-01-01

    Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The prevailing opinion is that growth cones appear to be guided by four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. In contrast to existing methods, we use optical trap to guide neuronal growth. The optical trap is a non-contact manipulation technology which is increasingly used for micromanipulation of living cells and organisms. An intense light gradient near the focal region of a near-infrared laser beam gives rise to forces that make possible optical trapping and manipulation of a variety of micron-sized objects. In the developing nervous system, microtubule and actin play a fundamental role. To change the microtubule polymerization by control the density of tubulins or exerting a persistent force on the whole growth cone, we have shown experimentally that we can use optical trap to guide the growth direction of a neuron. In order to guide the neuronal growth direction, a self-contrived optical trap is placed in front of a specific area of the edge of the cell's growth cone. We turned the neuronal growth direction and guided it to the direction we expected. Control over neuronal growth is a fundamental objective in neuroscience and guiding neuronal growth with optical trap may be very important for the formation of neural circuits as well as nerve regeneration.

  13. Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

    PubMed Central

    Bardy, Cedric; van den Hurk, Mark; Eames, Tameji; Marchand, Cynthia; Hernandez, Ruben V.; Kellogg, Mariko; Gorris, Mark; Galet, Ben; Palomares, Vanessa; Brown, Joshua; Bang, Anne G.; Mertens, Jerome; Böhnke, Lena; Boyer, Leah; Simon, Suzanne; Gage, Fred H.

    2015-01-01

    Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro. PMID:25870293

  14. Protocol for culturing low density pure rat hippocampal neurons supported by mature mixed neuron cultures.

    PubMed

    Yang, Qian; Ke, Yini; Luo, Jianhong; Tang, Yang

    2017-02-01

    primary hippocampal neuron cultures allow for subcellular morphological dissection, easy access to drug treatment and electrophysiology analysis of individual neurons, and is therefore an ideal model for the study of neuron physiology. While neuron and glia mixed cultures are relatively easy to prepare, pure neurons are particular hard to culture at low densities which are suitable for morphology studies. This may be due to a lack of neurotrophic factors such as brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and Glial cell line-derived neurotrophic factor (GDNF). In this study we used a two step protocol in which neuron-glia mixed cultures were initially prepared for maturation to support the growth of young neurons plated at very low densities. Our protocol showed that neurotrophic support resulted in physiologically functional hippocampal neurons with larger cell body, increased neurite length and decreased branching and complexity compared to cultures prepared using a conventional method. Our protocol provides a novel way to culture highly uniformed hippocampal neurons for acquiring high quality, neuron based data. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

    PubMed

    Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

    2012-06-20

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

  16. Efficient gene transduction of neurons by lentivirus with enhanced neuron-specific promoters.

    PubMed

    Hioki, H; Kameda, H; Nakamura, H; Okunomiya, T; Ohira, K; Nakamura, K; Kuroda, M; Furuta, T; Kaneko, T

    2007-06-01

    In the field of basic and clinical neurosciences, it is important to develop a method for easy delivery and persistent expression of transgene in central neurons. We firstly generated lentiviral vectors with five kinds of neuron-specific promoters, such as synapsin I (SYN), calcium/calmodulin-dependent protein kinase II, tubulin alpha I, neuron-specific enolase and platelet-derived growth factor beta chain promoters and then novel hybrid promoters by fusing cytomegalovirus enhancer (E) to those neuron-specific promoters. Neuron-specific expression of green fluorescent protein (GFP) with those promoters was examined in vivo by injecting the lentiviral vectors into the rat neostriatum, thalamus and neocortex. Among all the promoters, SYN promoter displayed the highest specificity for neuronal expression in all the regions examined (more than 96%). Although GFP production by the hybrid promoters was about 2-4 times larger than the non-enhanced promoters, the neuronal specificity was significantly decreased in most cases. However, the neuronal specificity of E/SYN hybrid promoter exhibited the least decrease only in the thalamus. Furthermore, the transcriptional activity and neuronal specificity of E/SYN promoter were sustained for up to 8 weeks. Thus, lentivirus with E/SYN promoter is the best vector for strong persistent expression in neurons.

  17. Understanding the Role of Adenosine A2AR Heteroreceptor Complexes in Neurodegeneration and Neuroinflammation.

    PubMed

    Borroto-Escuela, Dasiel O; Hinz, Sonja; Navarro, Gemma; Franco, Rafael; Müller, Christa E; Fuxe, Kjell

    2018-01-01

    Adenosine is a nucleoside mainly formed by degradation of ATP, located intracellularly or extracellularly, and acts as a neuromodulator. It operates as a volume transmission signal through diffusion and flow in the extracellular space to modulate the activity of both glial cells and neurons. The effects of adenosine are mediated via four adenosine receptor subtypes: A1R, A2AR, A2BR, A3R. The A2AR has a wide-spread distribution but it is especially enriched in the ventral and dorsal striatum where it is mainly located in the striato-pallidal GABA neurons at a synaptic and extrasynaptic location. A number of A2AR heteroreceptor complexes exist in the striatum. The existence of A2AR-D2R heteroreceptor complexes with antagonistic A2AR-D2R interactions in the striato-pallidal GABA neurons is well-known with A2AR activation inhibiting Gi/o mediated signaling of D2Rs. A2AR-mGluR5 heteroreceptor complexes were also found in with synergistic receptor-receptor interactions enhancing the inhibition of the D2R protomer signaling. They are located mainly in extrasynaptic regions of the striato-pallidal GABA neurons. Results recently demonstrated the existence of brain A2AR-A2BR heteroreceptor complexes, in which A2BR protomer constitutively inhibited the function of the A2AR protomer. These adenosine A2AR heteroreceptor complexes may modulate alpha-synuclein aggregation and toxicity through postulated bidirectional direct interactions leading to marked increases in A2AR signaling both in nerve cells and microglia. It is of high interest that formation of A2AR-A2ABR heteroreceptor complexes provides a brake on A2AR recognition and signaling opening up a novel strategy for treatment of A2AR mediated neurodegeneration.

  18. Acid-sensing hypothalamic neurons controlling arousal.

    PubMed

    Kernder, Anna; De Luca, Roberto; Yanovsky, Yevgenij; Haas, Helmut L; Sergeeva, Olga A

    2014-08-01

    Breathing and vigilance are regulated by pH and CO2 levels in the central nervous system. The hypocretin/orexin (Hcrt/Orx)- and histamine (HA)-containing hypothalamic neurons synergistically control different aspects of the waking state. Acidification inhibits firing of most neurons but these two groups in the caudal hypothalamus are excited by hypercapnia and protons, similar to the chemosensory neurons in the brain stem. Activation of hypothalamic wake-on neurons in response to hypercapnia, seen with the c-Fos assay, is supported by patch-clamp recordings in rodent brain slices: Hcrt/Orx and HA neurons are excited by acidification in the physiological range (pH from 7.4 to 7.0). Multiple molecular mechanisms mediate wake-promoting effects of protons in HA neurons in the tuberomamillary nucleus (TMN): among them are acid-sensing ion channels, Na(+),K(+)-ATPase, group I metabotropic glutamate receptors (mGluRI). HA neurons are remarkably sensitive to the mGluRI agonist DHPG (threshold concentration 0.5 µM) and mGluRI antagonists abolish proton-induced excitation of HA neurons. Hcrt/Orx neurons are excited through block of a potassium conductance and release glutamate with their peptides in TMN. The two hypothalamic nuclei and the serotonergic dorsal raphe cooperate toward CO2/acid-induced arousal. Their interactions and molecular mechanisms of H(+)/CO2-induced activation are relevant for the understanding and treatment of respiratory and metabolic disorders related to sleep-waking such as obstructive sleep apnea and sudden infant death syndrome.

  19. Context-aware modeling of neuronal morphologies

    PubMed Central

    Torben-Nielsen, Benjamin; De Schutter, Erik

    2014-01-01

    Neuronal morphologies are pivotal for brain functioning: physical overlap between dendrites and axons constrain the circuit topology, and the precise shape and composition of dendrites determine the integration of inputs to produce an output signal. At the same time, morphologies are highly diverse and variant. The variance, presumably, originates from neurons developing in a densely packed brain substrate where they interact (e.g., repulsion or attraction) with other actors in this substrate. However, when studying neurons their context is never part of the analysis and they are treated as if they existed in isolation. Here we argue that to fully understand neuronal morphology and its variance it is important to consider neurons in relation to each other and to other actors in the surrounding brain substrate, i.e., their context. We propose a context-aware computational framework, NeuroMaC, in which large numbers of neurons can be grown simultaneously according to growth rules expressed in terms of interactions between the developing neuron and the surrounding brain substrate. As a proof of principle, we demonstrate that by using NeuroMaC we can generate accurate virtual morphologies of distinct classes both in isolation and as part of neuronal forests. Accuracy is validated against population statistics of experimentally reconstructed morphologies. We show that context-aware generation of neurons can explain characteristics of variation. Indeed, plausible variation is an inherent property of the morphologies generated by context-aware rules. We speculate about the applicability of this framework to investigate morphologies and circuits, to classify healthy and pathological morphologies, and to generate large quantities of morphologies for large-scale modeling. PMID:25249944

  20. Gammaherpesvirus Infection of Human Neuronal Cells

    PubMed Central

    Jha, Hem Chandra; Mehta, Devan; Lu, Jie; El-Naccache, Darine; Shukla, Sanket K.; Kovacsics, Colleen; Kolson, Dennis

    2015-01-01

    ABSTRACT Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers. HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically associated with various neurological diseases such as primary central nervous system lymphoma, multiple sclerosis, Alzheimer’s disease, cerebellar ataxia, and encephalitis. However, the possibility that EBV and Kaposi’s sarcoma-associated herpesvirus (KSHV) can directly infect neurons has been largely overlooked. This study has, for the first time, characterized EBV infection in neural cell backgrounds by using the Sh-Sy5y neuroblastoma cell line, teratocarcinoma Ntera2 neurons, and primary human fetal neurons. Furthermore, we also demonstrated KSHV infection of neural Sh-Sy5y cells. These neuronal cells were infected with green fluorescent protein-expressing recombinant EBV or KSHV. Microscopy, genetic analysis, immunofluorescence, and Western blot analyses for specific viral antigens supported and validated the infection of these cells by EBV and KSHV and showed that the infection was efficient and productive. Progeny virus produced from infected neuronal cells efficiently infected fresh neuronal cells, as well as peripheral blood mononuclear cells. Furthermore, acyclovir was effective at inhibiting the production of virus from neuronal cells similar to lymphoblastoid cell lines; this suggests active lytic replication in infected neurons in vitro. These studies represent a potentially new in vitro model of EBV- and KSHV-associated neuronal disease development and pathogenesis. PMID:26628726

  1. Localization of preganglionic neurons that innervate choroidal neurons of pterygopalatine ganglion.

    PubMed

    Cuthbertson, Sherry; LeDoux, Mark S; Jones, Seth; Jones, Julia; Zhou, Qihong; Gong, Suzhen; Ryan, Patrick; Reiner, Anton

    2003-09-01

    The pterygopalatine ganglion (PPG) receives preganglionic input from the superior salivatory nucleus (SSN) of the facial motor complex and is the main source of parasympathetic input to the choroid in mammals. The present study was undertaken to determine in rats the location and neurotransmitters of SSN neurons innervating those PPG neurons that target the choroid and to determine the location and neurotransmitters of the PPG choroidal neurons themselves. Retrograde labeling from rat choroid using a fluorescent tracer, in combination with immunofluorescence labeling for nitric oxide synthase (NOS), vasoactive intestinal polypeptide (VIP), and choline acetyltransferase (ChAT), was used to characterize the location and neurotransmitters of choroidal PPG neurons. To identify SSN neurons that innervate the choroidal PPG neurons, the Bartha strain of the retrograde transneuronal tracer pseudorabies virus (PRV-Ba) was injected into rat choroid, and immunolabeling for NOS or ChAT was used to characterize their neurochemistry. Fluorescent retrograde labeling showed that PPG neurons projecting to the choroid contained NOS, VIP, and ChAT and were widely distributed in PPG and its preganglionic root, the greater petrosal nerve. SSN neurons were ChAT(+), and a subset of them was found to contain NOS. PRV-Ba transneuronal retrograde labeling revealed that choroidal preganglionic neurons were localized to the rostral medioventral part of the ipsilateral SSN. The choroidal SSN neurons were ChAT(+) and appeared largely to correspond to the NOS(+) neurons of the SSN. These results show that preganglionic neurons in rats that are presumed to regulate choroidal blood flow through the PPG reside within the rostral medioventral SSN, and that NOS is a marker for these SSN neurons.

  2. Vestibular neuronitis. An otoneurological evaluation.

    PubMed

    Silvoniemi, P

    1988-01-01

    Eighty-one cases with vestibular neuronitis were examined. The diagnostic criteria were a sudden onset of vertigo without previous symptoms, spontaneous nystagmus towards the healthy side, totally extinguished caloric responses with 44 degrees C and 30 degrees C water irrigation and no involvement of hearing associated with the onset of the disease. The series was divided into a prospective and a retrospective group. The prospective group A was examined at the acute stage, about 1 month and 1 year afterwards. The retrospective group B fulfilled the same criteria as group A and was examined 1-8 years after the acute stage. The results of the acute stage in group B were analysed from the case history reports, electronystagmo- and audiograms. The preceding and predisposing factors and symptoms were inquired. The examination scheme included the clinical otoneurological examination, the nystagmographic, audiological and clinical neurophysiological measurements and the serological and hematological specimens were collected at the acute stage of group A to examine the role of virus infections in the etiology of vestibular neuronitis. The liquor specimens of 16 cases available in group A were analysed. A recent respiratory infection was reported by 9 cases (27.3 percent) in group A and by 18 cases (37.5 percent) in group B. The serological evidence (increase of IgM-antibodies) was observed in 1 case against influenza A and in 1 case against parainfluenza 3 and the hematological examinations revealed clues of virus infection in 6 cases (18.2 percent) of group A. Cell counts and protein analyses of the liquor specimens were within normal limits. Cases with arterial hypertension under medical control were observed in 15.2 percent of group A and 14.6 percent in group B. These figures do not exceed the age- and sex-correlated prevalence of arterial hypertension in Finnish population. The clinical symptoms included an acute chiefly rotatory vertigo associated with nausea and

  3. Neuronal alignment on asymmetric textured surfaces

    NASA Astrophysics Data System (ADS)

    Beighley, Ross; Spedden, Elise; Sekeroglu, Koray; Atherton, Timothy; Demirel, Melik C.; Staii, Cristian

    2012-10-01

    Axonal growth and the formation of synaptic connections are key steps in the development of the nervous system. Here, we present experimental and theoretical results on axonal growth and interconnectivity in order to elucidate some of the basic rules that neuronal cells use for functional connections with one another. We demonstrate that a unidirectional nanotextured surface can bias axonal growth. We perform a systematic investigation of neuronal processes on asymmetric surfaces and quantify the role that biomechanical surface cues play in neuronal growth. These results represent an important step towards engineering directed axonal growth for neuro-regeneration studies.

  4. Neuronal Growth: A Bistable Stochastic Process

    NASA Astrophysics Data System (ADS)

    Betz, Timo; Lim, Daryl; Käs, Josef A.

    2006-03-01

    The fundamentally stochastic nature of neuronal growth has hardly been addressed in neuroscience. We report on the stochastic fluctuations of a neuronal growth cone’s leading edge movement, the basic step in neuronal growth. Describing the edge movement as a stochastic bistable process leads to an isotropic noise parameter that is successfully used to test the model. An analysis of growth cone motility confirms the model, and predicts that linear changes of the bistable potential, as known from stochastic filtering, result in directed growth cone translocation.

  5. Associative memory - An optimum binary neuron representation

    NASA Technical Reports Server (NTRS)

    Awwal, A. A.; Karim, M. A.; Liu, H. K.

    1989-01-01

    Convergence mechanism of vectors in the Hopfield's neural network is studied in terms of both weights (i.e., inner products) and Hamming distance. It is shown that Hamming distance should not always be used in determining the convergence of vectors. Instead, weights (which in turn depend on the neuron representation) are found to play a more dominant role in the convergence mechanism. Consequently, a new binary neuron representation for associative memory is proposed. With the new neuron representation, the associative memory responds unambiguously to the partial input in retrieving the stored information.

  6. Towards the automatic classification of neurons.

    PubMed

    Armañanzas, Rubén; Ascoli, Giorgio A

    2015-05-01

    The classification of neurons into types has been much debated since the inception of modern neuroscience. Recent experimental advances are accelerating the pace of data collection. The resulting growth of information about morphological, physiological, and molecular properties encourages efforts to automate neuronal classification by powerful machine learning techniques. We review state-of-the-art analysis approaches and the availability of suitable data and resources, highlighting prominent challenges and opportunities. The effective solution of the neuronal classification problem will require continuous development of computational methods, high-throughput data production, and systematic metadata organization to enable cross-laboratory integration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Linking neuronal lineage and wiring specificity.

    PubMed

    Li, Hongjie; Shuster, S Andrew; Li, Jiefu; Luo, Liqun

    2018-04-13

    Brain function requires precise neural circuit assembly during development. Establishing a functional circuit involves multiple coordinated steps ranging from neural cell fate specification to proper matching between pre- and post-synaptic partners. How neuronal lineage and birth timing influence wiring specificity remains an open question. Recent findings suggest that the relationships between lineage, birth timing, and wiring specificity vary in different neuronal circuits. In this review, we summarize our current understanding of the cellular, molecular, and developmental mechanisms linking neuronal lineage and birth timing to wiring specificity in a few specific systems in Drosophila and mice, and review different methods employed to explore these mechanisms.

  8. Reaction-diffusion in the NEURON simulator

    PubMed Central

    McDougal, Robert A.; Hines, Michael L.; Lytton, William W.

    2013-01-01

    In order to support research on the role of cell biological principles (genomics, proteomics, signaling cascades and reaction dynamics) on the dynamics of neuronal response in health and disease, NEURON's Reaction-Diffusion (rxd) module in Python provides specification and simulation for these dynamics, coupled with the electrophysiological dynamics of the cell membrane. Arithmetic operations on species and parameters are overloaded, allowing arbitrary reaction formulas to be specified using Python syntax. These expressions are then transparently compiled into bytecode that uses NumPy for fast vectorized calculations. At each time step, rxd combines NEURON's integrators with SciPy's sparse linear algebra library. PMID:24298253

  9. Differentiation-Dependent Energy Production and Metabolite Utilization: A Comparative Study on Neural Stem Cells, Neurons, and Astrocytes.

    PubMed

    Jády, Attila Gy; Nagy, Ádám M; Kőhidi, Tímea; Ferenczi, Szilamér; Tretter, László; Madarász, Emília

    2016-07-01

    While it is evident that the metabolic machinery of stem cells should be fairly different from that of differentiated neurons, the basic energy production pathways in neural stem cells (NSCs) or in neurons are far from clear. Using the model of in vitro neuron production by NE-4C NSCs, this study focused on the metabolic changes taking place during the in vitro neuronal differentiation. O2 consumption, H(+) production, and metabolic responses to single metabolites were measured in cultures of NSCs and in their neuronal derivatives, as well as in primary neuronal and astroglial cultures. In metabolite-free solutions, NSCs consumed little O2 and displayed a higher level of mitochondrial proton leak than neurons. In stem cells, glycolysis was the main source of energy for the survival of a 2.5-h period of metabolite deprivation. In contrast, stem cell-derived or primary neurons sustained a high-level oxidative phosphorylation during metabolite deprivation, indicating the consumption of own cellular material for energy production. The stem cells increased O2 consumption and mitochondrial ATP production in response to single metabolites (with the exception of glucose), showing rapid adaptation of the metabolic machinery to the available resources. In contrast, single metabolites did not increase the O2 consumption of neurons or astrocytes. In "starving" neurons, neither lactate nor pyruvate was utilized for mitochondrial ATP production. Gene expression studies also suggested that aerobic glycolysis and rapid metabolic adaptation characterize the NE-4C NSCs, while autophagy and alternative glucose utilization play important roles in the metabolism of stem cell-derived neurons.

  10. A novel enteric neuron-glia coculture system reveals the role of glia in neuronal development.

    PubMed

    Le Berre-Scoul, Catherine; Chevalier, Julien; Oleynikova, Elena; Cossais, François; Talon, Sophie; Neunlist, Michel; Boudin, Hélène

    2017-01-15

    Unlike astrocytes in the brain, the potential role of enteric glial cells (EGCs) in the formation of the enteric neuronal circuit is currently unknown. To examine the role of EGCs in the formation of the neuronal network, we developed a novel neuron-enriched culture model from embryonic rat intestine grown in indirect coculture with EGCs. We found that EGCs shape axonal complexity and synapse density in enteric neurons, through purinergic- and glial cell line-derived neurotrophic factor-dependent pathways. Using a novel and valuable culture model to study enteric neuron-glia interactions, our study identified EGCs as a key cellular actor regulating neuronal network maturation. In the nervous system, the formation of neuronal circuitry results from a complex and coordinated action of intrinsic and extrinsic factors. In the CNS, extrinsic mediators derived from astrocytes have been shown to play a key role in neuronal maturation, including dendritic shaping, axon guidance and synaptogenesis. In the enteric nervous system (ENS), the potential role of enteric glial cells (EGCs) in the maturation of developing enteric neuronal circuit is currently unknown. A major obstacle in addressing this question is the difficulty in obtaining a valuable experimental model in which enteric neurons could be isolated and maintained without EGCs. We adapted a cell culture method previously developed for CNS neurons to establish a neuron-enriched primary culture from embryonic rat intestine which was cultured in indirect coculture with EGCs. We demonstrated that enteric neurons grown in such conditions showed several structural, phenotypic and functional hallmarks of proper development and maturation. However, when neurons were grown without EGCs, the complexity of the axonal arbour and the density of synapses were markedly reduced, suggesting that glial-derived factors contribute strongly to the formation of the neuronal circuitry. We found that these effects played by EGCs were

  11. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons

    PubMed Central

    Murphy, Diane D.; Cole, Nelson B.; Segal, Menahem

    1998-01-01

    Dendritic spines are of major importance in information processing and memory formation in central neurons. Estradiol has been shown to induce an increase of dendritic spine density on hippocampal neurons in vivo and in vitro. The neurotrophin brain-derived neurotrophic factor (BDNF) recently has been implicated in neuronal maturation, plasticity, and regulation of GABAergic interneurons. We now demonstrate that estradiol down-regulates BDNF in cultured hippocampal neurons to 40% of control values within 24 hr of exposure. This, in turn, decreases inhibition and increases excitatory tone in pyramidal neurons, leading to a 2-fold increase in dendritic spine density. Exogenous BDNF blocks the effects of estradiol on spine formation, and BDNF depletion with a selective antisense oligonucleotide mimics the effects of estradiol. Addition of BDNF antibodies also increases spine density, and diazepam, which facilitates GABAergic neurotransmission, blocks estradiol-induced spine formation. These observations demonstrate a functional link between estradiol, BDNF as a potent regulator of GABAergic interneurons, and activity-dependent formation of dendritic spines in hippocampal neurons. PMID:9736750

  12. Cellular and molecular neuronal plasticity.

    PubMed

    Griesbach, Grace S; Hovda, David A

    2015-01-01

    The brain has the capability to adapt to function when tissue is compromised. This capability of adaptation paves the road to recovery and allows for rehabilitation after a traumatic brain injury (TBI). This chapter addresses neuroplasticity within the context of TBI. Here neuroplasticity is defined as changes in neuronal structure and function, including synaptic changes as well as modifications in neural pathways. First, the influence of TBI pathology on neuroplasticity is addressed. Here, proteins that are important in neuroplasticity are introduced and a description given of how these are affected in a temporal and severity-dependent manner. Secondly, given that we are becoming increasingly aware that the brain's response to injury is highly influenced by the environmental milieu, the manner in which behavioral manipulations have an effect on TBI-associated neuroplasticity is addressed. A description is given of how specific environmental qualities may facilitate or hinder neuroplasticity. Finally, the long-term effects of neuroplasticity and the relevance it has to rehabilitation are described. © 2015 Elsevier B.V. All rights reserved.

  13. The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release.

    PubMed

    Rau, Andrew R; Hentges, Shane T

    2017-08-02

    Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of μ-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation. SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons