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Sample records for a2 noradrenergic neurons

  1. Quantitative RT-PCR and immunoblot analyses reveal acclimated A2 noradrenergic neuron substrate fuel transporter, glucokinase, phospho-AMPK, and dopamine-β-hydroxylase responses to hypoglycemia.

    PubMed

    Cherian, Ajeesh Koshy; Briski, Karen P

    2011-07-01

    Cellular metabolic stasis is monitored in discrete brain sites, including the dorsal vagal complex (DVC), where A2 noradrenergic neurons perform this sensory function. Single-cell qPCR and high-sensitivity immunoblotting were used to determine if A2 neurons adapt to chronic hypoglycemia by increasing substrate fuel transporter expression, and whether such adjustments coincide with decreased cellular energy instability during this systemic metabolic stress. Tyrosine hydroxylase-immunolabeled neurons were laser-microdissected from the caudal DVC 2 hr after single or serial neutral protamine Hagedorn insulin (NPH) dosing. Preceding hypoglycemia suppressed basal A2 MCT2, GLUT3, and GLUT4 profiles and diminished MCT2, GLUT4, and glucokinase responses to recurring hypoglycemia. Acute NPH caused a robust increase in A2 phospho-AMPK protein levels; baseline phospho-AMPK expression was elevated after 3 days of insulin treatment but only slight augmented after a fourth NPH injection. Transcripts encoding the catecholamine biosynthetic enzyme dopamine-β-hydroxylase were unaffected by acute NPH but were diminished by serial insulin dosing. This evidence for diminished basal A2 glucose and lactate uptake and attenuated phospho-AMPK-mediated detection of hypoglycemia-associated energy deficits suggests that these cells acclimate to chronic hypoglycemia by adopting a new metabolic steady state characterized by energy paucity and reduced sensitivity to hypoglycemia. Because dopamine-β-hydroxylase mRNA was reduced after serial, but not single NPH dosing, A2 neurotransmitter biosynthesis may be impervious to acute hypoglycemia but inhibited when posthypoglycemic metabolic deficiency is exacerbated by recurring hypoglycemia. This research suggests that chronic hypoglycemia-associated adjustments in A2-sensory neurotransmission may reflect cellular energetic debilitation rather than adaptive attenuation of cellular metabolic imbalance. Copyright © 2011 Wiley-Liss, Inc.

  2. Vascular Mural Cells Promote Noradrenergic Differentiation of Embryonic Sympathetic Neurons.

    PubMed

    Fortuna, Vitor; Pardanaud, Luc; Brunet, Isabelle; Ola, Roxana; Ristori, Emma; Santoro, Massimo M; Nicoli, Stefania; Eichmann, Anne

    2015-06-23

    The sympathetic nervous system controls smooth muscle tone and heart rate in the cardiovascular system. Postganglionic sympathetic neurons (SNs) develop in close proximity to the dorsal aorta (DA) and innervate visceral smooth muscle targets. Here, we use the zebrafish embryo to ask whether the DA is required for SN development. We show that noradrenergic (NA) differentiation of SN precursors temporally coincides with vascular mural cell (VMC) recruitment to the DA and vascular maturation. Blocking vascular maturation inhibits VMC recruitment and blocks NA differentiation of SN precursors. Inhibition of platelet-derived growth factor receptor (PDGFR) signaling prevents VMC differentiation and also blocks NA differentiation of SN precursors. NA differentiation is normal in cloche mutants that are devoid of endothelial cells but have VMCs. Thus, PDGFR-mediated mural cell recruitment mediates neurovascular interactions between the aorta and sympathetic precursors and promotes their noradrenergic differentiation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Lesion of the commissural nucleus of the solitary tract/A2 noradrenergic neurons facilitates the activation of angiotensinergic mechanisms in response to hemorrhage.

    PubMed

    Freiria-Oliveira, A H; Blanch, G T; De Paula, P M; Menani, J V; Colombari, D S A

    2013-12-19

    In the present study, we investigated the effects of lesions of A2 neurons of the commissural nucleus of the solitary tract (cNTS) alone or combined with the blockade of angiotensinergic mechanisms on the recovery of arterial pressure (AP) to hemorrhage in conscious rats. Male Holtzman rats (280-320g) received an injection of anti-dopamine-beta-hydroxylase-saporin (12.6ng/60nl; cNTS/A2-lesion, n=28) or immunoglobulin G (IgG)-saporin (12.6ng/60nl, sham, n=24) into the cNTS and 15-21days later had a stainless steel cannula implanted in the lateral ventricle. After 6days, rats were submitted to hemorrhage (four blood withdrawals, 2ml/300g of body weight every 10min). Both cNTS/A2-lesioned and sham rats had similar hypotension to hemorrhage (-62±7 and -73±7mmHg, respectively), however cNTS/A2-lesioned rats rapidly recovered from hypotension (-5±3mmHg at 30min), whereas sham rats did not completely recover until the end of the recording (-20±3mmHg at 60min). Losartan (angiotensin type 1 receptor antagonist) injected intracerebroventricularly (100μg/1μl) or intravenously (i.v.) (10mg/kg of body weight) impaired the recovery of AP in cNTS/A2-lesioned rats (-24±6 and -35±7mmHg at 30min, respectively). In sham rats, only i.v. losartan affected the recovery of AP (-39±6mmHg at 60min). The results suggest that lesion of the A2 neurons in the cNTS facilitates the activation of the angiotensinergic pressor mechanisms in response to hemorrhage. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Hindbrain A2 noradrenergic neuron adenosine 5'-monophosphate-activated protein kinase activation, upstream kinase/phosphorylase protein expression, and receptivity to hormone and fuel reporters of short-term food deprivation are regulated by estradiol.

    PubMed

    Briski, Karen P; Alenazi, Fahaad S H; Shakya, Manita; Sylvester, Paul W

    2017-07-01

    Estradiol (E) mitigates acute and postacute adverse effects of 12 hr-food deprivation (FD) on energy balance. Hindbrain 5'-monophosphate-activated protein kinase (AMPK) regulates hyperphagic and hypothalamic metabolic neuropeptide and norepinephrine responses to FD in an E-dependent manner. Energy-state information from AMPK-expressing hindbrain A2 noradrenergic neurons shapes neural responses to metabolic imbalance. Here we investigate the hypothesis that FD causes divergent changes in A2 AMPK activity in E- vs. oil (O)-implanted ovariectomized female rats, alongside dissimilar adjustments in circulating metabolic fuel (glucose, free fatty acids [FFA]) and energy deficit-sensitive hormone (corticosterone, glucagon, leptin) levels. FD decreased blood glucose in oil (O)- but not E-implanted ovariectomized female rats and elevated and reduced glucagon levels in O and E, respectively. FD decreased circulating leptin in O and E, but increased corticosterone and FFA concentrations in E only. Western blot analysis of laser-microdissected A2 neurons showed that glucocorticoid receptor type II and very-long-chain acyl-CoA synthetase 3 protein profiles were amplified in FD/E vs. FD/O. A2 total AMPK protein was elevated without change in activity in FD/O, whereas FD/E exhibited increased AMPK activation along with decreased upstream phosphatase expression. The catecholamine biosynthetic enzyme dopamine-β-hydroxylase (DβH) was increased in FD/O but not FD/E A2 cells. The data show discordance between A2 AMPK activation and glycemic responses to FD; sensor activity was refractory to glucose decrements in FD/O but augmented in FD/E despite stabilized glucose and elevated FFA levels. E-dependent amplification of AMPK activity may reflect adaptive conversion to fatty acid oxidation and/or glucocorticoid stimulation. FD augmentation of A2 DβH protein profiles in FD/O but not FD/E animals suggests that FD may correspondingly regulate NE synthesis vs. metabolism/release in the

  5. Sex differences in the expression of estrogen receptor alpha within noradrenergic neurons in the sheep brain stem.

    PubMed

    Rose, J L; Hamlin, A S; Scott, C J

    2014-10-01

    In female sheep, high levels of estrogen exert a positive feedback action on gonadotropin releasing hormone (GnRH) secretion to stimulate a surge in luteinizing hormone (LH) secretion. Part of this action appears to be via brain stem noradrenergic neurons. By contrast, estrogen action in male sheep has a negative feedback action to inhibit GnRH and LH secretion. To investigate whether part of this sex difference is due to differences in estrogen action in the brain stem, we tested the hypothesis that the distribution of estrogen receptor α (ERα) within noradrenergic neurons in the brain stem differs between rams and ewes. To determine the distribution of ERα, we used double-label fluorescence immunohistochemistry for dopamine β-Hydroxylase, as a marker for noradrenergic and adrenergic cells, and ERα. In the ventrolateral medulla (A1 region), most ERα-immunoreactive (-ir) cells were located in the caudal part of the nucleus. Overall, there were more ERα-ir cells in rams than ewes, but the proportion of double-labeled cells was did not differ between sexes. Much greater numbers of ERα-ir cells were found in the nucleus of the solitary tract (A2 region), but <10% were double labeled and there were no sex differences. The majority of ERα-labeled cells in this nucleus was located in the more rostral areas. ERα-labeled cells were found in several rostral brain stem regions but none of these were double labeled and so were not quantified. Because there was no sex difference in the number of ERα-ir cells in the brain stem that were noradrenergic, the sex difference in the action of estrogen on gonadotropin secretion in sheep is unlikely to involve actions on brain stem noradrenergic cells. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

  6. 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

  7. Chlorotoxin-mediated disinhibition of noradrenergic locus coeruleus neurons using a conditional transgenic approach.

    PubMed

    Salbaum, J Michael; Cirelli, Chiara; Walcott, Elisabeth; Krushel, Les A; Edelman, Gerald M; Tononi, Giulio

    2004-07-30

    The noradrenergic locus coeruleus (LC) has been implicated in the promotion of arousal, in focused attention and learning, and in the regulation of the sleep/waking cycle. The complex biological functions of the central noradrenergic system have been investigated largely through electrophysiological recordings and neurotoxic lesions of LC neurons. Activation of LC neurons through electrical or chemical stimulation has also led to important insights, although these techniques have limited cellular specificity and short-term effects. Here, we describe a novel method aimed at stimulating the central noradrenergic system in a highly selective manner for prolonged periods of time. This was achieved through the conditional expression of a transgene for chlorotoxin (Cltx) in the LC of adult mice. Chlorotoxin is a component of scorpion venom that partially blocks small conductance chloride channels. In this manner, the influence of GABAergic and glycinergic inhibitory inputs on LC cells is greatly reduced, while their ability to respond to excitatory inputs is unaffected. We demonstrate that the unilateral induction of Cltx expression in the LC is associated with a concomitant ipsilateral increase in the expression of markers of noradrenergic activity in LC neurons. Moreover, LC disinhibition is associated with the ipsilateral induction of the immediate early gene NGFI-A in cortical and subcortical target areas. Unlike previous gain of function approaches, transgenic disinhibition of LC cells is highly selective and persists for at least several weeks. This method represents a powerful new tool to assess the long-term effects of LC activation and is potentially applicable to other neuronal systems.

  8. 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.

  9. Cholecystokinin-8 induces brain-derived neurotrophic factor expression in noradrenergic neuronal cells.

    PubMed

    Hwang, Cheol Kyu; Kim, Do Kyung; Chun, Hong Sung

    2013-08-01

    The sulfated cholecystokinin octapeptide (CCK-8S) is one of the most abundant CCK fragment in the brain, but the effects of CCK-8S on locus coeruleus (LC) noradrenergic (NA) neuronal cells activity have not been studied. In this study, we investigated the effects of CCK-8S on the expression of brain-derived neurotrophic factor (BDNF) in LC NA neuronal cell line, LC3541. Results showed that CCK-8S (10 nM) elevates BDNF levels time-dependently and by 1.82-fold after 4h of incubation. In addition, pretreatment with CCK-8S reversed H₂O₂ (100 μM)-mediated down-regulation of BDNF expression, and effectively suppressed H₂O₂-induced caspase-3 activation. Furthermore, CCK-8S markedly induced expression of neuronal survival markers, such as extracellular signal-regulated kinase 1/2 (ERK 1/2), Akt/protein kinase B (PKB), Bcl-2, and peroxisome proliferators-activated receptor gamma coactivator-1α (PGC-1α). Pharmacological inhibitors of ERK 1/2, Akt/PKB, and protein kinase A (PKA) reversed CCK-8S-mediated BDNF induction in LC3541 cells. These results suggest the first evidence that CCK-8S can protect noradrenergic neurons and enhance the expression of BDNF via ERK 1/2-Akt/PKB-PKA-dependent pathways. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine transporters, and the neurotrophin receptors tropomyosin-related kinase A and p75.

    PubMed

    Hoard, J L; Hoover, D B; Mabe, A M; Blakely, R D; Feng, N; Paolocci, N

    2008-09-22

    Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the mouse heart expresses enzymes needed for synthesis of norepinephrine (NE), but they lack the vesicular monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present study, we determined the full scope of noradrenergic properties (i.e. synthetic enzymes and transporters) expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of neurons expressing different elements of the noradrenergic phenotype, and evaluated the colocalization of cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH), including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine beta-hydroxylase (DBH) and norepinephrine transporter (NET) were present in all cholinergic somata, indicating a wider capability for dopamine metabolism and catecholamine uptake. Yet, cholinergic somata lacked VMAT2, precluding the potential for NE storage and vesicular release. In contrast to cholinergic somata, cardiac nerve fibers rarely showed colocalization of cholinergic and noradrenergic markers. Instead, these labels were closely apposed but clearly distinct from each other. Since cholinergic somata expressed several noradrenergic proteins, we questioned whether these neurons might also contain trophic factor receptors typical of noradrenergic neurons. Indeed, we found that all cholinergic cell bodies of mouse ICG, like noradrenergic cell bodies of the stellate ganglia, contained both tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptors. Collectively, these findings demonstrate that mouse intrinsic cardiac

  11. Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine transporters, and the neurotrophin receptors TrkA and p75

    PubMed Central

    Hoard, Jennifer L.; Hoover, Donald B.; Mabe, Abigail M.; Blakely, Randy D.; Feng, Ning; Paolocci, Nazareno

    2008-01-01

    Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the mouse heart express enzymes needed for synthesis of norepinephrine (NE), but they lack the vesicular monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present study, we determined the full scope of noradrenergic properties (i.e., synthetic enzymes and transporters) expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of neurons expressing different elements of the noradrenergic phenotype, and evaluated the colocalization of cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH), including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine β-hydroxylase (DBH) and NE transporter (NET) were present in all cholinergic somata, indicating a wider capability for dopamine metabolism and catecholamine uptake. Yet, cholinergic somata lacked VMAT2, precluding the potential for NE storage and vesicular release. In contrast to cholinergic somata, cardiac nerve fibers rarely showed colocalization of cholinergic and noradrenergic markers. Instead, these labels were closely apposed but clearly distinct from each other. Since cholinergic somata expressed several noradrenergic proteins, we questioned whether these neurons might also contain trophic factor receptors typical of noradrenergic neurons. Indeed, we found that all cholinergic cell bodies of mouse ICG, like noradrenergic cell bodies of the stellate ganglia, contained both tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptors. Collectively, these findings demonstrate that mouse intrinsic cardiac neurons (ICNs

  12. On the Origin of Cortical Dopamine: Is it a Co-Transmitter in Noradrenergic Neurons?

    PubMed Central

    Devoto, Paola; Flore, Giovanna

    2006-01-01

    Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover, microdialysis studies in rats have shown how pharmacological treatments that induce modifications of extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA. To explain the coupling of NA and DA changes, this article reviews the evidence supporting the hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-transmitter. Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex was found to be much higher than expected in view of the scarce dopaminergic innervation in these areas. Systemic administration or intra-cortical perfusion of α2-adrenoceptor agonists and antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal cortex. Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and DA in the mPFC. Electrical stimulation of the locus coeruleus led to an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced. Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely through blockade of α2-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital or parietal cortex. Acute administration of morphine did not increase DA levels in the PFC (where NA is diminished), in

  13. On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons?

    PubMed

    Devoto, Paola; Flore, Giovanna

    2006-04-01

    Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover, microdialysis studies in rats have shown how pharmacological treatments that induce modifications of extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA.To explain the coupling of NA and DA changes, this article reviews the evidence supporting the hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-transmitter.Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex was found to be much higher than expected in view of the scarce dopaminergic innervation in these areas.Systemic administration or intra-cortical perfusion of alpha(2)-adrenoceptor agonists and antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal cortex.Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and DA in the mPFC.Electrical stimulation of the locus coeruleus led to an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced.Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely through blockade of alpha(2)-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital or parietal cortex.Acute administration of morphine did not increase DA levels in the PFC (where NA is diminished

  14. 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

  15. In vitro characterization of noradrenergic modulation of chemosensitive neurons in the retrotrapezoid nucleus

    PubMed Central

    Kuo, Fu-Shan; Falquetto, Bárbara; Chen, Dawei; Oliveira, Luiz M.; Takakura, Ana C.

    2016-01-01

    Chemosensitive neurons in the retrotrapezoid nucleus (RTN) regulate breathing in response to CO2/H+ changes and serve as an integration center for other autonomic centers, including brain stem noradrenergic neurons. Norepinephrine (NE) contributes to respiratory control and chemoreception, and, since disruption of NE signaling may contribute to several breathing disorders, we sought to characterize effects of NE on RTN chemoreception. All neurons included in this study responded similarly to CO2/H+ but showed differential sensitivity to NE; we found that NE activated (79%), inhibited (7%), or had no effect on activity (14%) of RTN chemoreceptors. The excitatory effect of NE on RTN chemoreceptors was dose dependent, retained in the presence of neurotransmitter receptor blockers, and could be mimicked and blocked by pharmacological manipulation of α1-adrenergic receptors (ARs). In addition, NE-activation was blunted by XE991 (KCNQ channel blocker), and partially occluded the firing response to serotonin, suggesting involvement of KCNQ channels. However, in whole cell voltage clamp, activation of α1-ARs decreased outward current and conductance by what appears to be a mixed effect on multiple channels. The inhibitory effect of NE on RTN chemoreceptors was blunted by an α2-AR antagonist. A third group of RTN chemoreceptors was insensitive to NE. We also found that chemosensitive RTN astrocytes do not respond to NE with a change in voltage or by releasing ATP to enhance activity of chemosensitive neurons. These results indicate NE modulates subsets of RTN chemoreceptors by mechanisms involving α1- and α2-ARs. PMID:27306669

  16. 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

  17. 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.

  18. 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

    2018-06-01

    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.

  19. 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…

  20. Functional neuroanatomy of the central noradrenergic system.

    PubMed

    Szabadi, Elemer

    2013-08-01

    The central noradrenergic neurone, like the peripheral sympathetic neurone, is characterized by a diffusely arborizing terminal axonal network. The central neurones aggregate in distinct brainstem nuclei, of which the locus coeruleus (LC) is the most prominent. LC neurones project widely to most areas of the neuraxis, where they mediate dual effects: neuronal excitation by α₁-adrenoceptors and inhibition by α₂-adrenoceptors. The LC plays an important role in physiological regulatory networks. In the sleep/arousal network the LC promotes wakefulness, via excitatory projections to the cerebral cortex and other wakefulness-promoting nuclei, and inhibitory projections to sleep-promoting nuclei. The LC, together with other pontine noradrenergic nuclei, modulates autonomic functions by excitatory projections to preganglionic sympathetic, and inhibitory projections to preganglionic parasympathetic neurones. The LC also modulates the acute effects of light on physiological functions ('photomodulation'): stimulation of arousal and sympathetic activity by light via the LC opposes the inhibitory effects of light mediated by the ventrolateral preoptic nucleus on arousal and by the paraventricular nucleus on sympathetic activity. Photostimulation of arousal by light via the LC may enable diurnal animals to function during daytime. LC neurones degenerate early and progressively in Parkinson's disease and Alzheimer's disease, leading to cognitive impairment, depression and sleep disturbance.

  1. 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.

  2. The Role of the Central Noradrenergic System in Behavioral Inhibition

    PubMed Central

    Stone, Eric A.; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David

    2011-01-01

    Although the central noradrenergic system has been shown to be involved in a number of behavioral and neurophysiological processes, the relation of these to its role in depressive illness has been difficult to define. The present review discusses the hypothesis that one of its chief functions that may be related to affective illness is the inhibition of behavioral activation, a prominent symptom of the disorder. This hypothesis is found to be consistent with most previous neuropsychopharmacological and immunohistochemical experiments on active behavior in rodents in a variety of experimental conditions using manipulation of neurotransmission at both locus coeruleus and forebrain adrenergic receptors. The findings support a mechanism in which high rates of noradrenergic neural activity suppress the neural activity of principal neurons in forebrain regions mediating active behavior. The suppression may be mediated through postsynaptic galaninergic and adrenergic receptors, and via the release of corticotrophin-releasing hormone. The hypothesis is consistent with clinical evidence for central noradrenergic system hyperactivity in depressives and with the view that this hyperactivity is a contributing etiological factor in the disorder. A similar mechanism may underlie the ability of the noradrenergic system to suppress seizure activity suggesting that inhibition of the spread of neural activation may be a unifying function. PMID:21315760

  3. Selective deficiencies in descending inhibitory modulation in neuropathic rats: implications for enhancing noradrenergic tone.

    PubMed

    Patel, Ryan; Qu, Chaoling; Xie, Jennifer Y; Porreca, Frank; Dickenson, Anthony H

    2018-06-22

    Pontine noradrenergic neurones form part of a descending inhibitory system that influences spinal nociceptive processing. Weak or absent descending inhibition is a common feature of chronic pain patients. We examined the extent to which the descending noradrenergic system is tonically active, how control of spinal neuronal excitability is integrated into thalamic relays within sensory-discriminative projection pathways, and how this inhibitory control is altered after nerve injury. In vivo electrophysiology was performed in anaesthetised spinal nerve-ligated (SNL) and sham-operated rats to record from wide dynamic range neurones in the ventral posterolateral thalamus (VPL). In sham rats, spinal block of α2-adrenoceptors with atipamezole resulted in enhanced stimulus-evoked and spontaneous firing in the VPL, and produced conditioned place avoidance. However, in SNL rats, these conditioned avoidance behaviours were absent. Furthermore, inhibitory control of evoked neuronal responses was lost, but spinal atipamezole markedly increased spontaneous firing. Augmenting spinal noradrenergic tone in neuropathic rats with reboxetine, a selective noradrenergic reuptake inhibitor, modestly reinstated inhibitory control of evoked responses in the VPL but had no effect on spontaneous firing. By contrast, clonidine, an α2 agonist, inhibited both evoked and spontaneous firing, and exhibited increased potency in SNL rats compared with sham controls. These data suggest descending noradrenergic inhibitory pathways are tonically active in sham rats. Moreover, in neuropathic states, descending inhibitory control is diminished, but not completely absent, and distinguishes between spontaneous and evoked neuronal activity. These observations may have implications for how analgesics targeting the noradrenergic system provide relief.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and

  4. 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.

  5. Noradrenergic dysregulation in the pathophysiology of PTSD.

    PubMed

    Hendrickson, Rebecca C; Raskind, Murray A

    2016-10-01

    A central role for noradrenergic dysregulation in the pathophysiology of post-traumatic stress disorder (PTSD) is increasingly suggested by both clinical and basic neuroscience research. Here, we integrate recent findings from clinical and animal research with the earlier literature. We first review the evidence for net upregulation of the noradrenergic system and its responsivity to stress in individuals with PTSD. Next, we trace the evidence that the α 1 noradrenergic receptor antagonist prazosin decreases many of the symptoms of PTSD from initial clinical observations, to case series, to randomized controlled trials. Finally, we review the basic science work that has begun to explain the mechanism for this efficacy, as well as to explore its possible limitations and areas for further advancement. We suggest a view of the noradrenergic system as a central, modifiable link in a network of interconnected stress-response systems, which also includes the amygdala and its modulation by medial prefrontal cortex. Particular attention is paid to the evidence for bidirectional signaling between noradrenaline and corticotropin-releasing factor (CRF) in coordinating these interconnected systems. The multiple different ways in which the sensitivity and reactivity of the noradrenergic system may be altered in PTSD are highlighted, as is the evidence for possible heterogeneity in the pathophysiology of PTSD between different individuals who appear clinically similar. We conclude by noting the importance moving forward of improved measures of noradrenergic functioning in clinical populations, which will allow better recognition of clinical heterogeneity and further assessment of the functional implications of different aspects of noradrenergic dysregulation. Published by Elsevier Inc.

  6. Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease.

    PubMed

    Sugama, Shuei; Sekiyama, Kazunari; Kodama, Tohru; Takamatsu, Yoshiki; Takenouchi, Takato; Hashimoto, Makoto; Bruno, Conti; Kakinuma, Yoshihiko

    2016-01-01

    Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and, to a lesser extent, in the noradrenergic neurons of the locus coeruleus (LC). Most cases of PD are idiopathic and sporadic and are believed to be the result of both environmental and genetic factors. Here, to the best of our knowledge, we report the first evidence that chronic restraint stress (8h/day, 5days/week) substantially reduces nigral DA and LC noradrenergic neuronal cell numbers in rats. Loss of DA neurons in the SNpc was evident after 2weeks of stress and progressed in a time-dependent manner, reaching up to 61% at 16weeks. This reduction was accompanied by robust microglial activation and oxidative stress and was marked by nitrotyrosine in the SNpc and LC of the midbrain. These results indicate that chronic stress triggers DA and noradrenergic neurodegeneration by increasing oxidative stress, and that activated microglia in the substantia nigra and LC may play an important role in modulating the neurotoxic effects of oxidative stress. Taken together, these data suggest that exposure to chronic stress triggers DA and noradrenergic neurodegeneration, which is a cause of PD. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. A noradrenergic lesion exacerbates neurodegeneration in a Down syndrome mouse model.

    PubMed

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

    2011-01-01

    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.

  8. 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

  9. Entry of Botulinum Neurotoxin Subtypes A1 and A2 into Neurons.

    PubMed

    Kroken, Abby R; Blum, Faith C; Zuverink, Madison; Barbieri, Joseph T

    2017-01-01

    Botulinum neurotoxins (BoNTs) are the most toxic proteins for humans but also are common therapies for neurological diseases. BoNTs are dichain toxins, comprising an N-terminal catalytic domain (LC) disulfide bond linked to a C-terminal heavy chain (HC) which includes a translocation domain (H N ) and a receptor binding domain (H C ). Recently, the BoNT serotype A (BoNT/A) subtypes A1 and A2 were reported to possess similar potencies but different rates of cellular intoxication and pathology in a mouse model of botulism. The current study measured H C A1 and H C A2 entry into rat primary neurons and cultured Neuro2A cells. We found that there were two sequential steps during the association of BoNT/A with neurons. The initial step was ganglioside dependent, while the subsequent step involved association with synaptic vesicles. H C A1 and H C A2 entered the same population of synaptic vesicles and entered cells at similar rates. The primary difference was that H C A2 had a higher degree of receptor occupancy for cells and neurons than HcA1. Thus, H C A2 and H C A1 share receptors and entry pathway but differ in their affinity for receptor. The initial interaction of H C A1 and H C A2 with neurons may contribute to the unique pathologies of BoNT/A1 and BoNT/A2 in mouse models. Copyright © 2016 American Society for Microbiology.

  10. Entry of Botulinum Neurotoxin Subtypes A1 and A2 into Neurons

    PubMed Central

    Kroken, Abby R.; Blum, Faith C.; Zuverink, Madison

    2016-01-01

    ABSTRACT Botulinum neurotoxins (BoNTs) are the most toxic proteins for humans but also are common therapies for neurological diseases. BoNTs are dichain toxins, comprising an N-terminal catalytic domain (LC) disulfide bond linked to a C-terminal heavy chain (HC) which includes a translocation domain (HN) and a receptor binding domain (HC). Recently, the BoNT serotype A (BoNT/A) subtypes A1 and A2 were reported to possess similar potencies but different rates of cellular intoxication and pathology in a mouse model of botulism. The current study measured HCA1 and HCA2 entry into rat primary neurons and cultured Neuro2A cells. We found that there were two sequential steps during the association of BoNT/A with neurons. The initial step was ganglioside dependent, while the subsequent step involved association with synaptic vesicles. HCA1 and HCA2 entered the same population of synaptic vesicles and entered cells at similar rates. The primary difference was that HCA2 had a higher degree of receptor occupancy for cells and neurons than HcA1. Thus, HCA2 and HCA1 share receptors and entry pathway but differ in their affinity for receptor. The initial interaction of HCA1 and HCA2 with neurons may contribute to the unique pathologies of BoNT/A1 and BoNT/A2 in mouse models. PMID:27795365

  11. Augmentation of the noradrenergic system in alpha-2 adrenergic receptor deficient mice: anatomical changes associated with enhanced fear memory.

    PubMed

    Davies, M Frances; Tsui, Janet Y; Flannery, Judy A; Li, Xiangqi; DeLorey, Timothy M; Hoffman, Brian B

    2003-10-03

    We have investigated sensitivity to the conditioned fear procedure of mice is influenced by the genetic deletion of alpha2A adrenoceptors (ARs). We observed a heightened freezing response in the discrete cue memory test in alpha2A AR knockout (alpha2A AR KO) mice and in D79N mice, a transgenic mouse strain with functionally impaired alpha2A ARs. No significant differences in contextual memory were observed between control and alpha2A AR KO or D79N mice suggesting a minimal role for the noradrenergic system in contextual memory. We speculated that the increased freezing response of the alpha2A AR KO and D79N mice in the discrete cue setting was due to increased release of norepinephrine evoked by the unconditioned footshock stimulus. In alpha2A AR KO mice we measured a doubling in the number of noradrenergic neurons in the locus coeruleus (LC) and a large increase in the cell volume of tyrosine hydroxylase positive neurons, likely due to selective preservation of large, multipolar neurons in the subcoeruleus. Hyperplasia of the noradrenergic neurons in the nucleus tractus solitarius, A5 and A7, was also observed. Alpha2A AR KO mice exhibit greater c-Fos expression in the LC compared to wild type mice suggesting that the LC neurons in the alpha2A AR KO mice were spontaneously more active. This study suggests that alpha2A ARs are involved in the development of the central noradrenergic system and raises the possibility that alterations in alpha2A AR expression may contribute to variations in fear and stress responses.

  12. Noradrenergic modulation of neural erotic stimulus perception.

    PubMed

    Graf, Heiko; Wiegers, Maike; Metzger, Coraline Danielle; Walter, Martin; Grön, Georg; Abler, Birgit

    2017-09-01

    We recently investigated neuromodulatory effects of the noradrenergic agent reboxetine and the dopamine receptor affine amisulpride in healthy subjects on dynamic erotic stimulus processing. Whereas amisulpride left sexual functions and neural activations unimpaired, we observed detrimental activations under reboxetine within the caudate nucleus corresponding to motivational components of sexual behavior. However, broadly impaired subjective sexual functioning under reboxetine suggested effects on further neural components. We now investigated the same sample under these two agents with static erotic picture stimulation as alternative stimulus presentation mode to potentially observe further neural treatment effects of reboxetine. 19 healthy males were investigated under reboxetine, amisulpride and placebo for 7 days each within a double-blind cross-over design. During fMRI static erotic picture were presented with preceding anticipation periods. Subjective sexual functions were assessed by a self-reported questionnaire. Neural activations were attenuated within the caudate nucleus, putamen, ventral striatum, the pregenual and anterior midcingulate cortex and in the orbitofrontal cortex under reboxetine. Subjective diminished sexual arousal under reboxetine was correlated with attenuated neural reactivity within the posterior insula. Again, amisulpride left neural activations along with subjective sexual functioning unimpaired. Neither reboxetine nor amisulpride altered differential neural activations during anticipation of erotic stimuli. Our results verified detrimental effects of noradrenergic agents on neural motivational but also emotional and autonomic components of sexual behavior. Considering the overlap of neural network alterations with those evoked by serotonergic agents, our results suggest similar neuromodulatory effects of serotonergic and noradrenergic agents on common neural pathways relevant for sexual behavior. Copyright © 2017 Elsevier B.V. and

  13. Noradrenergic Stimulation Impairs Memory Generalization in Women.

    PubMed

    Kluen, Lisa Marieke; Agorastos, Agorastos; Wiedemann, Klaus; Schwabe, Lars

    2017-07-01

    Memory generalization is essential for adaptive decision-making and action. Our ability to generalize across past experiences relies on medial-temporal lobe structures, known to be highly sensitive to stress. Recent evidence suggests that stressful events may indeed interfere with memory generalization. Yet, the mechanisms involved in this generalization impairment are unknown. We tested here whether a pharmacological elevation of major stress mediators-noradrenaline and glucocorticoids-is sufficient to disrupt memory generalization. In a double-blind, placebo-controlled design, healthy men and women received orally a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine that leads to increased noradrenergic stimulation, or both drugs, before they completed an associative learning task probing memory generalization. Drugs left learning performance intact. Yohimbine, however, led to a striking generalization impairment in women, but not in men. Hydrocortisone, in turn, had no effect on memory generalization, neither in men nor in women. The present findings indicate that increased noradrenergic activity, but not cortisol, is sufficient to disrupt memory generalization in a sex-specific manner, with relevant implications for stress-related mental disorders characterized by generalization deficits.

  14. Group IIA secretory phospholipase A2 (GIIA) mediates apoptotic death during NMDA receptor activation in rat primary cortical neurons.

    PubMed

    Chiricozzi, Elena; Fernandez-Fernandez, Seila; Nardicchi, Vincenza; Almeida, Angeles; Bolaños, Juan Pedro; Goracci, Gianfrancesco

    2010-03-01

    Phospholipases A(2) (PLA(2)) participate in neuronal death signalling pathways because of their ability to release lipid mediators, although the contribution of each isoform and mechanism of neurotoxicity are still elusive. Using a novel fluorogenic method to assess changes in a PLA(2) activity by flow cytometry, here we show that the group IIA secretory phospholipase A(2) isoform (GIIA) was specifically activated in cortical neurons following stimulation of N-methyl-d-aspartate glutamate receptor subtype (NMDAR). For activation, GIIA required Ca(2+) and reactive oxygen/nitrogen species, and inhibition of its activity fully prevented NMDAR-mediated neuronal apoptotic death. Superoxide, nitric oxide or peroxynitrite donors stimulated GIIA activity, which mediated neuronal death. Intriguingly, we also found that GIIA activity induced mitochondrial superoxide production after NMDAR stimulation. These results reveal a novel role for GIIA in excitotoxicity both as target and producer of superoxide in a positive-loop of activation that may contribute to the propagation of neurodegeneration.

  15. Neurotoxicity of coral snake phospholipases A2 in cultured rat hippocampal neurons.

    PubMed

    de Carvalho, Nathalia Delazeri; Garcia, Raphael CaioTamborelli; Ferreira, Adilson Kleber; Batista, Daniel Rodrigo; Cassola, Antonio Carlos; Maria, Durvanei; Lebrun, Ivo; Carneiro, Sylvia Mendes; Afeche, Solange Castro; Marcourakis, Tania; Sandoval, Maria Regina Lopes

    2014-03-13

    The neurotoxicity of two secreted Phospholipases A2 from Brazilian coral snake venom in rat primary hippocampal cell culture was investigated. Following exposure to Mlx-8 or Mlx-9 toxins, an increase in free cytosolic Ca(2+) and a reduction in mitochondrial transmembrane potential (ΔΨm) became evident and occurred prior to the morphological changes and cytotoxicity. Exposure of hippocampal neurons to Mlx-8 or Mlx-9 caused a decrease in the cell viability as assessed by MTT and LDH assays. Inspection using fluorescent images and ultrastructural analysis by scanning and transmission electron microscopy showed that multiphase injury is characterized by overlapping cell death phenotypes. Shrinkage, membrane blebbing, chromatin condensation, nucleosomal DNA fragmentation and the formation of apoptotic bodies were observed. The most striking alteration observed in the electron microscopy was the fragmentation and rarefaction of the neuron processes network. Degenerated terminal synapses, cell debris and apoptotic bodies were observed among the fragmented fibers. Numerous large vacuoles as well as swollen mitochondria and dilated Golgi were noted. Necrotic signs such as a large amount of cellular debris and membrane fragmentation were observed mainly when the cells were exposed to highest concentration of the PLA2-neurotoxins. PLA2s exposed cultures showed cytoplasmic vacuoles filled with cell debris, clusters of mitochondria presented mitophagy-like structures that are in accordance to patterns of programmed cell death by autophagy. Finally, we demonstrated that the sPLA2s, Mlx-8 and Mlx-9, isolated from the Micrurus lemniscatus snake venom induce a hybrid cell death with apoptotic, autophagic and necrotic features. Furthermore, this study suggests that the augment in free cytosolic Ca(2+) and mitochondrial dysfunction are involved in the neurotoxicity of Elapid coral snake venom sPLA2s. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. 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

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

    PubMed Central

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

    2011-01-01

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

  18. Deepened extinction following compound stimulus presentation: Noradrenergic modulation

    PubMed Central

    Janak, Patricia H.; Corbit, Laura H.

    2011-01-01

    Behavioral extinction is an active form of new learning involving the prediction of nonreward where reward has previously been present. The expression of extinction learning can be disrupted by the presentation of reward itself or reward-predictive stimuli (reinstatement) as well as the passage of time (spontaneous recovery) or contextual changes (renewal). The following experiments replicated the demonstration that presenting multiple previously rewarded stimuli in compound during extinction enhances extinction learning. To explore the pharmacological basis for this we next examined the effects of pharmacological treatments that either facilitated or blocked noradrenergic activity to test the hypothesis that increased noradrenergic activity at the time of extinction training would improve, whereas blockade of noradrenergic activity would impair the extinction of appetitive stimulus–reward memories. Different groups of rats were trained in a discriminative stimulus paradigm to lever-press for food reward. Once stable responding was achieved, responding was extinguished for 2 d. Prior to a third extinction session, rats received systemic administration of either saline, yohimbine (α2 antagonist), atomoxetine (norepinephrine reuptake inhibitor), or propranolol (β-receptor antagonist). Spontaneous recovery of responding to the stimuli was tested 4 wk later. Our results indicate that increasing noradrenergic activity during extinction augments extinction learning resulting in less recovery of responding at test. These results have important implications for models of relapse to drug seeking and the development of extinction-based therapies. PMID:21224211

  19. Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning

    PubMed Central

    Wei, Catherine J.; Singer, Philipp; Coelho, Joana; Boison, Detlev; Feldon, Joram; Yee, Benjamin K.; Chen, Jiang-Fan

    2011-01-01

    The adenosine A2A receptor (A2AR) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A2AR inactivation can be pro-cognitive, analyses of A2AR's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A2ARs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A2ARs. Specifically, we evaluated the cognitive impacts of conditional A2AR deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb-A2AR KO) or to striatum alone (st-A2AR KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A2AR-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility—enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A2ARs as they were captured by A2AR deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D1, D2, or A1 receptor expression was found. This study provides the first direct demonstration that targeting striatal A2ARs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions. PMID:21693634

  20. Selective inactivation of adenosine A(2A) receptors in striatal neurons enhances working memory and reversal learning.

    PubMed

    Wei, Catherine J; Singer, Philipp; Coelho, Joana; Boison, Detlev; Feldon, Joram; Yee, Benjamin K; Chen, Jiang-Fan

    2011-01-01

    The adenosine A(2A) receptor (A(2A)R) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A(2A)R inactivation can be pro-cognitive, analyses of A(2A)R's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A(2A)Rs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A(2A)Rs. Specifically, we evaluated the cognitive impacts of conditional A(2A)R deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb-A(2A)R KO) or to striatum alone (st-A(2A)R KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A(2A)R-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility-enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A(2A)Rs as they were captured by A(2A)R deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D(1), D(2), or A(1) receptor expression was found. This study provides the first direct demonstration that targeting striatal A(2A)Rs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions.

  1. 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.

  2. 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

  3. 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

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

    PubMed

    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

    2015-06-23

    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.

  5. 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.

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

    PubMed Central

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

    2017-01-01

    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. DOI: http://dx.doi.org/10.7554/eLife.18247.001 PMID:28708061

  7. 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.

  8. Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited α-synuclein accumulation and age-dependent sensorimotor deficits

    PubMed Central

    Schultheis, Patrick J.; Fleming, Sheila M.; Clippinger, Amy K.; Lewis, Jada; Tsunemi, Taiji; Giasson, Benoit; Dickson, Dennis W.; Mazzulli, Joseph R.; Bardgett, Mark E.; Haik, Kristi L.; Ekhator, Osunde; Chava, Anil Kumar; Howard, John; Gannon, Matt; Hoffman, Elizabeth; Chen, Yinhuai; Prasad, Vikram; Linn, Stephen C.; Tamargo, Rafael J.; Westbroek, Wendy; Sidransky, Ellen; Krainc, Dimitri; Shull, Gary E.

    2013-01-01

    Mutations in ATP13A2 (PARK9), encoding a lysosomal P-type ATPase, are associated with both Kufor–Rakeb syndrome (KRS) and neuronal ceroid lipofuscinosis (NCL). KRS has recently been classified as a rare genetic form of Parkinson's disease (PD), whereas NCL is a lysosomal storage disorder. Although the transport activity of ATP13A2 has not been defined, in vitro studies show that its loss compromises lysosomal function, which in turn is thought to cause neuronal degeneration. To understand the role of ATP13A2 dysfunction in disease, we disrupted its gene in mice. Atp13a2−/− and Atp13a2+/+ mice were tested behaviorally to assess sensorimotor and cognitive function at multiple ages. In the brain, lipofuscin accumulation, α-synuclein aggregation and dopaminergic pathology were measured. Behaviorally, Atp13a2−/− mice displayed late-onset sensorimotor deficits. Accelerated deposition of autofluorescent storage material (lipofuscin) was observed in the cerebellum and in neurons of the hippocampus and the cortex of Atp13a2−/− mice. Immunoblot analysis showed increased insoluble α-synuclein in the hippocampus, but not in the cortex or cerebellum. There was no change in the number of dopaminergic neurons in the substantia nigra or in striatal dopamine levels in aged Atp13a2−/− mice. These results show that the loss of Atp13a2 causes sensorimotor impairments, α-synuclein accumulation as occurs in PD and related synucleinopathies, and accumulation of lipofuscin deposits characteristic of NCL, thus providing the first direct demonstration that null mutations in Atp13a2 can cause pathological features of both diseases in the same organism. PMID:23393156

  9. 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

  10. 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.

  11. Noradrenergic System in Down Syndrome and Alzheimer's Disease A Target for Therapy.

    PubMed

    Phillips, Cristy; Fahimi, Atoossa; Das, Devsmita; Mojabi, Fatemeh S; Ponnusamy, Ravikumar; Salehi, Ahmad

    2016-01-01

    Locus coeruleus (LC) neurons in the brainstem send extensive noradrenergic (NE)-ergic terminals to the majority of brain regions, particularly those involved in cognitive function. Both Alzheimer's disease (AD) and Down syndrome (DS) are characterized by similar pathology including significant LC degeneration and dysfunction of the NE-ergic system. Extensive loss of NE-ergic terminals has been linked to alterations in brain regions vital for cognition, mood, and executive function. While the mechanisms by which NE-ergic abnormalities contribute to cognitive dysfunction are not fully understood, emergent evidence suggests that rescue of NE-ergic system can attenuate neuropathology and cognitive decline in both AD and DS. Therapeutic strategies to enhance NE neurotransmission have undergone limited testing. Among those deployed to date are NE reuptake inhibitors, presynaptic α-adrenergic receptor antagonists, NE prodrugs, and β-adrenergic agonists. Here we examine alterations in the NE-ergic system in AD and DS and suggest that NE-ergic system rescue is a plausible treatment strategy for targeting cognitive decline in both disorders.

  12. 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.

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

    PubMed

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

    2014-01-01

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

  14. Noradrenergic modulation of risk/reward decision making.

    PubMed

    Montes, David R; Stopper, Colin M; Floresco, Stan B

    2015-08-01

    Catecholamine transmission modulates numerous cognitive and reward-related processes that can subserve more complex functions such as cost/benefit decision making. Dopamine has been shown to play an integral role in decisions involving reward uncertainty, yet there is a paucity of research investigating the contributions of noradrenaline (NA) transmission to these functions. The present study was designed to elucidate the contribution of NA to risk/reward decision making in rats, assessed with a probabilistic discounting task. We examined the effects of reducing noradrenergic transmission with the α2 agonist clonidine (10-100 μg/kg), and increasing activity at α2A receptor sites with the agonist guanfacine (0.1-1 mg/kg), the α2 antagonist yohimbine (1-3 mg/kg), and the noradrenaline transporter (NET) inhibitor atomoxetine (0.3-3 mg/kg) on probabilistic discounting. Rats chose between a small/certain reward and a larger/risky reward, wherein the probability of obtaining the larger reward either decreased (100-12.5 %) or increased (12.5-100 %) over a session. In well-trained rats, clonidine reduced risky choice by decreasing reward sensitivity, whereas guanfacine did not affect choice behavior. Yohimbine impaired adjustments in decision biases as reward probability changed within a session by altering negative feedback sensitivity. In a subset of rats that displayed prominent discounting of probabilistic rewards, the lowest dose of atomoxetine increased preference for the large/risky reward when this option had greater long-term utility. These data highlight an important and previously uncharacterized role for noradrenergic transmission in mediating different aspects of risk/reward decision making and mediating reward and negative feedback sensitivity.

  15. Noradrenergic mechanisms of arousal's bidirectional effects on episodic memory.

    PubMed

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

    2017-01-01

    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. Copyright © 2016

  16. 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.

  17. Noradrenergic Dysfunction in Alzheimer's and Parkinson's Diseases-An Overview of Imaging Studies.

    PubMed

    Peterson, Andrew C; Li, Chiang-Shan R

    2018-01-01

    Noradrenergic dysfunction contributes to cognitive impairment in Alzheimer's Disease (AD) and Parkinson's Disease (PD). Conventional therapeutic strategies seek to enhance cholinergic and dopaminergic neurotransmission in AD and PD, respectively, and few studies have examined noradrenergic dysfunction as a target for medication development. We review the literature of noradrenergic dysfunction in AD and PD with a focus on human imaging studies that implicate the locus coeruleus (LC) circuit. The LC sends noradrenergic projections diffusely throughout the cerebral cortex and plays a critical role in attention, learning, working memory, and cognitive control. The LC undergoes considerable degeneration in both AD and PD. Advances in magnetic resonance imaging have facilitated greater understanding of how structural and functional alteration of the LC may contribute to cognitive decline in AD and PD. We discuss the potential roles of the noradrenergic system in the pathogenesis of AD and PD with an emphasis on postmortem anatomical studies, structural MRI studies, and functional MRI studies, where we highlight changes in LC connectivity with the default mode network (DMN). LC degeneration may accompany deficient capacity in suppressing DMN activity and increasing saliency and task control network activities to meet behavioral challenges. We finish by proposing potential and new directions of research to address noradrenergic dysfunction in AD and PD.

  18. 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.

  19. Cholinergic, But Not Dopaminergic or Noradrenergic, Enhancement Sharpens Visual Spatial Perception in Humans

    PubMed Central

    Wallace, Deanna L.

    2017-01-01

    unknown. Here we demonstrate that cholinergic enhancement improves detection of a target flanked by distractors, consistent with sharpened visuospatial perceptual representations. Furthermore, whereas most pharmacological studies focus on a single neurotransmitter, many neuromodulators can have related effects on cognition and perception. Thus, we also demonstrate that enhancing noradrenergic and dopaminergic systems does not systematically improve visuospatial perception or alter its tuning. Our results link visuospatial tuning effects of acetylcholine at the neuronal and perceptual levels and provide insights into the connection between cholinergic signaling and visual attention. PMID:28336568

  20. 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.

  1. The noradrenergic component in tapentadol action counteracts μ-opioid receptor-mediated adverse effects on adult neurogenesis.

    PubMed

    Meneghini, Vasco; Cuccurazzu, Bruna; Bortolotto, Valeria; Ramazzotti, Vera; Ubezio, Federica; Tzschentke, Thomas M; Canonico, Pier Luigi; Grilli, Mariagrazia

    2014-05-01

    Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether tapentadol, a novel central analgesic combining μ-opioid receptor (MOR) agonism with norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where the MOR component is predominant. On the contrary, at higher (micromolar) concentrations, tapentadol elicited proneurogenic and antiapoptotic effects via activation of β2 and α2 adrenergic receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing long-term use of opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared with classic opiates.

  2. 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.

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

    PubMed

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

    2017-02-21

    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.

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

    PubMed Central

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

    2017-01-01

    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. PMID:28220877

  5. Caudal fourth ventricular administration of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside regulates glucose and counterregulatory hormone profiles, dorsal vagal complex metabolosensory neuron function, and hypothalamic Fos expression.

    PubMed

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

    2013-09-01

    This study investigated the hypothesis that estrogen controls hindbrain AMP-activated protein kinase (AMPK) activity and regulation of blood glucose, counterregulatory hormone secretion, and hypothalamic nerve cell transcriptional status. Dorsal vagal complex A2 noradrenergic neurons were laser microdissected from estradiol benzoate (E)- or oil (O)-implanted ovariectomized female rats after caudal fourth ventricular (CV4) delivery of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR), for Western blot analysis. E advanced AICAR-induced increases in A2 phospho-AMPK (pAMPK) expression and in blood glucose levels and was required for augmentation of Fos, estrogen receptor-α (ERα), monocarboxylate transporter-2, and glucose transporter-3 protein in A2 neurons and enhancement of corticosterone secretion by this treatment paradigm. CV4 AICAR also resulted in site-specific modifications in Fos immunolabeling of hypothalamic metabolic structures, including the paraventricular, ventromedial, and arcuate nuclei. The current studies demonstrate that estrogen regulates AMPK activation in caudal hindbrain A2 noradrenergic neurons during pharmacological replication of energy shortage in this area of the brain, and that this sensor is involved in neural regulation of glucostasis, in part, through control of corticosterone secretion. The data provide unique evidence that A2 neurons express both ERα and -β proteins and that AMPK upregulates cellular sensitivity to ERα-mediated signaling during simulated energy insufficiency. The results also imply that estrogen promotes glucose and lactate uptake by these cells under those conditions. Evidence for correlation between hindbrain AMPK and hypothalamic nerve cell genomic activation provides novel proof for functional connectivity between this hindbrain sensor and higher order metabolic brain loci while demonstrating a modulatory role for estrogen in this interaction. Copyright © 2013 Wiley Periodicals, Inc.

  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. Haploinsufficiency for Translation Elongation Factor eEF1A2 in Aged Mouse Muscle and Neurons Is Compatible with Normal Function

    PubMed Central

    Griffiths, Lowri A.; Doig, Jennifer; Churchhouse, Antonia M. D.; Davies, Faith C. J.; Squires, Charlotte E.; Newbery, Helen J.; Abbott, Catherine M.

    2012-01-01

    Translation elongation factor isoform eEF1A2 is expressed in muscle and neurons. Deletion of eEF1A2 in mice gives rise to the neurodegenerative phenotype “wasted” (wst). Mice homozygous for the wasted mutation die of muscle wasting and neurodegeneration at four weeks post-natal. Although the mutation is said to be recessive, aged heterozygous mice have never been examined in detail; a number of other mouse models of motor neuron degeneration have recently been shown to have similar, albeit less severe, phenotypic abnormalities in the heterozygous state. We therefore examined the effects of ageing on a cohort of heterozygous +/wst mice and control mice, in order to establish whether a presumed 50% reduction in eEF1A2 expression was compatible with normal function. We evaluated the grip strength assay as a way of distinguishing between wasted and wild-type mice at 3–4 weeks, and then performed the same assay in older +/wst and wild-type mice. We also used rotarod performance and immunohistochemistry of spinal cord sections to evaluate the phenotype of aged heterozygous mice. Heterozygous mutant mice showed no deficit in neuromuscular function or signs of spinal cord pathology, in spite of the low levels of eEF1A2. PMID:22848658

  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. Evidence for a role of corticopetal, noradrenergic systems in the development of executive function.

    PubMed

    Mokler, David J; Miller, Christine E; McGaughy, Jill A

    2017-09-01

    Adolescence is a period during which many aspects of executive function are maturing. Much of the literature has focused on discrepancies between sub-cortical and cortical development that is hypothesized to lead to over-processing of reinforcement related stimuli unchecked by fully matured response inhibition. Specifically, maturation of sub-cortical dopaminergic systems that terminate in the nucleus accumbens has been suggested to occur prior to the full maturation of corticopetal dopaminergic systems. However, converging evidence supports the hypothesis that many aspects of cognitive control are critically linked to cortical noradrenergic systems, that the effectiveness of drugs used to treat disorders of executive function, e.g. ADHD, may result primarily from increases in cortical norepinephrine (NE) and that cortical noradrenergic systems mature across adolescence. However, little attention has been given to the development of this system during adolescence or to its influence in executive function. In the present paper, we discuss the developmental trajectory of the noradrenergic system of the forebrain, highlight the interactions between noradrenergic and dopaminergic systems, and highlight the contribution of the immature corticopetal noradrenergic systems in the ontogeny of several aspects of executive function. Finally we compare data from adolescent rats to those gathered after selective depletion of NE in sub-regions of the prefrontal cortex with an emphasis on the similarities in performance of NE lesioned rats and adolescents. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Neuropeptide S interacts with the basolateral amygdala noradrenergic system in facilitating object recognition memory consolidation.

    PubMed

    Han, Ren-Wen; Xu, Hong-Jiao; Zhang, Rui-San; Wang, Pei; Chang, Min; Peng, Ya-Li; Deng, Ke-Yu; Wang, Rui

    2014-01-01

    The noradrenergic activity in the basolateral amygdala (BLA) was reported to be involved in the regulation of object recognition memory. As the BLA expresses high density of receptors for Neuropeptide S (NPS), we investigated whether the BLA is involved in mediating NPS's effects on object recognition memory consolidation and whether such effects require noradrenergic activity. Intracerebroventricular infusion of NPS (1nmol) post training facilitated 24-h memory in a mouse novel object recognition task. The memory-enhancing effect of NPS could be blocked by the β-adrenoceptor antagonist propranolol. Furthermore, post-training intra-BLA infusions of NPS (0.5nmol/side) improved 24-h memory for objects, which was impaired by co-administration of propranolol (0.5μg/side). Taken together, these results indicate that NPS interacts with the BLA noradrenergic system in improving object recognition memory during consolidation. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Noradrenergic innervation of the rat spinal cord caudal to a complete spinal cord transection: effects of olfactory ensheathing glia.

    PubMed

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

    2010-03-01

    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. Copyright 2009 Elsevier Inc. 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. Functional role of striatal A2A, D2, and mGlu5 receptor interactions in regulating striatopallidal GABA neuronal transmission.

    PubMed

    Beggiato, Sarah; Tomasini, Maria Cristina; Borelli, Andrea Celeste; Borroto-Escuela, Dasiel Oscar; Fuxe, Kjell; Antonelli, Tiziana; Tanganelli, Sergio; Ferraro, Luca

    2016-07-01

    In this study, the functional role of individual striatal receptors for adenosine (A2AR), dopamine (D2R), and the metabotropic glutamate receptor mGlu5R in regulating rat basal ganglia activity was characterized in vivo using dual-probe microdialysis in freely moving rats. In particular, intrastriatal perfusion with the D2R agonist quinpirole (10 μM, 60 min) decreased ipsilateral pallidal GABA and glutamate levels, whereas intrastriatal CGS21680 (A2AR agonist; 1 μM, 60 min) was ineffective on either pallidal GABA and glutamate levels or the quinpirole-induced effects. Intrastriatal perfusion with the mGlu5R agonist (RS)-2-chloro-5-hydroxyphenylglycine (600 μM, 60 min), by itself ineffective on pallidal GABA and glutamate levels, partially counteracted the effects of quinpirole. When combined with CGS21680 (1 μM, 60 min), (RS)-2-chloro-5-hydroxyphenylglycine (CHPG; 600 μM, 60 min) fully counteracted the quinpirole (10 μM, 60 min)-induced reduction in ipsilateral pallidal GABA and glutamate levels. These effects were fully counteracted by local perfusion with the mGlu5R antagonist MPEP (300 μM) or the A2AR antagonist ZM 241385 (100 nM). These results suggest that A2ARs and mGlu5Rs interact synergistically in modulating the D2R-mediated control of striatopallidal GABA neurons. Using dual-probe microdialysis, we characterized the functional role of striatal adenosine A2A receptor (A2AR), dopamine D2 receptor (D2R), and metabotropic glutamate receptor 5 (mGluR5) interactions in regulating rat basal ganglia activity. The results suggest the possible usefulness of using an A2AR antagonist and mGluR5 antagonist combination in the treatment of Parkinson's disease to increase the inhibitory D2 signaling on striatopallidal GABA neurons. © 2016 International Society for Neurochemistry.

  14. Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease

    PubMed Central

    Wang, Bing; Chen, Li-Hua

    2016-01-01

    In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain. PMID:27747105

  15. 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…

  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. 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…

  20. 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

  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 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

  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. The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized anxiety and phobias.

    PubMed

    Sullivan, G M; Coplan, J D; Kent, J M; Gorman, J M

    1999-11-01

    Over the past three decades of psychiatric research, abnormalities in the noradrenergic system have been identified in particular anxiety disorders such as panic disorder. Simultaneously, neuroscience research on fear pathways and the stress response have delineated central functions for the noradrenergic system. This review focuses on the noradrenergic system in anxiety spectrum disorders such as panic disorder, generalized anxiety disorder, and phobias for the purpose of elucidating current conceptualizations of the pathophysiologies. Neuroanatomic pathways that are theoretically relevant in anxiogenesis are discussed and the implications for treatment reviewed.

  5. α(2) noradrenergic receptor suppressed CaMKII signaling in spinal dorsal horn of mice with inflammatory pain.

    PubMed

    Wang, Xin-Tai; Lian, Xia; Xu, Ying-Ming; Suo, Zhan-Wei; Yang, Xian; Hu, Xiao-Dong

    2014-02-05

    Intrathecal application of α2 noradrenergic receptor agonists effectively alleviates the pathological pain induced by peripheral tissue injury. However, the spinal antinociceptive mechanisms of α2 noradrenergic receptors remain to be characterized. The present study performed immunohistochemistry and western blot to elucidate the signaling pathway initiated by α2 noradrenergic receptors in spinal dorsal horn of mice, and identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an important target for noradrenergic suppression of inflammatory pain. Our data showed that intraplantar injection of Complete Freund's Adjuvant (CFA) substantially enhanced CaMKII autophosphorylation at Threonine 286, which could be abolished by intrathecal administration of α2 noradrenergic receptor agonist clonidine. Gi protein-coupled α2 noradrenergic receptor might inhibit cAMP-dependent protein kinase (PKA) to disturb CaMKII signaling. We found that pharmacological activation of PKA in intact mice also enhanced spinal CaMKII autophosphorylation level, which was completely antagonized by clonidine. Moreover, direct PKA inhibition in CFA-injected mice mimicked the suppressive effect of α2 noradrenergic receptors on CaMKII. PKA inhibition has been shown to downregulate CaMKII by enhancing protein phosphatase activity. Consistent with this notion, spinal treatment with protein phosphatase inhibitor okadaic acid ruled out clonidine-mediated CaMKII dephosphorylation in CFA-injected mice. Through PKA/protein phosphatase/CaMKII pathway, clonidine noticeably decreased CFA-evoked phosphorylation of N-methyl-d-aspartate subtype glutamate receptor GluN1 and GluN2B subunit as well as α-amino-3-hydroxy-5-methylisoxazole-4-propionic Acid subtype glutamate receptor GluA1 subunit. These data suggested that interference with CaMKII signaling might represent an important mechanism underlying noradrenergic suppression of inflammatory pain. Copyright © 2013 Elsevier B.V. All rights

  6. Effects of chronic sleep fragmentation on wake-active neurons and the hypercapnic arousal response.

    PubMed

    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

    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. 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. 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). 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.

  7. 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.

  8. Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress

    PubMed Central

    Fitzgerald, Paul J.; Giustino, Thomas F.; Seemann, Jocelyn R.; Maren, Stephen

    2015-01-01

    Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a β-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that β-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma. PMID:26124100

  9. Interaction of brain noradrenergic system and the hypothalamic-pituitary-adrenal (HPA) axis in man.

    PubMed

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

    2005-09-01

    Numerous interactions between the brainstem locus coeruleus system and the HPA axis have been shown in experimental animals. This relationship is less well characterized in humans and little is known about the influence of psychiatric disorders, which disturb one of these systems, on this relationship. Untreated subjects with pure MDD (n = 13), MDD with comorbid anxiety disorders (n = 17), and pure anxiety disorders (n = 15) were recruited by advertising. Age and sex matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 45). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for ACTH assay. These same subjects also underwent a clonidine challenge study for assessment of growth hormone release as a marker of tonic noradrenergic activation. Examining log transformed area under the curve response for each hormone, a significant negative relationship (simple regression) was observed between systems in normal subjects. This relationship was preserved in anxiety subjects. However, both pure depressed and comorbid depressed and anxiety subjects demonstrated disruption of this relationship. Under normal circumstances, noradrenergic systems can influence the magnitude of the HPA axis response to stress. However, in subjects with major depression, HPA axis activation appears autonomous of noradrenergic influence.

  10. 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

  11. 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

  12. Genetically determined differences in noradrenergic function: The spontaneously hypertensive rat model.

    PubMed

    Sterley, Toni-Lee; Howells, Fleur M; Russell, Vivienne A

    2016-06-15

    While genetic predisposition is a major factor, it is not known how development of attention-deficit/hyperactivity disorder (ADHD) is modulated by early life stress. The spontaneously hypertensive rat (SHR) displays the behavioral characteristics of ADHD (poorly sustained attention, impulsivity, hyperactivity) and is the most widely studied genetic model of ADHD. We have previously shown that SHR have disturbances in the noradrenergic system and that the early life stress of maternal separation failed to produce anxiety-like behavior in SHR, contrary to control Sprague-Dawley and Wistar-Kyoto (WKY) who showed typical anxiety-like behavior in later life. In the present study we investigated the effect of maternal separation on approach behavior (response to a novel object in a familiar environment) in preadolescent SHR and WKY. We also investigated whether maternal separation altered GABAA and NMDA receptor-mediated regulation of norepinephrine release in preadolescent SHR and WKY hippocampus. We found that female SHR, similar to male SHR, exhibited greater exploratory activity than WKY. Maternal separation significantly increased GABAA receptor-mediated inhibition of glutamate-stimulated release of norepinephrine in male and female SHR hippocampus but had no significant effect in WKY. Maternal separation had opposite effects on NMDA receptor-mediated inhibition of norepinephrine release in SHR and WKY hippocampus, as it increased inhibition of both glutamate-stimulated and depolarization-evoked release in SHR hippocampus but not in WKY. The results of the present study show that noradrenergic function is similarly altered by the early life stress of maternal separation in male and female SHR, while GABA- and glutamate-regulation of norepinephrine release remained unaffected by maternal separation in the control, WKY, rat strain. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Prenatal Drug Exposures Sensitize Noradrenergic Circuits to Subsequent Disruption by Chlorpyrifos

    PubMed Central

    Slotkin, Theodore A.; Skavicus, Samantha; Seidler, Frederic J.

    2015-01-01

    We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3 mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1–4, at a dose (1 mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17–19 at a standard therapeutic dose (0.2 mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants. PMID:26419632

  14. Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos.

    PubMed

    Slotkin, Theodore A; Skavicus, Samantha; Seidler, Frederic J

    2015-12-02

    We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. 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.

    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

  16. One-single physical exercise session after object recognition learning promotes memory persistence through hippocampal noradrenergic mechanisms.

    PubMed

    da Silva de Vargas, Liane; Neves, Ben-Hur Souto das; Roehrs, Rafael; Izquierdo, Iván; Mello-Carpes, Pâmela

    2017-06-30

    Previously we showed the involvement of the hippocampal noradrenergic system in the consolidation and persistence of object recognition (OR) memory. Here we show that one-single physical exercise session performed immediately after learning promotes OR memory persistence and increases norepinephrine levels in the hippocampus. Additionally, effects of exercise on memory are avoided by an intra-hippocampal beta-adrenergic antagonist infusion. Taken together, these results suggest that exercise effects on memory can be related to noradrenergic mechanisms and acute physical exercise can be a non-pharmacological intervention to assist memory consolidation and persistence, with few or no side effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Dopamine modulates male sexual behavior in Japanese quail in part via actions on noradrenergic receptors.

    PubMed

    Cornil, Charlotte A; Dejace, Christel; Ball, Gregory F; Balthazart, Jacques

    2005-08-30

    In rats, dopamine (DA) facilitates male sexual behavior through its combined action on D1- and D2-like receptors, in the medial preoptic area (MPOA) as well as other brain areas. In Japanese quail, systemic injections of dopaminergic drugs suggested a similar pharmacology but central injections have never been performed. Recent electrophysiological experiments demonstrated that DA effects in the MPOA of quail are mediated mainly through the activation of alpha2-noradrenergic receptors. Previous studies of DA action on behavior used specific dopaminergic agonists/antagonists and therefore unintentionally avoided the potential cross-reaction with alpha2-receptors. The present study was thus designed to investigate directly the effects of DA on male sexual behavior and to test whether the interaction of DA with heterologous receptors affects this behavior. Intracerebroventricular (i.c.v.) injection of DA or NE inhibited copulation in a dose-dependent manner. Systemic injections of yohimbine, an alpha2-noradrenergic antagonist, modulated copulation in a bimodal manner depending on the dose injected. Interestingly, a behaviorally ineffective dose of yohimbine markedly reduced the inhibitory effects of DA when injected 15min before. Together, these results show for the first time that i.c.v. injections of DA itself inhibit male sexual behavior in quail and suggest that the interaction of DA with alpha2-receptors has behavioral significance.

  18. Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder.

    PubMed

    Croonenberghs, J; Delmeire, L; Verkerk, R; Lin, A H; Meskal, A; Neels, H; Van der Planken, M; Scharpe, S; Deboutte, D; Pison, G; Maes, M

    2000-03-01

    Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12-18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years.

  19. Central noradrenergic mechanisms and the acute stress response during painful stimulation.

    PubMed

    Chapman, C Richard; Bradshaw, David H; Donaldson, Gary W; Jacobson, Robert C; Nakamura, Yoshio

    2014-12-01

    Events that threaten tissue integrity including noxious stimulation activate central noradrenergic circuits, particularly locus coeruleus and its projections. Recent advances in theory hold that an adaptive, defensive shift in brain activity takes place in response to threat. In principle, this shift may accentuate the autonomic and central biomarkers of the perception of painful events and the experience of pain itself. We have examined the effects of an alpha-2 agonist on pupil dilation responses, skin conductance responses, near field somatosensory evoked potentials and pain reports in normal volunteers undergoing repeated trials of painful fingertip stimulation delivered at low, medium and high intensities. In a double-blinded study, 114 healthy male and female volunteers underwent repeated noxious stimulation under baseline, placebo and active drug conditions where the active drug was the alpha-2 agonist tizanidine 4 mg. In contrast to baseline and placebo conditions, tizanidine 4 mg significantly reduced the magnitudes of the mean pupil dilation response, the mean skin conductance response, the mean near field somatosensory evoked potential peak-to-peak amplitude and the mean pain intensity rating. Stimulus intensity significantly altered all three biomarkers and the pain report in a graded fashion. There were no sex differences. These findings support the hypotheses that painful events activate central noradrenergic circuits, and that these circuits play a role in the autonomic and central arousal associated with pain. © The Author(s) 2014.

  20. The dorsal tegmental noradrenergic projection: an analysis of its role in maze learning.

    PubMed

    Roberts, D C; Price, M T; Fibiger, H C

    1976-04-01

    The hypothesis that the noradrenergic projection from the locus coeruleus (LC) to the cerebral cortex and hippocampus is an important neural substrate for learning was evaluated. Maze performance was studied in rats receiving either electrolytic lesions of LC or 6-hydroxydopamine (6-OHDA) lesions of the dorsal tegmental noradrenergic projection. The LC lesions did not disrupt the acquisition of a running response for food reinforcement in an L-shaped runway, even though hippocampal-cortical norepinephrine (NE) was reduced to 29%. Greater telencephalic NE depletions (to 6% of control levels) produced by 6-OHDA also failed to disrupt the acquisition of this behavior or to impair the acquisition of a food-reinforced position habit in a T-maze. Neither locomotor activity nor habituation to a novel environment was affected by the 6-OHDA lesions. Rats with such lesions were, however, found to be significantly more distractible than were controls during the performance of a previously trained response. The hypothesis that telencephalic NE is of fundamental importance in learning was not supported. The data suggest that this system may participate in attentional mechanisms.

  1. The influence of botulinum toxin type A (BTX) on the immunohistochemical characteristics of noradrenergic and cholinergic nerve fibers supplying the porcine urinary bladder wall.

    PubMed

    Lepiarczyk, E; Bossowska, A; Kaleczyc, J; Majewski, M

    2011-01-01

    Botulinum toxin (BTX) belongs to a family of neurotoxins which strongly influence the function of autonomic neurons supplying the urinary bladder. Accordingly, BTX has been used as an effective drug in experimental therapies of a range of neurogenic bladder disorders. However, there is no detailed information dealing with the influence of BTX on the morphological and chemical properties of nerve fibres supplying the urinary bladder wall. Therefore, the present study investigated, using double-labeling immunohistochemistry, the distribution, relative frequency and chemical coding of cholinergic and noradrenergic nerve fibers supplying the wall of the urinary bladder in normal female pigs (n = 6) and in the pigs (n = 6) after intravesical BTX injections. In the pigs injected with BTX, the number of adrenergic (DbetaH-positive) nerve fibers distributed in the bladder wall (urothelium, submucosa and muscle coat) was distinctly higher while the number of cholinergic (VAChT-positive) nerve terminals was lower than that found in the control animals. Moreover, the injections of BTX resulted in some changes dealing with the chemical coding of the adrenergic nerve fibers. In contrast to the normal pigs, in BTX injected animals the number of DbetaH/NPY- or DbetaH/CGRP-positive axons was higher in the muscle coat, and some fibres distributed in the urothelium and submucosa expressed immunoreactivity to CGRP. The results obtained suggest that the therapeutic effects of BTX on the urinary bladder might be dependent on changes in the distribution and chemical coding of nerve fibers supplying this organ.

  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. 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

  4. Noradrenergic innervation of the hypothalamus of rhesus monkeys: distribution of dopamine-beta-hydroxylase immunoreactive fibers and quantitative analysis of varicosities in the paraventricular nucleus.

    PubMed

    Ginsberg, S D; Hof, P R; Young, W G; Morrison, J H

    1993-01-22

    the paraventricular nucleus of the hypothalamus. The methodology employed in this study allowed for the high resolution of immunoreactive profiles through the volume of tissue being analyzed, and was more accurate than conventional light microscopy in terms of varicosity quantification. Quantitatively, a significant difference in the density of dopamine-beta-hydroxylase-immunoreactive varicosities was found between magnocellular and parvicellular regions, suggesting that parvicellular neurons received a denser noradrenergic input. These differential patterns may reflect an important functional role for norepinephrine in the regulation of anterior pituitary secretion through the hypothalamic-pituitary-adrenal stress axis.

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

    PubMed

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

    2016-03-01

    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. 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. 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. 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. The present report demonstrates that analgesic effect of ILEX in orofacial formalin test is due mainly to modulation of noradrenergic pathways. 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 orofacial nociception model induced by formalin, and study its mechanism of

  6. Stimulation of the noradrenergic system during memory formation impairs extinction learning but not the disruption of reconsolidation.

    PubMed

    Soeter, Marieke; Kindt, Merel

    2012-04-01

    The noradrenergic system plays a critical role in the 'consolidation' of emotional memory. If we are to target 'reconsolidation' in patients with anxiety disorders, the noradrenergic strengthening of fear memory should not impair the disruption of reconsolidation. In Experiment I, we addressed this issue using a differential fear conditioning procedure allowing selective reactivation of one of two fear associations. First, we strengthened fear memory by administering an α(2)-adrenergic receptor antagonist (ie, yohimbine HCl; double-blind placebo-controlled study) 30 min before acquisition (time for peak value yohimbine HCl <1 h). Next, the reconsolidation of one of the fear associations was manipulated by administering a β-adrenergic receptor antagonist (ie, propranolol HCl) 90 min before its selective reactivation (time for peak value propranolol HCl <2 h). In Experiment II, we administered propranolol HCl after reactivation of the memory to rule out a possible effect of the pharmacological manipulation on the memory retrieval itself. The excessive release of noradrenaline during memory formation not only delayed the process of extinction 48 h later, but also triggered broader fear generalization. Yet, the β-adrenergic receptor blocker during reconsolidation selectively 'neutralized' the fear-arousing aspects of the noradrenergic-strengthened memory and undermined the generalization of fear. We observed a similar reduction in fear responding when propranolol HCl was administered after reactivation of the memory. The present findings demonstrate the involvement of noradrenergic modulation in the formation as well as generalization of human fear memory. Given that the noradrenergic strengthening of fear memory impaired extinction learning but not the disruption of reconsolidation, our findings may have implications for the treatment of anxiety disorders.

  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. Close Vicinity of PrP Expressing Cells (FDC) with Noradrenergic Fibers in Healthy Sheep Spleen

    PubMed Central

    Lezmi, S.; Hunsmann, G.; Baron, T.

    2001-01-01

    In naturally and experimentally occurring scrapie in sheep, prions invade the immune system and replicate in lymphoid organs. Here we analysed immunohistochemically, in seven spleens of 6-month-old healthy sheep, the nature of the cells expressing prion protein (PrP) potentially supporting prion replication, as well as their relationship with autonomic innervation. PrP was identified using either RB1 rabbit antiserum or 4F2 monoclonal antibody directed against AA 108–123 portion of the bovine and AA 79–92 of human prion protein respectively. Using double labelling analysis, we demonstrated that PrPc is expressed by follicular dendritic cells using a specific monoclonal antibody (CNA42). We also showed the close vicinity of these PrP expressing cells with noradrenergic fibers, using a polyclonal tyrosine hydroxylase antibody. Our results may help the study of the cellular requirements for the possible neuroinvasion from the spleen. PMID:11785673

  9. Noradrenergic Regulation of Central Amygdala in Aversive Pavlovian-to-Instrumental Transfer

    PubMed Central

    Soroeta, Jose M.

    2017-01-01

    Abstract The neural mechanisms through which a Pavlovian conditioned stimulus (CS) elicits innate defense responses are well understood. But a Pavlovian CS can also invigorate ongoing instrumental responding, as shown by studies of aversive Pavlovian-to-instrumental transfer (PIT). While the neural circuitry of appetitive PIT has been studied extensively, little is known about the brain mechanisms of aversive PIT. We recently showed the central amygdala (CeA) is essential for aversive PIT. In the current studies, using pharmacology and designer receptors in rodents, we demonstrate that noradrenergic (NE) activity negatively regulates PIT via brainstem locus coeruleus (LC) activity and LC projections to CeA. Our results provide evidence for a novel pathway through which response modulation occurs between brainstem neuromodulatory systems and CeA to invigorate adaptive behavior in the face of threat. PMID:29071299

  10. Involvement of brain ketone bodies and the noradrenergic pathway in diabetic hyperphagia in rats.

    PubMed

    Iwata, Kinuyo; Kinoshita, Mika; Yamada, Shunji; Imamura, Takuya; Uenoyama, Yoshihisa; Tsukamura, Hiroko; Maeda, Kei-Ichiro

    2011-03-01

    Uncontrolled type 1 diabetes leads to hyperphagia and severe ketosis. This study was conducted to test the hypothesis that ketone bodies act on the hindbrain as a starvation signal to induce diabetic hyperphagia. Injection of an inhibitor of monocarboxylate transporter 1, a ketone body transporter, into the fourth ventricle normalized the increase in food intake in streptozotocin (STZ)-induced diabetic rats. Blockade of catecholamine synthesis in the hypothalamic paraventricular nucleus (PVN) also restored food intake to normal levels in diabetic animals. On the other hand, hindbrain injection of the ketone body induced feeding, hyperglycemia, and fatty acid mobilization via increased sympathetic activity and also norepinephrine release in the PVN. This result provides evidence that hyperphagia in STZ-induced type 1 diabetes is signaled by a ketone body sensed in the hindbrain, and mediated by noradrenergic inputs to the PVN.

  11. 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

  12. C1 neurons: the body's EMTs.

    PubMed

    Guyenet, Patrice G; Stornetta, Ruth L; Bochorishvili, Genrieta; Depuy, Seth D; Burke, Peter G R; Abbott, Stephen B G

    2013-08-01

    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.

  13. Initiating or blocking locomotion in spinal cats by applying noradrenergic drugs to restricted lumbar spinal segments.

    PubMed

    Marcoux, J; Rossignol, S

    2000-11-15

    After an acute low thoracic spinal transection (T13), cats can be made to walk with the hindlimbs on a treadmill with clonidine, an alpha2-noradrenergic agonist. Because previous studies of neonatal rat spinal cord in vitro suggest that the most important lumbar segments for rhythmogenesis are L1-L2, we investigated the role of various lumbar segments in the initiation of walking movements on a treadmill of adult cats spinalized (T13), 5-6 d earlier. The locomotor activities were evaluated from electromyographic and video recordings. The results show that: (1) localized topical application of clonidine in restricted baths over either the L3-L4 or the L5-L7 segments was sufficient to induce walking movements. Yohimbine, an alpha2-noradrenergic antagonist, could block this locomotion when applied over L3-L4 or L5-L7; (2) microinjections of clonidine in one or two lumbar segments from L3 to L5 could also induce locomotion; (3) after an intravenous injection of clonidine, locomotion was blocked by microinjections of yohimbine in segments L3, L4, or L5 but not if the injection was in L6; (4) locomotion was also blocked in all cases by additional spinal transections at L3 or L4. These results show that it is possible to initiate walking in the adult spinal cat with a pharmacological stimulation of a restricted number of lumbar segments and also that the integrity of the L3-L4 segments is necessary to sustain the locomotor activity.

  14. Does Growth Impairment Underlie the Adverse Effects of Dexamethasone on Development of Noradrenergic Systems?

    PubMed

    Slotkin, Theodore A; Ko, Ashley; Seidler, Frederic J

    2018-06-20

    Glucocorticoids are given in preterm labor to prevent respiratory distress but these agents evoke neurobehavioral deficits in association with reduced brain region volumes. To determine whether the neurodevelopmental effects are distinct from growth impairment, we gave developing rats dexamethasone at doses below or within the therapeutic range (0.05, 0.2 or 0.8 mg/kg) at different stages: gestational days (GD) 17-19, postnatal days (PN) 1-3 or PN7-9. In adolescence and adulthood, we assessed the impact on noradrenergic systems in multiple brain regions, comparing the effects to those on somatic growth or on brain region growth. Somatic growth was reduced with exposure in all three stages, with greater sensitivity for the postnatal regimens; brain region growth was impaired to a lesser extent. Norepinephrine content and concentration were reduced depending on the treatment regimen, with a rank order of deficits of PN7-9 > PN1-3 > GD17-19. However, brain growth impairment did not parallel reduced norepinephrine content in magnitude, dose threshold, sex or regional selectivity, or temporal pattern, and even when corrected for reduced brain region weights (norepinephrine per g tissue), the dexamethasone-exposed animals showed subnormal values. Regression analysis showed that somatic growth impairment accounted for an insubstantial amount of the reduction in norepinephrine content, and brain growth impairment accounted for only 12%, whereas specific effects on norepinephrine accounted for most of the effect. The adverse effects of dexamethasone on noradrenergic system development are not simply related to impaired somatic or brain region growth, but rather include specific targeting of neurodifferentiation. Copyright © 2018. Published by Elsevier B.V.

  15. 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

  16. 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

  17. Ultrastructural identification of noradrenergic nerve terminals and vasopressin-containing neurons of the paraventricular nucleus in the same thin section.

    PubMed

    Silverman, A J; Hou-Yu, A; Oldfield, B J

    1983-09-01

    Since many peptidergic cell groups receive a diverse and complex monoaminergic innervation, we have developed a double-label procedure to visualize a peptide and a catecholamine in the same ultrathin section. Radiolabeled norepinephrine (NE) is applied locally and its reuptake into NE terminals is demonstrated by ultrastructural radioautography. Controls in this and other studies demonstrate that the NE labels only NE (and possibly epinephrine) terminals and not dopaminergic or serotonergic terminals. In the same tissue, vasopressin is localized by immunocytochemistry on unembedded sections that are subsequently embedded in epoxy resins for thin sectioning. The procedure as described here shows that NE terminals in the periventricular zone of the paraventricular nucleus of the hypothalamus innervate both vasopressin-positive and vasopressin-negative structures. This technique is useful in determining the chemical connectivity of the hypothalamus.

  18. 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.

  19. Selective ablation of dorsal horn NK1 expressing cells reveals a modulation of spinal alpha2-adrenergic inhibition of dorsal horn neurones.

    PubMed

    Rahman, Wahida; Suzuki, Rie; Hunt, Stephen P; Dickenson, Anthony H

    2008-06-01

    Activity in descending systems from the brainstem modulates nociceptive transmission through the dorsal horn. Intrathecal injection of the neurotoxin saporin conjugated to SP (SP-SAP) into the lumbar spinal cord results in the selective ablation of NK(1) receptor expressing (NK(1)+ve) neurones in the superficial dorsal horn (lamina I/III). Loss of these NK(1)+ve neurones attenuates excitability of deep dorsal horn neurones due to a disruption of both intrinsic spinal circuits and a spino-bulbo-spinal loop, which activates a descending excitatory drive, mediated through spinal 5HT(3) receptors. Descending inhibitory pathways also modulate spinal activity and hence control the level of nociceptive transmission relayed to higher centres. To ascertain the spinal origins of the major descending noradrenergic inhibitory pathway we studied the effects of a selective alpha2-adrenoceptor antagonist, atipamezole, on neuronal activity in animals pre-treated with SP-SAP. Intrathecal application of atipamezole dose dependently facilitated the mechanically evoked neuronal responses of deep dorsal horn neurones to low intensity von Frey hairs (5-15 g) and noxious thermal (45-50 degrees C) evoked responses in SAP control animals indicating a physiological alpha2-adrenoceptor control. This facilitatory effect of atipamezole was lost in the SP-SAP treated group. These data suggest that activity within noradrenergic pathways have a dependence on dorsal horn NK(1)+ve cells. Further, noradrenergic descending inhibition may in part be driven by lamina I/III (NK(1)+ve) cells, and mediated via spinal alpha2-adrenoceptor activation. Since the same neuronal population drives descending facilitation and inhibition, the reduced excitability of lamina V/VI WDR neurones seen after loss of these NK(1)+ve neurones indicates a dominant role of descending facilitation.

  20. Selective increases in serotonin 5-HT1B/1D and 5-HT2A/2C binding sites in adult rat basal ganglia following lesions of serotonergic neurons.

    PubMed

    Compan, V; Segu, L; Buhot, M C; Daszuta, A

    1998-05-18

    Quantitative autoradiography was used to examine possible adaptive changes in serotonin 5-HT1B/1D and 5-HT2A/2C receptor binding sites in adult rat basal ganglia, after partial or severe lesions of serotonergic neurons produced by intraraphe injections of variable amounts of 5,7-dihydroxytryptamine. In controls, the 5-HT1B/1D sites labeled with S-CM-G[125I]TNH2 were evenly distributed in the core and the shell of the nucleus accumbens. The density of 5-HT1B/1D sites was higher in the ventral than dorsal part of the striatum and no regional differences were detected along the rostrocaudal axis of the structure. The 5-HT2A/2C sites labeled with [125I]DOI were preferentially distributed in the mediodorsal striatum and higher densities were detected in the shell than core of the nucleus accumbens. Following 5,7-dihydroxytryptamine injections, there were no changes in binding of either receptor subtype after partial lesions entailing 80-90% 5-HT depletions. After severe 5-HT depletions (over 95%), large increases in 5-HT1B/1D binding were observed in the substantia nigra (78%), but no changes took place in the globus pallidus. Increases in 5-HT1B/1D binding were also detected in the shell of the nucleus accumbens (27%). Similar sized increases in 5-HT2A/2C binding (22%) were restricted to the medial striatum. The present results suggest a preferential association between 5-HT1B/1D receptors and the striatonigral neurons containing substance P, as indicated by the striatal distribution of these receptors and their selective increases in the substantia nigra after severe 5-HT deprivation. We recently proposed a similar relationship between the 5-HT4 receptors and the striatopallidal neurons containing met-enkephalin. Moreover, the increases in 5-HT1B/1D binding in the substantia nigra and in the shell of the nucleus accumbens reinforce the view of an implication of this receptor subtype in motor functions. In contrast, the prominent increases in 5-HT2A/2C binding after

  1. Glutamatergic transmission in the nucleus of the solitary tract modulates memory through influences on amygdala noradrenergic systems.

    PubMed

    Miyashita, Teiko; Williams, Cedric L

    2002-02-01

    The authors examined whether glutamate release from the vagus nerve onto the nucleus of the solitary tract (NTS) is one mechanism by which the vagus influences memory and neural activity in limbic structures. Rats trained to drink from a spout were given a footshock (0.35 mA) on Day 5 after approaching the spout. Phosphate-buffered saline or 5.0, 50.0, or 100.0 nmol/0.5 microl glutamate was then infused into the NTS. Glutamate (5.0 or 50.0 nmol) significantly enhanced memory on the retention test. In Experiment 2, this effect was attenuated by blocking noradrenergic receptors in the amygdala with propranolol (0.3 microg/0.5 microl). Experiment 3 used in vivo microdialysis to determine whether footshock plus glutamate (50.0 nmol) alters noradrenergic output in the amygdala. These treatments caused a significant and long-lasting increase in amygdala noradrenergic concentrations. The results indicate that glutamate may be one transmitter that conveys the effects of vagal activation on brain systems that process memory.

  2. Enhanced noradrenergic activity in the amygdala contributes to hyperarousal in an animal model of PTSD.

    PubMed

    Ronzoni, Giacomo; Del Arco, Alberto; Mora, Francisco; Segovia, Gregorio

    2016-08-01

    Increased activity of the noradrenergic system in the amygdala has been suggested to contribute to the hyperarousal symptoms associated with post-traumatic stress disorder (PTSD). However, only two studies have examined the content of noradrenaline or its metabolites in the amygdala of rats previously exposed to traumatic stress showing inconsistent results. The aim of this study was to investigate the effects of an inescapable foot shock (IFS) procedure (1) on reactivity to novelty in an open-field (as an index of hyperarousal), and (2) on noradrenaline release in the amygdala during an acute stress. To test the role of noradrenaline in amygdala, we also investigated the effects of microinjections of propranolol, a β-adrenoreceptor antagonist, and clenbuterol, a β-adrenoreceptor agonist, into the amygdala of IFS and control animals. Finally, we evaluated the expression of mRNA levels of β-adrenoreceptors (β1 and β2) in the amygdala, the hippocampus and the prefrontal cortex. Male Wistar rats (3 months) were stereotaxically implanted with bilateral guide cannulae. After recovering from surgery, animals were exposed to IFS (10 shocks, 0.86mA, and 6s per shock) and seven days later either microdialysis or microinjections were performed in amygdala. Animals exposed to IFS showed a reduced locomotion compared to non-shocked animals during the first 5min in the open-field. In the amygdala, IFS animals showed an enhanced increase of noradrenaline induced by stress compared to control animals. Bilateral microinjections of propranolol (0.5μg) into the amygdala one hour before testing in the open-field normalized the decreased locomotion observed in IFS animals. On the other hand, bilateral microinjections of clenbuterol (30ng) into the amygdala of control animals did not change the exploratory activity induced by novelty in the open field. IFS modified the mRNA expression of β1 and β2 adrenoreceptors in the prefrontal cortex and the hippocampus. These results

  3. A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque

    PubMed Central

    Hassani, S. A.; Oemisch, M.; Balcarras, M.; Westendorff, S.; Ardid, S.; van der Meer, M. A.; Tiesinga, P.; Womelsdorf, T.

    2017-01-01

    Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves specific attention and learning mechanisms beyond working memory, and whether the drug effects can be formalized computationally to allow single subject predictions. We tested and confirmed these suggestions in a case study with a healthy nonhuman primate performing a feature-based reversal learning task evaluating performance using Bayesian and Reinforcement learning models. In an initial dose-testing phase we found a Guanfacine dose that increased performance accuracy, decreased distractibility and improved learning. In a second experimental phase using only that dose we examined the faster feature-based reversal learning with Guanfacine with single-subject computational modeling. Parameter estimation suggested that improved learning is not accounted for by varying a single reinforcement learning mechanism, but by changing the set of parameter values to higher learning rates and stronger suppression of non-chosen over chosen feature information. These findings provide an important starting point for developing nonhuman primate models to discern the synaptic mechanisms of attention and learning functions within the context of a computational neuropsychiatry framework. PMID:28091572

  4. 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

  5. Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities.

    PubMed

    Katayama, K; Yamada, K; Ornthanalai, V G; Inoue, T; Ota, M; Murphy, N P; Aruga, J

    2010-02-01

    Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1 encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the nervous system. However, the role of this protein is largely unknown, except that it can modulate neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol. Administration of clonidine, an alpha2-adrenergic agonist that is frequently used to treat patients with Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated plus-maze test. These results lead us to conclude that noradrenergic mechanisms are involved in the behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and trichotillomania.

  6. DIAZINON AND PARATHION DIVERGE IN THEIR EFFECTS ON DEVELOPMENT OF NORADRENERGIC SYSTEMS

    PubMed Central

    Slotkin, Theodore A.; Skavicus, Samantha; Seidler, Frederic J.

    2017-01-01

    Organophosphate pesticides elicit developmental neurotoxicity through mechanisms over and above their shared property as cholinesterase inhibitors. We compared the consequences of neonatal exposure (postnatal days PN1-4) to diazinon or parathion on development of norepinephrine systems in rat brain, using treatments designed to produce equivalent effects on cholinesterase, straddling the threshold for barely-detectable inhibition. Norepinephrine levels were measured throughout development from the immediate posttreatment period (PN5), to early adolescence (PN30), young adulthood (PN60) and full adulthood (PN100); we assessed multiple brain regions containing all the major noradrenergic synaptic projections. Diazinon elicited a significant overall deficit of norepinephrine, whereas parathion produced a net increase. The effects were not immediately apparent (PN5) but rather emerged over the course of development, indicating that the organophosphate effects represent alteration of the trajectory of development, not just continuance of an initial injury. There were no comparable effects on β-adrenergic receptors, indicating that the presynaptic changes were not an adaptation to an underlying, primary effect on postsynaptic receptor signaling. Because we used the cholinesterase inhibition benchmark, the absolute dose of diazinon was much higher than that of parathion, since the latter is a more potent cholinesterase inhibitor. Our results are consistent with the growing evidence that the various organophosphates can differ in their impact on brain development and that consequently, the cholinesterase benchmark is an inadequate predictor of adverse neurodevelopmental effects. PMID:28235599

  7. Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate

    PubMed Central

    Engert, Veronika; Pruessner, Jens C

    2008-01-01

    Attention Deficit Hyperactivity Disorder (ADHD) is a childhood psychiatric condition characterized by severe impulsiveness, inattention and overactivity. Methylphenidate (MPH), a psychostimulant affecting both the dopaminergic and the noradrenergic systems, is one of the most frequently prescribed treatments for ADHD. Despite the widespread use of MPH and its proven effectiveness, its precise neurochemical mechanisms of action are under debate. For the most part, MPH’s influence on subcortical dopamine neurotransmission is thought to play a crucial role in its behavioral and cognitive effects. In their hypothesis of biphasic MPH action, Seeman and Madras [42, 43] suggest that therapeutic doses of MPH elevate tonic dopamine while inhibiting phasic transmitter release in subcortical structures, leading to reduced postsynaptic receptor stimulation and psychomotor activation in response to salient stimuli. Volkow and colleagues [56] suggest that by amplifying a weak striatal dopamine signal, MPH increases the perception of a stimulus or task as salient. The enhanced interest for the task is thought to increase attention and improve performance. Recent animal studies have however shown that when administered at doses producing clinically relevant drug plasma levels and enhancing cognitive function, MPH preferentially activates dopamine and noradrenaline efflux within the prefrontal cortex relative to the subcortical structures [5]. Overall, we suggest that the delineated theories of MPH therapeutic action should not be discussed as exclusive. Studies are outlined that allow integrating the different findings and models. PMID:19587853

  8. Functional Neuroanatomy of the Noradrenergic Locus Coeruleus: Its Roles in the Regulation of Arousal and Autonomic Function Part II: Physiological and Pharmacological Manipulations and Pathological Alterations of Locus Coeruleus Activity in Humans

    PubMed Central

    Samuels, E. R; Szabadi, E

    2008-01-01

    The locus coeruleus (LC), the major noradrenergic nucleus of the brain, gives rise to fibres innervating most structures of the neuraxis. Recent advances in neuroscience have helped to unravel the neuronal circuitry controlling a number of physiological functions in which the LC plays a central role. Two such functions are the regulation of arousal and autonomic activity, which are inseparably linked largely via the involvement of the LC. Alterations in LC activity due to physiological or pharmacological manipulations or pathological processes can lead to distinct patterns of change in arousal and autonomic function. Physiological manipulations considered here include the presentation of noxious or anxiety-provoking stimuli and extremes in ambient temperature. The modification of LC-controlled functions by drug administration is discussed in detail, including drugs which directly modify the activity of LC neurones (e.g., via autoreceptors, storage, reuptake) or have an indirect effect through modulating excitatory or inhibitory inputs. The early vulnerability of the LC to the ageing process and to neurodegenerative disease (Parkinson’s and Alzheimer’s diseases) is of considerable clinical significance. In general, physiological manipulations and the administration of stimulant drugs, α2-adrenoceptor antagonists and noradrenaline uptake inhibitors increase LC activity and thus cause heightened arousal and activation of the sympathetic nervous system. In contrast, the administration of sedative drugs, including α2-adrenoceptor agonists, and pathological changes in LC function in neurodegenerative disorders and ageing reduce LC activity and result in sedation and activation of the parasympathetic nervous system. PMID:19506724

  9. A53T-α-synuclein overexpression in murine locus coeruleus induces Parkinson's disease-like pathology in neurons and glia.

    PubMed

    Henrich, Martin Timo; Geibl, Fanni Fruzsina; Lee, Bolam; Chiu, Wei-Hua; Koprich, James Benjamin; Brotchie, Jonathan Michael; Timmermann, Lars; Decher, Niels; Matschke, Lina Anita; Oertel, Wolfgang Hermann

    2018-05-10

    Degeneration of noradrenergic locus coeruleus neurons occurs during the prodromal phase of Parkinson's disease and contributes to a variety of non-motor symptoms, e.g. depression, anxiety and REM sleep behavior disorder. This study was designed to establish the first locus coeruleus α-synucleinopathy mouse model, which should provide sufficient information about the time-course of noradrenergic neurodegeneration, replicate cardinal histopathological features of the human Parkinson's disease neuropathology and finally lead to robust histological markers, which are sufficient to assess the pathological changes in a quantitative and qualitative way. We show that targeted viral vector-mediated overexpression of human mutant A53T-α-synuclein in vivo in locus coeruleus neurons of wild-type mice resulted in progressive noradrenergic neurodegeneration over a time frame of 9 weeks. Observed neuronal cell loss was accompanied by progressive α-synuclein phosphorylation, formation of proteinase K-resistant α-synuclein-aggregates, accumulation of Ubi-1- and p62-positive inclusions in microglia and induction of progressive micro- and astrogliosis. Apart from this local pathology, abundant α-synuclein-positive axons were found in locus coeruleus output regions, indicating rapid anterograde axonal transport of A53T-α-synuclein. Taken together, we present the first model of α-synucleinopathy in the murine locus coeruleus, replicating essential morphological features of human Parkinson's disease pathology. This new model may contribute to the research on prodromal Parkinson's disease, in respect to pathophysiology and the development of disease-modifying therapy.

  10. Damage to Arousal-Promoting Brainstem Neurons with Traumatic Brain Injury

    PubMed Central

    Valko, Philipp O.; Gavrilov, Yuri V.; Yamamoto, Mihoko; Noaín, Daniela; Reddy, Hasini; Haybaeck, Johannes; Weis, Serge; Baumann, Christian R.; Scammell, Thomas E.

    2016-01-01

    Study Objectives: Coma and chronic sleepiness are common after traumatic brain injury (TBI). Here, we explored whether injury to arousal-promoting brainstem neurons occurs in patients with fatal TBI. Methods: Postmortem examination of 8 TBI patients and 10 controls. Results: Compared to controls, TBI patients had 17% fewer serotonergic neurons in the dorsal raphe nucleus (effect size: 1.25), but the number of serotonergic neurons did not differ in the median raphe nucleus. TBI patients also had 29% fewer noradrenergic neurons in the locus coeruleus (effect size: 0.96). The number of cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) was similar in TBI patients and controls. Conclusions: TBI injures arousal-promoting neurons of the mesopontine tegmentum, but this injury is less severe than previously observed in hypothalamic arousal-promoting neurons. Most likely, posttraumatic arousal disturbances are not primarily caused by damage to these brainstem neurons, but arise from an aggregate of injuries, including damage to hypothalamic arousal nuclei and disruption of other arousal-related circuitries. Citation: Valko PO, Gavrilov YV, Yamamoto M, Noain D, Reddy H, Haybaeck J, Weis S, Baumann CR, Scammell TE. Damage to arousal-promoting brainstem neurons with traumatic brain injury. SLEEP 2016;39(6):1249–1252. PMID:27091531

  11. Acute and Chronic Noradrenergic Effects on Cortical Excitability in Healthy Humans

    PubMed Central

    Kuo, Hsiao-I; Paulus, Walter; Batsikadze, Giorgi; Jamil, Asif; Kuo, Min-Fang

    2017-01-01

    Abstract Background Noradrenaline is a major neuromodulator in the central nervous system, and it is involved in the pathophysiology of diverse neuropsychiatric diseases. Previous transcranial magnetic stimulation studies suggested that acute application of selective noradrenaline reuptake inhibitors enhances cortical excitability in the human brain. However, other, such like clinical effects, usually require prolonged noradrenaline reuptake inhibitor treatment, which might go along with different physiological effects. Methods The purpose of this study was to investigate the acute and chronic effects of the selective noradrenaline reuptake inhibitor reboxetine on cortical excitability in healthy humans in a double-blind, placebo-controlled, randomized crossover study. Sixteen subjects were assessed with different transcranial magnetic stimulation measurements: motor thresholds, input-output curve, short-latency intracortical inhibition and intracortical facilitation, I-wave facilitation, and short-interval afferent inhibition before and after placebo or reboxetine (8 mg) single-dose administration. Afterwards, the same subjects took reboxetine (8 mg/d) consecutively for 21 days. During this period (subjects underwent 2 experimental sessions with identical transcranial magnetic stimulation measures under placebo or reboxetine), transcranial magnetic stimulation measurements were assessed before and after drug intake. Results Both single-dose and chronic administration of reboxetine increased cortical excitability; increased the slope of the input-output curve, intracortical facilitation, and I-wave facilitation; but decreased short-latency intracortical inhibition and short-interval afferent inhibition. Moreover, chronic reboxetine showed a larger enhancement of intracortical facilitation and I-wave facilitation compared with single-dose application. Conclusions The results show physiological mechanisms of noradrenergic enhancement possibly underlying the

  12. 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

  13. 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

  14. Effects of lesions to the dorsal noradrenergic bundle on counterconditioning of punished barpressing.

    PubMed

    Tsaltas, E; Gray, J A; Preston, G C

    1987-01-01

    The possible contribution of the dorsal noradrenergic bundle (DB) to the development of a simple form of counterconditioning (an associative mechanism leading to behavioural tolerance for stress) was assessed by comparison of the performance of animals with 6-hydroxydopamine-induced lesions of the DB to that of sham-operated (SH) animals. Animals engaging in barpressing for food reward on a random-interval (RI) 64 sec schedule were presented with a stimulus signalling the concurrent operation of an RI-64 sec schedule of response-contingent shock. In the control condition (punishment), shock and reward never occurred as a result of the same barpress. In the experimental condition (counterconditioning), the frequency of shock and reward were the same as for the punishment condition but the two events always occurred in succession, with food following shock, as a consequence of the same barpress. DB lesions had no effect on the acquisition of rewarded barpressing or on the initial acquisition of the discrimination between the shock-free and shock-containing (signalled) components of the schedule. However, once performance on the discrimination had reached asymptote, DB animals in the punishment control group showed significantly less suppression to the signal than SH animals. The counterconditioning schedule used was effective, leading to significantly reduced response suppression in the SH animals in comparison to the SH group subjected to punishment. The pattern of findings in the DB groups was consistent with a blockade by the lesion of the development of counterconditioning. These results suggest, therefore, that the DB is involved in at least one associative mechanism leading to tolerance for stress.

  15. Genetic deletion of GPR52 enhances the locomotor-stimulating effect of an adenosine A2A receptor antagonist in mice: A potential role of GPR52 in the function of striatopallidal neurons.

    PubMed

    Nishiyama, Keiji; Suzuki, Hirobumi; Maruyama, Minoru; Yoshihara, Tomoki; Ohta, Hiroyuki

    2017-09-01

    G protein-coupled receptor 52 (GPR52) is largely co-expressed with dopamine D 2 receptor (DRD2) in the striatum and nucleus accumbens, and this expression pattern is similar to that of adenosine A 2A receptor (ADORA2A). GPR52 has been proposed as a therapeutic target for positive symptoms of schizophrenia, based on observations from pharmacological and transgenic mouse studies. However, the physiological role of GPR52 in dopaminergic functions in the basal ganglia remains unclear. Here, we used GPR52 knockout (KO) mice to examine the role of GPR52 in dopamine receptor-mediated and ADORA2A-mediated locomotor activity and dopamine receptor signaling. High expression of GPR52 protein in the striatum, nucleus accumbens, and lateral globus pallidus of wild type (WT) littermates was confirmed by immunohistochemical analysis. GPR52 KO and WT mice exhibited almost identical locomotor responses to the dopamine releaser methamphetamine and the N-methyl-d-aspartate antagonist MK-801. In contrast, the locomotor response to the ADORA2A antagonist istradefylline was significantly augmented in GPR52 KO mice compared to WT mice. Gene expression analysis revealed that striatal expression of DRD2, but not of dopamine D 1 receptor and ADORA2A, was significantly decreased in GPR52 KO mice. Moreover, a significant reduction in the mRNA expression of enkephalin, a marker of the activity of striatopallidal neurons, was observed in the striatum of GPR52 KO mice, suggesting that GPR52 deletion could enhance DRD2 signaling. Taken together, these results imply the physiological relevance of GPR52 in modulating the function of striatopallidal neurons, possibly by interaction of GPR52 with ADORA2A and DRD2. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Noradrenergic stimulation modulates activation of extinction-related brain regions and enhances contextual extinction learning without affecting renewal

    PubMed Central

    Lissek, Silke; Glaubitz, Benjamin; Güntürkün, Onur; Tegenthoff, Martin

    2015-01-01

    Renewal in extinction learning describes the recovery of an extinguished response if the extinction context differs from the context present during acquisition and recall. Attention may have a role in contextual modulation of behavior and contribute to the renewal effect, while noradrenaline (NA) is involved in attentional processing. In this functional magnetic resonance imaging (fMRI) study we investigated the role of the noradrenergic system for behavioral and brain activation correlates of contextual extinction and renewal, with a particular focus upon hippocampus and ventromedial prefrontal cortex (PFC), which have crucial roles in processing of renewal. Healthy human volunteers received a single dose of the NA reuptake inhibitor atomoxetine prior to extinction learning. During extinction of previously acquired cue-outcome associations, cues were presented in a novel context (ABA) or in the acquisition context (AAA). In recall, all cues were again presented in the acquisition context. Atomoxetine participants (ATO) showed significantly faster extinction compared to placebo (PLAC). However, atomoxetine did not affect renewal. Hippocampal activation was higher in ATO during extinction and recall, as was ventromedial PFC activation, except for ABA recall. Moreover, ATO showed stronger recruitment of insula, anterior cingulate, and dorsolateral/orbitofrontal PFC. Across groups, cingulate, hippocampus and vmPFC activity during ABA extinction correlated with recall performance, suggesting high relevance of these regions for processing the renewal effect. In summary, the noradrenergic system appears to be involved in the modification of established associations during extinction learning and thus has a role in behavioral flexibility. The assignment of an association to a context and the subsequent decision on an adequate response, however, presumably operate largely independently of noradrenergic mechanisms. PMID:25745389

  17. Noradrenergic α1 Receptor Antagonist Treatment Attenuates Positive Subjective Effects of Cocaine in Humans: A Randomized Trial

    PubMed Central

    Newton, Thomas F.; De La Garza, Richard; Brown, Gregory; Kosten, Thomas R.; Mahoney, James J.; Haile, Colin N.

    2012-01-01

    Background Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α1 receptor antagonist doxazosin on the positive subjective effects of cocaine. Methods Thirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind. Results Doxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of “high”, “stimulated”, “like cocaine”, “desire cocaine”, “any drug effect”, and “likely to use cocaine if had access” (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of “stimulated”, “like cocaine”, and “likely to use cocaine if had access” (p<.05). There were trends for doxazosin to reduce ratings of “stimulated”, “desire cocaine”, and “likely to use cocaine if had access” (p<.10). Conclusions Medications that block noradrenergic α1 receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further. Trial

  18. REM Sleep–like Atonia of Hypoglossal (XII) Motoneurons Is Caused by Loss of Noradrenergic and Serotonergic Inputs

    PubMed Central

    Fenik, Victor B.; Davies, Richard O.; Kubin, Leszek

    2017-01-01

    Rationale Studies of hypoglossal (XII) motoneurons that innervate the genioglossus muscle, an upper airway dilator, suggested that the suppression of upper airway motor tone during REM sleep is caused by withdrawal of excitation mediated by norepinephrine and serotonin. Objectives Our objectives were to determine whether antagonism of aminergic receptors located in the XII nucleus region can abolish the REM sleep–like atonia of XII motoneurons, and whether both serotonergic and noradrenergic antagonists are required to achieve this effect. Methods REM sleep–like episodes were elicited in anesthetized rats by pontine carbachol injections before and at various times after microinjection of prazosin and methysergide combined, or of only one of the drugs, into the XII nucleus. Measurements and Main Results Spontaneous XII nerve activity was significantly reduced, by 35 to 81%, by each antagonist alone and in combination, indicating that XII motoneurons were under both noradrenergic and serotonergic endogenous excitatory drives. During the 32 to 81 min after microinjections of both antagonists, pontine carbachol caused no depression of XII nerve activity, whereas other characteristic effects (activation of the hippocampal and cortical EEG, and slowing of the respiratory rate) remained intact. A partial recovery of the depressant effect of carbachol then occurred parallel to the recovery of spontaneous XII nerve activity from the depressant effect of the antagonists. Microinjections of either antagonist alone did not eliminate the depressant effect of carbachol. Conclusions The REM sleep–like depression of XII motoneuronal activity induced by pontine carbachol can be fully accounted for by the combined withdrawal of noradrenergic and serotonergic effects on XII motoneurons. PMID:16100007

  19. Monoamine neurons in the human brain stem: anatomy, magnetic resonance imaging findings, and clinical implications.

    PubMed

    Sasaki, Makoto; Shibata, Eri; Tohyama, Koujiro; Kudo, Kohsuke; Endoh, Jin; Otsuka, Kotaro; Sakai, Akio

    2008-11-19

    By using high-resolution, conventional, and neuromelanin-sensitive magnetic resonance imaging techniques, we reviewed the normal anatomy of the nuclei consisting of monoamine neurons such as dopaminergic, noradrenergic, and serotoninergic neurons and noted the changes in these nuclei that occur in some degenerative and psychiatric disorders. Multimodal MR images can directly or indirectly help in identifying the substantia nigra, locus ceruleus, and raphe nuclei that contain monoamine neurons. Neuromelanin-sensitive magnetic resonance imaging can detect signal alterations in the substantia nigra pars compacta and/or locus ceruleus that occur in Parkinson's disease and psychiatric disorders such as depression and schizophrenia. This technique seems to be promising for the noninvasive evaluation of the pathological or functional changes in the monoamine system that occur in degenerative and psychiatric disorders.

  20. Hindbrain lactate regulates preoptic gonadotropin-releasing hormone (GnRH) neuron GnRH-I protein but not AMPK responses to hypoglycemia in the steroid-primed ovariectomized female rat.

    PubMed

    Shrestha, P K; Briski, K P

    2015-07-09

    Steroid positive-feedback activation of the gonadotropin-releasing hormone (GnRH)-pituitary luteinizing hormone (LH) neuroendocrine axis propagates the pre ovulatory LH surge, a crucial component of female reproduction. Our work shows that this key event is restrained by inhibitory metabolic input from hindbrain A2 noradrenergic neurons. GnRH neurons express the ultra-sensitive energy sensor adenosine 5'-monophosphate-activated protein kinase (AMPK); here, we investigated the hypothesis that GnRH nerve cell AMPK and peptide neurotransmitter responses to insulin-induced hypoglycemia are controlled by hindbrain lack of the oxidizable glycolytic end-product L-lactate. Data show that hypoglycemic inhibition of LH release in steroid-primed ovariectomized female rats was reversed by coincident caudal hindbrain lactate infusion. Western blot analyses of laser-microdissected A2 neurons demonstrate hypoglycemic augmentation [Fos, estrogen receptor-beta (ER-β), phosphoAMPK (pAMPK)] and inhibition (dopamine-beta-hydroxylase, GLUT3, MCT2) of protein expression in these cells, responses that were normalized by insulin plus lactate treatment. Hypoglycemia diminished rostral preoptic GnRH nerve cell GnRH-I protein and pAMPK content; the former, but not the latter response was reversed by lactate. Results implicate caudal hindbrain lactoprivic signaling in hypoglycemia-induced suppression of the LH surge, demonstrating that lactate repletion of that site reverses decrements in A2 catecholamine biosynthetic enzyme and GnRH neuropeptide precursor protein expression. Lack of effect of lactate on hypoglycemic patterns of GnRH AMPK activity suggests that this sensor is uninvolved in metabolic-inhibition of positive-feedback-stimulated hypophysiotropic signaling to pituitary gonadotropes. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  1. Damage to Arousal-Promoting Brainstem Neurons with Traumatic Brain Injury.

    PubMed

    Valko, Philipp O; Gavrilov, Yuri V; Yamamoto, Mihoko; Noaín, Daniela; Reddy, Hasini; Haybaeck, Johannes; Weis, Serge; Baumann, Christian R; Scammell, Thomas E

    2016-06-01

    Coma and chronic sleepiness are common after traumatic brain injury (TBI). Here, we explored whether injury to arousal-promoting brainstem neurons occurs in patients with fatal TBI. Postmortem examination of 8 TBI patients and 10 controls. Compared to controls, TBI patients had 17% fewer serotonergic neurons in the dorsal raphe nucleus (effect size: 1.25), but the number of serotonergic neurons did not differ in the median raphe nucleus. TBI patients also had 29% fewer noradrenergic neurons in the locus coeruleus (effect size: 0.96). The number of cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) was similar in TBI patients and controls. TBI injures arousal-promoting neurons of the mesopontine tegmentum, but this injury is less severe than previously observed in hypothalamic arousal-promoting neurons. Most likely, posttraumatic arousal disturbances are not primarily caused by damage to these brainstem neurons, but arise from an aggregate of injuries, including damage to hypothalamic arousal nuclei and disruption of other arousal-related circuitries. © 2016 Associated Professional Sleep Societies, LLC.

  2. Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease.

    PubMed

    Farrand, Ariana Q; Helke, Kristi L; Gregory, Rebecca A; Gooz, Monika; Hinson, Vanessa K; Boger, Heather A

    Parkinson's disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. To assess therapeutic potential of VNS in a PD model. To mimic the progression of PD degeneration, rats received a systemic injection of noradrenergic neurotoxin DSP-4, followed one week later by bilateral intrastriatal injection of dopaminergic neurotoxin 6-hydroxydopamine. At this time, a subset of rats also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for ten days, and locomotion was measured during each afternoon session. Immediately following final stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), α-synuclein, astrocytes (GFAP) and microglia (Iba-1). VNS significantly increased locomotion of lesioned rats. VNS also resulted in increased expression of TH in striatum, SN, and LC; decreased SN α-synuclein expression; and decreased expression of glial markers in the SN and LC of lesioned rats. Additionally, saline-treated rats after VNS, had higher LC TH and lower SN Iba-1. Our findings of increased locomotion, beneficial effects on LC-NE and SN-DA neurons, decreased α-synuclein density in SN TH-positive neurons, and neuroinflammation suggest VNS has potential as a novel PD therapeutic. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Noradrenaline Triggers GABAA Inhibition of Bed Nucleus of the Stria Terminalis Neurons Projecting to the Ventral Tegmental Area

    PubMed Central

    Dumont, Éric C.; Williams, John T.

    2014-01-01

    The lateral part of the ventral bed nucleus of the stria terminalis (vlBNST) is a critical site for the antiaversive effects of noradrenergic drugs during opioid withdrawal. The objective of the present study is to identify the cellular action(s) of noradrenaline in the vlBNST after withdrawal from a 5 d treatment with morphine. The vlBNST is a heterogeneous cell group with multiple efferent projections. Therefore, neurons projecting to the midbrain were identified by retrograde transport of fluorescent microspheres injected in the ventral tegmental area (VTA). Whole-cell voltage clamp recordings of these neurons and of those sharing physiological properties were done in brain slices. Noradrenaline activated α1-adrenergic receptors to increase GABAA-IPSC frequency. Noradrenaline produced a similar increase in GABAA-IPSCs during acute opioid withdrawal, but this increase resulted from activation of β-adrenergic receptors, adenylyl cyclase, and protein kinase A, as well as α1-adrenergic receptors. Given that neurons in the vlBNST send an excitatory projection to the VTA, noradrenaline may reduce excitatory drive to mesolimbic dopamine cells. This mechanism might contribute to the withdrawal-induced inhibition of dopamine neurons and explain how noradrenergic drugs microinjected into the vlBNST reduce aversive aspects of opioid withdrawal. PMID:15385602

  4. Noradrenaline and dopamine neurons in the reward/effort trade-off: a direct electrophysiological comparison in behaving monkeys.

    PubMed

    Varazzani, Chiara; San-Galli, Aurore; Gilardeau, Sophie; Bouret, Sebastien

    2015-05-20

    Motivation determines multiple aspects of behavior, including action selection and energization of behavior. Several components of the underlying neural systems have been examined closely, but the specific role of the different neuromodulatory systems in motivation remains unclear. Here, we compare directly the activity of dopaminergic neurons from the substantia nigra pars compacta and noradrenergic neurons from the locus coeruleus in monkeys performing a task manipulating the reward/effort trade-off. Consistent with previous reports, dopaminergic neurons encoded the expected reward, but we found that they also anticipated the upcoming effort cost in connection with its negative influence on action selection. Conversely, the firing of noradrenergic neurons increased with both pupil dilation and effort production in relation to the energization of behavior. Therefore, this work underlines the contribution of dopamine to effort-based decision making and uncovers a specific role of noradrenaline in energizing behavior to face challenges. Copyright © 2015 the authors 0270-6474/15/357866-12$15.00/0.

  5. Alleviation of response suppression to conditioned aversive stimuli by lesions of the dorsal noradrenergic bundle.

    PubMed

    Tsaltas, E; Gray, J A; Fillenz, M

    1984-08-01

    Rats with neurotoxic lesions of the dorsal ascending noradrenergic bundle (DB) were compared with sham-operated (SH) controls on the acquisition, steady state and extinction of response suppression maintained by a classical (conditioned suppression) or an instrumental (discriminated punishment) contingency. DB lesions interfered neither with the acquisition of the reference response of sucrose-rewarded barpressing nor with unconditioned responding to the overhead flashing light subsequently used as a signal of shock. The acquisition of discriminated response suppression was also unaffected by the lesion under both types of contingency. However, once discriminated suppression had stabilized, both the conditioned and the discriminative stimulus used were significantly less effective in maintaining suppression in DB animals than in SH controls provided that low intensity footshock (0.2 mA) was used as the unconditioned stimulus (UCS). Upon increase of UCS intensity (to 0.5 mA) normal suppression was observed in the DB group under both contingencies. Extinction of the classical contingency reinstated the difference between DB and SH performance: DB lesion resulted in significantly faster extinction of fear. In contrast, extinction of the discriminated punishment contingency was unaffected by the lesion, although generalized response suppression dissipated faster in the DB than in the SH animals trained under this condition. Our results offer no support for the reinforcement hypothesis of DB function (normal acquisition of barpressing and of discriminated suppression of barpressing); mixed support (greater initial generalization of suppression in DB animals) and contradiction (more rapid extinction of conditioned suppression in DB animals) for the attentional hypothesis; and weak support (reduced suppression and more rapid extinction of suppression in DB animals, but only within limited experimental parameters) for the anxiety hypothesis of DB function. Hence none of

  6. Effect of Noradrenergic Neurotoxin DSP-4 and Maprotiline on Heart Rate Spectral Components in Stressed and Resting Rats.

    PubMed

    Kur'yanova, E V; Zhukova, Yu D; Teplyi, D L

    2017-07-01

    The effects of intraperitoneal DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a noradrenergic neurotoxin) and maprotiline (an inhibitor of norepinephrine reuptake in synapses) on spectral components of heart rhythm variability were examined in outbred male and female rats treated with these agents in daily doses of 10 mg/kg for 3 days. At rest, DSP-4 elevated LF and VLF spectral components in male and female rats. Maprotiline elevated LF and VLF components in males at rest, increased HR and reduced all spectral components in resting females. Stress against the background of DSP-4 treatment sharply increased heart rate and reduced the powers of all spectral components (especially LF and VLF components). In maprotiline-treated rats, stress increased the powers of LF and VLF components. Thus, the central noradrenergic system participates in the formation of LF and VLF spectral components of heart rate variability at rest and especially during stressful stimulation, which can determine the phasic character of changes in the heart rate variability observed in stressed organism.

  7. 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.

  8. Post-stress facilitation of serotonergic, but not noradrenergic, neurotransmission in the dorsal hippocampus prevents learned helplessness development in rats.

    PubMed

    Joca, Sâmia Regiane Lourenço; Zanelati, Tatiane; Guimarães, Francisco Silveira

    2006-05-04

    Recent pieces of evidence suggest that the dorsal hippocampus may mediate adaptation to severe and inescapable stress, possibly by the facilitation of serotonergic and/or noradrenergic neurotransmission. Chronic social stress and high corticosteroid levels would impair this coping mechanism, predisposing animals to learned helplessness. To test the hypothesis that increasing serotonin or noradrenaline levels in the dorsal hippocampus would attenuate the development of learned helplessness (LH), rats received inescapable foot shock (IS) and were tested in a shuttle box 24 h latter. Prestressed animals showed impairment of escape responses. This effect was prevented by bilateral intrahippocampal injections of zimelidine (100 nmol/0.5 microl), a serotonin reuptake blocker, immediately after IS. This effect was not observed when zimelidine was administered before or 2 h after IS. Bilateral intrahippocampal injections of desipramine (3 or 30 nmol/0.5 microl), a noradrenaline reuptake blocker, before IS or immediately after it did not prevent LH development. Desipramine (30 nmol) enhanced LH development when injected before IS. These data suggest that poststress facilitation of hippocampal serotonergic, but not noradrenergic, neurotransmission in the dorsal hippocampus facilitates adaptation to severe inescapable stress. Antidepressant effects of noradrenaline-selective drugs seem to depend on other structures than the dorsal hippocampus.

  9. Disinhibition by propranolol and chlordiazepoxide of nonrewarded lever-pressing in the rat is unaffected by dorsal noradrenergic bundle lesion.

    PubMed

    Salmon, P; Tsaltas, E; Gray, J A

    1989-03-01

    Ten male Sprague-Dawley rats received 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle and 10 others underwent control operations. The lesion depleted levels of noradrenaline in the hippocampus to 2% of those in the controls. All rats were then trained for 16 sessions to lever-press in a Skinner box on a variable interval 18 sec schedule of food-reinforcement, then for 42 days on a successive discrimination between periods of variable interval (VI 18 sec) food-reinforcement and periods of extinction. This report describes the effects of chlordiazepoxide (CDP; 5 mg/kg) and propranolol (5 and 10 mg/kg) injected intraperitoneally in both groups on modified ABBA designs after this training. Both drugs increased the response rates in extinction periods. The effect of propranolol was similar at each dose and smaller than that of CDP. Although CDP and propranolol (5 mg/kg) increased variable interval response rates also, this could not account for the effect on extinction response rates. Responding did not differ between the lesioned and control animals and the effects of drugs were similar in each group. It is unlikely that CDP or propranolol release nonrewarded responding by disrupting transmission in the dorsal noradrenergic bundle.

  10. 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.

  11. 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

  12. [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.

  13. 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...

  14. Lesion of the locus coeruleus aggravates dopaminergic neuron degeneration by modulating microglial function in mouse models of Parkinson׳s disease.

    PubMed

    Yao, Ning; Wu, Yanhong; Zhou, Yan; Ju, Lili; Liu, Yujun; Ju, Rongkai; Duan, Deyi; Xu, Qunyuan

    2015-11-02

    The degeneration of noradrenergic neurons in the locus coeruleus (LC) commonly occurs in patients with Parkinson's disease (PD), which is characterized by a selective injury of dopaminergic neurons in the substantia nigra (SN). The pathological impact of the LC on the SN in the disease is unknown. In the present study, we used a noradrenergic toxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), to deplete noradrenaline (NA) derived from the LC to explore its influence on degeneration or injury of dopaminergic neurons in the SN in mouse model produced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide (LPS). Our results demonstrated that lesion of the LC could change microglial function in the brain, which led to enhanced or prolonged expression of pro-inflammatory cytokines, diminished neurotrophic factors, and weakened ability of anti-oxidation in the SN. The in vitro experiments further confirmed that NA could reduce the inflammatory reaction of microglia. The selective injury of dopaminergic neurons by inflammation, however, was due to the inflammation in different brain regions rather than the depletion of NA. Our results indicate that the lesion in the LC is an important factor in promoting dopaminergic neuron degeneration by impacting the function of microglia in the midbrain. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation by chronic treatment with desipramine.

    PubMed

    Bondi, Corina O; Barrera, Gabriel; Lapiz, M Danet S; Bedard, Tania; Mahan, Amy; Morilak, David A

    2007-03-30

    We have previously shown that acute stress-induced release of norepinephrine (NE) facilitates anxiety-like behavioral responses to stress, such as reduction in open-arm exploration on the elevated-plus maze and in social behavior on the social interaction test. Since these responses represent inhibition of ongoing behavior, it is important to also address whether NE facilitates a response that represents an activation of behavior. Correspondingly, it is unknown how a chronic elevation in tonic steady-state noradrenergic (NA) neurotransmission induced by NE reuptake blockade might alter this acute modulatory function, a regulatory process that may be pertinent to the anxiolytic effects of NE reuptake blockers such as desipramine (DMI). Therefore, in this study, we investigated noradrenergic modulation of the shock-probe defensive burying response in the lateral septum (LS). In experiment 1, shock-probe exposure induced an acute 3-fold increase in NE levels measured in LS of male Sprague-Dawley rats by microdialysis. Shock-probe exposure also induced a modest rise in plasma ACTH, taken as an indicator of perceived stress, that returned to baseline more rapidly in rats that were allowed to bury the probe compared to rats prevented from burying by providing them with minimal bedding, indicating that the active defensive burying behavior is an effective coping strategy that reduces the impact of acute shock probe-induced stress. In experiment 2, blockade of either alpha(1)- or beta-adrenergic receptors in LS by local antagonist microinjection immediately before testing reduced defensive burying and increased immobility. In the next experiment, chronic DMI treatment increased basal extracellular NE levels in LS, and attenuated the acute shock probe-induced increase in NE release in LS relative to baseline. Chronic DMI treatment decreased shock-probe defensive burying behavior in a time-dependent manner, apparent only after 2 weeks or more of drug treatment. Moreover

  16. Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex.

    PubMed

    Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Frau, Roberto; Gessa, Gian L

    2015-10-01

    Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release. Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors. Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats. This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The

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

    PubMed

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

    2015-10-01

    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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. 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

  19. β-Adrenergic enhancement of neuronal excitability in the lateral amygdala is developmentally gated.

    PubMed

    Fink, Ann E; LeDoux, Joseph E

    2018-05-01

    Noradrenergic signaling in the amygdala is important for processing threats and other emotionally salient stimuli, and β-adrenergic receptor activation is known to enhance neuronal spiking in the lateral amygdala (LA) of juvenile animals. Nevertheless, intracellular recordings have not yet been conducted to determine the effect of β-adrenergic receptor activation on spike properties in the adult LA, despite the potential significance of developmental changes between adolescence and adulthood. Here we demonstrate that the β-adrenergic agonist isoproterenol (15 μM) enhances spike frequency in dorsal LA principal neurons of juvenile male C57BL/6 mice and fails to do so in strain- and sex-matched adults. Furthermore, we find that the age-dependent effect of isoproterenol on spike frequency is occluded by the GABA A receptor blocker picrotoxin (75 μM), suggesting that β-adrenergic receptors downregulate tonic inhibition specifically in juvenile animals. These findings indicate a significant shift during adolescence in the cellular mechanisms of β-adrenergic modulation in the amygdala. NEW & NOTEWORTHY β-Adrenergic receptors (β-ARs) in amygdala are important in processing emotionally salient stimuli. Most cellular recordings have examined juvenile animals, while behavioral data are often obtained from adults. We replicate findings showing that β-ARs enhance spiking of principal cells in the lateral amygdala of juveniles, but we fail to find this in adults. These findings have notable scientific and clinical implications regarding the noradrenergic modulation of threat processing, alterations of which underlie fear and anxiety disorders.

  20. 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

  1. Selective Serotonergic (SSRI) Versus Noradrenergic (SNRI) Reuptake Inhibitors with and without Acetylsalicylic Acid in Major Depressive Disorder.

    PubMed

    Zdanowicz, Nicolas; Reynaert, Christine; Jacques, Denis; Lepiece, Brice; Dubois, Thomas

    2017-09-01

    Antidepressant medication efficacy remains a major research challenge. Here, we explored four questions: whether noradrenergic antidepressants are more effective than serotonergic antidepressants; whether the addition of 100 mg acetylsalicylic acid (ASA) changes antidepressant efficacy; whether the long-term efficacy differs depending on the antidepressant and the addition of ASA; and whether serum levels of brain-derived neurotrophic factor (BDNF) are clinically informative. In a two-year study, forty people with major depressive disorder were randomly assigned to groups that received an SSRI (escitalopram) or an SNRI (duloxetine), each group received concomitant ASA (100 mg) or a placebo. Sociodemographic data were recorded and patients under went regular assessments with the Hamilton depression scale (HDS) and clinical global impression (CGI) scale. Serum levels of BDNF were measured four times per year. There was no significant difference in efficacy between the two antidepressants or between antidepressant treatment with and without ASA. However, subgroup comparisons revealed that the duloxetine + ASA (DASA) subgroup showed a more rapid improvement in HDS score as early as 2 months (t=-3.114, p=0.01), in CGI score at 5 months (t=-2.119, p=0.05), and a better remission rate (χ 2 =6.296, p 0.012) than the escitalopram + placebo (EP) subgroup. Serum BDNF before treatment was also higher in the DASA subgroup than in the EP subgroup (t=3.713; p=0.002). This suggest two hypotheses: either a noradrenergic agent combined with ASA is more effective in treating depression than a serotonergic agent alone, or the level of serum BDNF before treatment is a precursor marker of the response to antidepressants. Further research is needed to test these hypotheses.

  2. Local and Global Resting State Activity in the Noradrenergic and Dopaminergic Pathway Modulated by Reboxetine and Amisulpride in Healthy Subjects

    PubMed Central

    Wiegers, Maike; Walter, Martin; Abler, Birgit; Graf, Heiko

    2016-01-01

    Background: Various psychiatric populations are currently investigated with resting state fMRI, with the aim of individualizing diagnostics and treatment options and improving treatment outcomes. Many of these studies are conducted in large naturalistic samples, providing rich insights regarding disease-related neural alterations, but with the common psychopharmacological medication limiting interpretations of the results. We therefore investigated the effects of common noradrenergic and anti-dopaminergic medications on local and global resting state activity (rs-activity) in healthy volunteers to further the understanding of the respective effects independent from disease-related alterations. Methods: Within a randomized, double-blind, placebo-controlled crossover design, we investigated 19 healthy male subjects by resting state fMRI after the intake of reboxetine (4mg/d), amisulpride (200mg/d), and placebo for 7 days each. Treatment-related differences in local and global rs-activity were measured by the fractional amplitude of low frequency fluctuations (fALFF) and resting state functional connectivity (rs-FC). Results: fALFF revealed alterations of local rs-activity within regions of the core noradrenergic pathway, including the locus coeruleus under reboxetine, correlated with its plasma levels. Moreover, reboxetine led to increased rs-FC between regions within this pathway, i.e. the locus coeruleus, tectum, thalamus, and amygdala. Amisulpride modulated local rs-activity of regions within the dopaminergic pathway, with the altered signal in the putamen correlating with amisulpride plasma levels. Correspondingly, amisulpride increased rs-FC between regions of the dopaminergic pathway comprising the substantia nigra and putamen. Conclusion: Our data provide evidence of how psychopharmacological agents alter local and global rs-activity within the respective neuroanatomical pathways in healthy subjects, which may help with interpreting data in psychiatric

  3. Enhancement of extinction memory consolidation: the role of the noradrenergic and GABAergic systems within the basolateral amygdala.

    PubMed

    Berlau, Daniel J; McGaugh, James L

    2006-09-01

    Evidence from previous studies indicates that the noradrenergic and GABAergic influences within the basolateral amygdala (BLA) modulate the consolidation of memory for fear conditioning. The present experiments investigated whether the same modulatory influences are involved in regulating the extinction of fear-based learning. To investigate this issue, male Sprague Dawley rats implanted with unilateral or bilateral cannula aimed at the BLA were trained on a contextual fear conditioning (CFC) task and 24 and 48 h later were given extinction training. Immediately following each extinction session they received intra-BLA infusions of the GABAergic antagonist bicuculline (50 ng), the beta-adrenocepter antagonist propranolol (500 ng), bicuculline with propranolol, norepinephrine (NE) (0.3, 1.0, and 3.0 microg), the GABAergic agonist muscimol (125 ng), NE with muscimol or a control solution. To investigate the involvement of the dorsal hippocampus (DH) as a possible target of BLA activation during extinction, other animals were given infusions of muscimol (500 ng) via an ipsilateral cannula implanted in the DH. Bilateral BLA infusions of bicuculline significantly enhanced extinction, as did infusions into the right, but not left BLA. Propranolol infused into the right BLA together with bicuculline blocked the bicuculline-induced memory enhancement. Norepinephrine infused into the right BLA also enhanced extinction, and this effect was not blocked by co-infusions of muscimol. Additionally, muscimol infused into the DH did not attenuate the memory enhancing effects of norepinephrine infused into the BLA. These findings provide evidence that, as with original CFC learning, noradrenergic activation within the BLA modulates the consolidation of CFC extinction. The findings also suggest that the BLA influence on extinction is not mediated by an interaction with the dorsal hippocampus.

  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 Central

    Ebitz, R. Becket; Platt, Michael L.

    2014-01-01

    Summary 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 for the first time 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. PMID:25654259

  6. Arousal amplifies biased competition between high and low priority memories more in women than in men: the role of elevated noradrenergic activity

    PubMed Central

    Clewett, David; Sakaki, Michiko; Huang, Ringo; Nielsen, Shawn E.; Mather, Mara

    2017-01-01

    Recent findings indicate that emotional arousal can enhance memory consolidation of goal-relevant stimuli while impairing it for irrelevant stimuli. According to one recent model, these goal-dependent memory tradeoffs are driven by arousal-induced release of norepinephrine (NE), which amplifies neural gain in target sensory and memory processing brain regions. Past work also shows that ovarian hormones modulate activity in the same regions thought to support NE’s effects on memory, such as the amygdala, suggesting that men and women may be differentially susceptible to arousal’s dual effects on episodic memory. Here, we aimed to determine the neurohormonal mechanisms that mediate arousal-biased competition processes in memory. In a competitive visuo-attention task, participants viewed images of a transparent object overlaid on a background scene and explicitly memorized one of these stimuli while ignoring the other. Participants then heard emotional or neutral audio-clips and provided a subjective arousal rating. Hierarchical generalized linear modeling (HGLM) analyses revealed that greater pre-to-post task increases in salivary alpha-amylase (sAA), a biomarker of noradrenergic activity, was associated with significantly greater arousal-enhanced memory tradeoffs in women than in men. These sex-dependent effects appeared to result from phasic and background noradrenergic activity interacting to suppress task-irrelevant representations in women but enhancing them in men. Additionally, in naturally cycling women, low ovarian hormone levels interacted with increased noradrenergic activity to amplify memory selectivity independently of emotion-induced arousal. Together these findings suggest that increased noradrenergic transmission enhances preferential consolidation of goal-relevant memory traces according to phasic arousal and ovarian hormone levels in women. PMID:28324703

  7. Arousal amplifies biased competition between high and low priority memories more in women than in men: The role of elevated noradrenergic activity.

    PubMed

    Clewett, David; Sakaki, Michiko; Huang, Ringo; Nielsen, Shawn E; Mather, Mara

    2017-06-01

    Recent findings indicate that emotional arousal can enhance memory consolidation of goal-relevant stimuli while impairing it for irrelevant stimuli. According to one recent model, these goal-dependent memory tradeoffs are driven by arousal-induced release of norepinephrine (NE), which amplifies neural gain in target sensory and memory processing brain regions. Past work also shows that ovarian hormones modulate activity in the same regions thought to support NE's effects on memory, such as the amygdala, suggesting that men and women may be differentially susceptible to arousal's dual effects on episodic memory. Here, we aimed to determine the neurohormonal mechanisms that mediate arousal-biased competition processes in memory. In a competitive visuo-attention task, participants viewed images of a transparent object overlaid on a background scene and explicitly memorized one of these stimuli while ignoring the other. Participants then heard emotional or neutral audio-clips and provided a subjective arousal rating. Hierarchical generalized linear modeling (HGLM) analyses revealed that greater pre-to-post task increases in salivary alpha-amylase (sAA), a biomarker of noradrenergic activity, was associated with significantly greater arousal-enhanced memory tradeoffs in women than in men. These sex-dependent effects appeared to result from phasic and background noradrenergic activity interacting to suppress task-irrelevant representations in women but enhancing them in men. Additionally, in naturally cycling women, low ovarian hormone levels interacted with increased noradrenergic activity to amplify memory selectivity independently of emotion-induced arousal. Together these findings suggest that increased noradrenergic transmission enhances preferential consolidation of goal-relevant memory traces according to phasic arousal and ovarian hormone levels in women. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. 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

  9. Acute and chronic effects of noradrenergic enhancement on transcranial direct current stimulation-induced neuroplasticity in humans.

    PubMed

    Kuo, Hsiao-I; Paulus, Walter; Batsikadze, Giorgi; Jamil, Asif; Kuo, Min-Fang; Nitsche, Michael A

    2017-02-15

    Chronic administration of the selective noradrenaline reuptake inhibitor (NRI) reboxetine (RBX) increased and prolonged the long-term potentiation-like plasticity induced by anodal transcranial direct current stimulation (tDCS) for over 24 h. Chronic administration of RBX converted cathodal tDCS-induced long-term depression-like plasticity into facilitation for 120 min. Chronic noradrenergic activity enhancement on plasticity of the human brain might partially explain the delayed therapeutic impact of selective NRIs in depression and other neuropsychiatric diseases. Noradrenaline affects cognition and motor learning processes via its impact on long-term potentiation (LTP) and depression (LTD). We aimed to explore the impact of single dose and chronic administration of the selective noradrenaline reuptake inhibitor (NRI) reboxetine (RBX) on plasticity induced by transcranial direct current stimulation (tDCS) in healthy humans via a double-blinded, placebo-controlled, randomized crossover study. Sixteen healthy volunteers received placebo or single dose RBX (8 mg) before anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took RBX (8 mg day -1 ) consecutively for 21 days. During this period, two additional interventions were performed (RBX with anodal or cathodal tDCS), to explore the impact of chronic RBX treatment on plasticity. Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic administration of RBX increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h. Chronic RBX significantly converted cathodal tDCS-induced LTD-like plasticity into facilitation, as compared to the single dose condition, for 120 min after stimulation. The results show a prominent impact of chronic noradrenergic enhancement on plasticity of the human brain that might partially explain the delayed therapeutic impact of selective NRIs in depression and other

  10. The PDAPP mouse model of Alzheimer's disease: locus coeruleus neuronal shrinkage.

    PubMed

    German, Dwight C; Nelson, Omar; Liang, Fen; Liang, Chang-Lin; Games, Dora

    2005-11-28

    Alzheimer's disease is characterized by neuronal degeneration in the cerebral cortex and hippocampus and subcortical neuronal degeneration in such nuclei as the locus coeruleus (LC). Transgenic mice overexpressing mutant human amyloid precursor protein V717F, PDAPP mice, develop several Alzheimer's disease-like lesions. The present study sought to determine whether there is also loss of LC noradrenergic neurons or evidence of degenerative changes in these animals. PDAPP hemizygous and wild-type littermate control mice were examined at 23 months of age, at a time when there are numerous amyloid-beta (Abeta) plaques in the neocortex and hippocampus. Tissue sections were stained immunohistochemically with an antibody against tyrosine hydroxylase (TH) to identify LC neurons. Computer imaging procedures were used to count the TH-immunoreactive somata in sections through the rostral-caudal extent of the nucleus. There was no loss of LC neurons in the hemizygous mice. In a second experiment, homozygous PDAPP and wild-type mice were examined, at 2 months and 24 months of age. Again there was no age-related loss of neurons in the homozygous animals. In the portion of the LC where neurons reside that project to the cortex and hippocampus, however, the neurons were decreased in size selectively in the 24-month-old transgenic animals. These data indicate that overt LC cell loss does not occur following abundant overexpression of Abeta peptide. However, the selective size reduction of the LC neuronal population projecting to cortical and hippocampal regions containing Abeta-related neuropathology implies that these cells may be subjected to a retrograde-mediated stress. Copyright 2005 Wiley-Liss, Inc.

  11. 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.

  12. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development.

    PubMed

    Ignatius, Myron S; Unal Eroglu, Arife; Malireddy, Smitha; Gallagher, Glen; Nambiar, Roopa M; Henion, Paul D

    2013-01-01

    The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382) mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382) mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382) mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382) defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

  13. The antinociceptive effect of intravenous imipramine in colorectal distension-induced visceral pain in rats: the role of serotonergic and noradrenergic receptors.

    PubMed

    İlkaya, Fatih; Bilge, S Sırrı; Bozkurt, Ayhan; Baş, Duygu B; Erdal, Arzu; Çiftçioğlu, Engin; Kesim, Yüksel

    2014-07-01

    It has been shown that imipramine, a tricyclic antidepressant (TCA), is a potent analgesic agent. However, the effect of imipramine on visceral pain has not been extensively investigated. In the current study, our aim was to characterise the putative analgesic effect of intravenous imipramine on visceral pain in rats. Our second aim was to assess the involvement of serotonergic (5-HT₂,₃,₄) and noradrenergic (α(2A, 2B, 2C)) receptor subtypes in this putative antinociceptive effect of imipramine. Male Sprague Dawley rats (250-300 g) were implanted with venous catheters for drug administration and implanted with enamelled nichrome electrodes for electromyography of the external oblique muscles. Noxious visceral stimulation was applied via by colorectal distension (CRD). The visceromotor responses (VMRs) to CRD were quantified electromyographically before and after imipramine administration at 5, 15, 30, 60, 90 and 120 min. In the antagonist groups, the agents were administered 10 min before imipramine. The administration of imipramine (5-40 mg/kg) produced a dose-dependent reduction in VMR. The administration of yohimbine (a nonselective α₂-adrenoceptor antagonist, 1 mg/kg), BRL-44408 (an α(2A)-adrenoceptor antagonist, 1 mg/kg) or MK-912 (an α2C-adrenoceptor antagonist, 300 μg/kg) but not imiloxan (an α(2B)-adrenoceptor antagonist, 1 mg/kg) inhibited the antinociceptive effect of imipramine (20 mg/kg). Additionally, ketanserin (a 5-HT₂ receptor antagonist, 0.5, 1, and 2 mg/kg) and GR113808 (a 5-HT₄ receptor antagonist, 1 mg/kg) enhanced, and ondansetron (a 5-HT₃ receptor antagonist, 0.5, 1, and 2 mg/kg) failed to alter the imipramine-induced antinociceptive effect. Our data demonstrated that, in the CDR-induced rat visceral pain model, intravenous imipramine appeared to have antinociceptive potential and that α(2A)-/α(2C)-adrenoceptors and 5-HT₂/5-HT₄ receptors may be responsible for the antinociceptive effect of imipramine on visceral pain

  14. Sensitivity of Locus Ceruleus Neurons to Reward Value for Goal-Directed Actions

    PubMed Central

    Richmond, Barry J.

    2015-01-01

    The noradrenergic nucleus locus ceruleus (LC) is associated classically with arousal and attention. Recent data suggest that it might also play a role in motivation. To study how LC neuronal responses are related to motivational intensity, we recorded 121 single neurons from two monkeys while reward size (one, two, or four drops) and the manner of obtaining reward (passive vs active) were both manipulated. The monkeys received reward under three conditions: (1) releasing a bar when a visual target changed color; (2) passively holding a bar; or (3) touching and releasing a bar. In the first two conditions, a visual cue indicated the size of the upcoming reward, and, in the third, the reward was constant through each block of 25 trials. Performance levels and lipping intensity (an appetitive behavior) both showed that the monkeys' motivation in the task was related to the predicted reward size. In conditions 1 and 2, LC neurons were activated phasically in relation to cue onset, and this activation strengthened with increasing expected reward size. In conditions 1 and 3, LC neurons were activated before the bar-release action, and the activation weakened with increasing expected reward size but only in task 1. These effects evolved as monkeys progressed through behavioral sessions, because increasing fatigue and satiety presumably progressively decreased the value of the upcoming reward. These data indicate that LC neurons integrate motivationally relevant information: both external cues and internal drives. The LC might provide the impetus to act when the predicted outcome value is low. PMID:25740528

  15. NORADRENERGIC CONTROL OF CORTICO-STRIATO-THALAMIC AND MESOLIMBIC CROSS-STRUCTURAL SYNCHRONY

    PubMed Central

    Dzirasa, Kafui; Phillips, H. Westley; Sotnikova, Tatyana D.; Salahpour, Ali; Kumar, Sunil; Gainetdinov, Raul R.; Caron, Marc G.; Nicolelis, Miguel A. L.

    2010-01-01

    While normal dopaminergic tone has been shown to be essential for the induction of cortico-striatal and mesolimbic theta oscillatory activity, the influence of norepinephrine on these brain networks remains relatively unknown. To address this question, we simultaneously recorded local field potentials (LFPs) and single neuron activity across ten interconnected brain areas (ventral striatum, frontal association cortex hippocampus, primary motor cortex, orbital frontal cortex, prelimbic cortex, dorsal lateral striatum, medial dorsal nucleus of thalamus, substantia nigra pars reticularis, and ventral tegmental area) in a combined genetically and pharmacologically induced mouse model of hyponoradrenergia. Our results show that norepinephrine (NE) depletion induces a novel state in male mice characterized by a profound disruption of coherence across multiple cortico-striatal circuits, and an increase in mesolimbic cross-structural coherence. Moreover, this brain state is accompanied by a complex behavioral phenotype consisting of transient hyperactivity, stereotypic behaviors, and an acute twelve-fold increase in grooming. Notably, treatment with a norepinephrine precursors (L-DOPA 100mg/kg or L-DOPS 5mg/kg), or a selective serotonin reuptake inhibitor (fluoxetine 20mg/kg) attenuates the abnormal behaviors and selectively reverses the circuit changes observed in NE depleted mice. Together, our results demonstrate that norepinephrine modulates the dynamic tuning of coherence across cortico-striatal-thalamic circuits, and they suggest that changes in coherence across these circuits mediate the abnormal generation of hyperactivity and repetitive behaviors. PMID:20445065

  16. Noradrenergic control of cortico-striato-thalamic and mesolimbic cross-structural synchrony.

    PubMed

    Dzirasa, Kafui; Phillips, H Westley; Sotnikova, Tatyana D; Salahpour, Ali; Kumar, Sunil; Gainetdinov, Raul R; Caron, Marc G; Nicolelis, Miguel A L

    2010-05-05

    Although normal dopaminergic tone has been shown to be essential for the induction of cortico-striatal and mesolimbic theta oscillatory activity, the influence of norepinephrine on these brain networks remains relatively unknown. To address this question, we simultaneously recorded local field potentials and single-neuron activity across 10 interconnected brain areas (ventral striatum, frontal association cortex, hippocampus, primary motor cortex, orbital frontal cortex, prelimbic cortex, dorsal lateral striatum, medial dorsal nucleus of thalamus, substantia nigra pars reticularis, and ventral tegmental area) in a combined genetically and pharmacologically induced mouse model of hyponoradrenergia. Our results show that norepinephrine (NE) depletion induces a novel state in male mice characterized by a profound disruption of coherence across multiple cortico-striatal circuits and an increase in mesolimbic cross-structural coherence. Moreover, this brain state is accompanied by a complex behavioral phenotype consisting of transient hyperactivity, stereotypic behaviors, and an acute 12-fold increase in grooming. Notably, treatment with a norepinephrine precursors (l-3,4-dihydroxyphenylalanine at 100 mg/kg or l-threo-dihydroxyphenylserine at 5 mg/kg) or a selective serotonin reuptake inhibitor (fluoxetine at 20 mg/kg) attenuates the abnormal behaviors and selectively reverses the circuit changes observed in NE-depleted mice. Together, our results demonstrate that norepinephrine modulates the dynamic tuning of coherence across cortico-striato-thalamic circuits, and they suggest that changes in coherence across these circuits mediate the abnormal generation of hyperactivity and repetitive behaviors.

  17. 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

  18. Short-term serotonergic but not noradrenergic antidepressant administration reduces attentional vigilance to threat in healthy volunteers.

    PubMed

    Murphy, Susannah E; Yiend, Jenny; Lester, Kathryn J; Cowen, Philip J; Harmer, Catherine J

    2009-03-01

    Anxiety is associated with threat-related biases in information processing such as heightened attentional vigilance to potential threat. Such biases are an important focus of psychological treatments for anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of a range of anxiety disorders. The aim of this study was to assess the effect of an SSRI on the processing of threat in healthy volunteers. A selective noradrenergic reuptake inhibitor (SNRI), which is not generally used in the treatment of anxiety, was used as a contrast to assess the specificity of SSRI effects on threat processing. Forty-two healthy volunteers were randomly assigned to 7 d double-blind intervention with the SSRI citalopram (20 mg/d), the SNRI reboxetine (8 mg/d), or placebo. On the final day, attentional and interpretative bias to threat was assessed using the attentional probe and the homograph primed lexical decision tasks. Citalopram reduced attentional vigilance towards fearful faces but did not affect the interpretation of ambiguous homographs as threatening. Reboxetine had no significant effect on either of these measures. Citalopram reduces attentional orienting to threatening stimuli, which is potentially relevant to its clinical use in the treatment of anxiety disorders. This finding supports a growing literature suggesting that an important mechanism through which pharmacological agents may exert their effects on mood is by reversing the cognitive biases that characterize the disorders that they treat. Future studies are needed to clarify the neural mechanisms through which these effects on threat processing are mediated.

  19. Noradrenergic synaptic function in the bed nucleus of the stria terminalis varies in animal models of anxiety and addiction.

    PubMed

    McElligott, Zoé A; Fox, Megan E; Walsh, Paul L; Urban, Daniel J; Ferrel, Martilias S; Roth, Bryan L; Wightman, R Mark

    2013-08-01

    Lewis rats show increased anxiety-like behaviors and drug consumption compared with Sprague-Dawley rats. Prior work suggests norepinephrine (NE) signaling in the bed nucleus of the stria terminalis (BNST) could have a role in mediating these phenotypes. Here, we investigated NE content and dynamics in the ventral BNST (vBNST) using fast-scan cyclic voltammetry in these two rat strains. We found that NE release evoked by electrical stimulus and its subsequent uptake was dysregulated in the more anxious Lewis rats. Because addiction is a multifaceted disease influenced by both genetic and environmental factors, we hypothesized NE dynamics would vary in these strains after the induction of a physical dependence on morphine. Following naloxone-precipitated morphine withdrawal, NE release and uptake dynamics were not changed in Lewis rats but were significantly altered in Sprague-Dawley rats. The alterations in Sprague-Dawley rats were accompanied by an increase in anxiety-like behavior in those animals as measured with the elevated plus maze. These studies suggest novel mechanisms involved in the development of affective disorders, and highlight the noradrenergic system in the vBNST as a common substrate for the manifestation of pathological anxiety and addiction.

  20. Corticosteroid involvement in the changes in noradrenergic responsiveness of tissues from rats made hypertensive by short-term isolation

    PubMed Central

    Bennett, T.; Gardiner, Sheila M.

    1978-01-01

    1 The responses to noradrenaline and to noradrenergic nerve stimulation of spontaneously beating right atria, electrically driven left atria and vasa deferentia taken from rats made hypertensive by short-term isolation have been compared with the responses of tissues from normotensive, group-housed animals. 2 Adrenocortical activity of isolated animals was assessed by plasma corticosterone determinations and measurement of adrenal weights. 3 The hearts of the isolated animals were weighed and the myocardial contents of water, sodium, potassium and calcium were measured. 4 Spontaneously beating right atria from isolated animals showed a lower resting rate, no difference in the response to nerve stimulation but a greater sensitivity to noradrenaline compared to atria from group-housed animals. 5 Vasa deferentia from isolated animals showed a decreased maximal response to noradrenaline, but no change in noradrenaline sensitivity or in the response to transmural stimulation. 6 There were indications of hyperactivity of the adrenals throughout a 5 week period of isolation, manifest as elevated plasma corticosteroid levels and increased adrenal weights. 7 Myocardial levels of sodium and calcium were elevated at the same time as the tissue level of potassium was reduced, but heart weights did not significantly change. 8 It is possible that adrenal steroid action caused the changes in tissue ionic balance. These ionic disturbances may have been responsible for some of the changes in tissue sensitivity found in the isolated hypertensive animals. PMID:698476

  1. 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.

  2. Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states.

    PubMed

    Lecrux, C; Hamel, E

    2016-10-05

    Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as 'neurovascular coupling (NVC)'. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. © 2016 The Author(s).

  3. Frontotemporal dementia: evidence for impairment of ascending serotoninergic but not noradrenergic innervation. Immunocytochemical and quantitative study using a graph method.

    PubMed

    Yang, Y; Schmitt, H P

    2001-03-01

    A graph method was employed to analyze the spatial neuronal patterns of nuclear grays of the pontine tegmentum with ascending aminergic projections to the forebrain in 12 cases of frontotemporal dementia (FTD). The nuclear grays examined were the nucleus centralis superior (NCS), a part of the nucleus raphae dorsalis (NRD), and the locus coeruleus (LC). The results were compared with 30 cases of Alzheimer's disease (AD) and 35 non-demented controls. In addition to the graph evaluations, neuronal cytoplasmic inclusion bodies were stained by silver impregnation and ubiquitin (Ub) and tau immunohistochemistry. The FTD cases showed a significant, 40%, decline in number of neurons in the NCS and NRD, while the LC was spared. The magnitude of neuronal loss matched that of AD where, by contrast, the LC was also severely changed. Amyloid deposition and Alzheimer neurofibrillary tangles occurred in the aminergic nuclei almost exclusively in AD and, to a minor extent, in some aged controls. No cytoplasmic inclusion bodies were found in the aminergic nuclei of the FTD cases. However, 6 cases had Ub-positive but tau-negative neuronal inclusions in the hippocampal dentate fascia and in layer 2 of the prefrontal isocortex, and 3 showed clinical and histological signs of motor neuron disease. Our results suggest that the serotoninergic raphe nuclei with ascending projections to the forebrain, but not the LC, become directly or indirectly involved in frontotemporal dementia both with and without motor neuron disease.

  4. Neuronize: a tool for building realistic neuronal cell morphologies

    PubMed Central

    Brito, Juan P.; Mata, Susana; Bayona, Sofia; Pastor, Luis; DeFelipe, Javier; Benavides-Piccione, Ruth

    2013-01-01

    This study presents a tool, Neuronize, for building realistic three-dimensional models of neuronal cells from the morphological information extracted through computer-aided tracing applications. Neuronize consists of a set of methods designed to build 3D neural meshes that approximate the cell membrane at different resolution levels, allowing a balance to be reached between the complexity and the quality of the final model. The main contribution of the present study is the proposal of a novel approach to build a realistic and accurate 3D shape of the soma from the incomplete information stored in the digitally traced neuron, which usually consists of a 2D cell body contour. This technique is based on the deformation of an initial shape driven by the position and thickness of the first order dendrites. The addition of a set of spines along the dendrites completes the model, building a final 3D neuronal cell suitable for its visualization in a wide range of 3D environments. PMID:23761740

  5. Neuronize: a tool for building realistic neuronal cell morphologies.

    PubMed

    Brito, Juan P; Mata, Susana; Bayona, Sofia; Pastor, Luis; Defelipe, Javier; Benavides-Piccione, Ruth

    2013-01-01

    This study presents a tool, Neuronize, for building realistic three-dimensional models of neuronal cells from the morphological information extracted through computer-aided tracing applications. Neuronize consists of a set of methods designed to build 3D neural meshes that approximate the cell membrane at different resolution levels, allowing a balance to be reached between the complexity and the quality of the final model. The main contribution of the present study is the proposal of a novel approach to build a realistic and accurate 3D shape of the soma from the incomplete information stored in the digitally traced neuron, which usually consists of a 2D cell body contour. This technique is based on the deformation of an initial shape driven by the position and thickness of the first order dendrites. The addition of a set of spines along the dendrites completes the model, building a final 3D neuronal cell suitable for its visualization in a wide range of 3D environments.

  6. Noradrenaline and acetylcholine responsiveness of glucose-monitoring and glucose-insensitive neurons in the mediodorsal prefrontal cortex.

    PubMed

    Nagy, Bernadett; Szabó, István; Csetényi, Bettina; Hormay, Edina; Papp, Szilárd; Keresztes, Dóra; Karádi, Zoltán

    2014-01-16

    The mediodorsal prefrontal cortex (mdPFC), as part of the forebrain glucose-monitoring (GM) system, plays important role in several regulatory processes to control the internal state of the organism and to initiate behavioral outputs accordingly. Little is known, however, about the neurochemical sensitivity of neurons located in this area. Substantial evidence indicates that the locus ceruleus - noradrenaline (NA) projection system and the nucleus basalis magnocellularis - cholinergic projection system regulate behavioral state and state dependent processing of sensory information, various cognitive functions already associated with the mdPFC. The main goal of the present study was to examine noradrenergic and cholinergic responsiveness of glucose-monitoring and glucose-insensitive (GIS) neurons in the mediodorsal prefrontal cortex. One fifth of the neurons tested changed in firing rate to microelectrophoretically applied NA. Responsiveness of the GM cells to this catecholamine proved to be significantly higher than that of the GIS units. Microiontophoretic application of acetylcholine (Ach) resulted in activity changes (predominantly facilitation) of more than 40% of the mdPFC neurons. Proportion of Ach sensitive units among the GM and the GIS neurons was found to be similar. The glucose-monitoring neurons of the mdPFC and their distinct NA and remarkable Ach sensitivity are suggested to be of particular significance in prefrontal control of adaptive behaviors. © 2013 Published by Elsevier B.V.

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

    PubMed

    Wieczorek, Marek; Dunn, Adrian J

    2006-09-01

    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-1beta (1 microg 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-1beta injections resulted in prolonged elevations of microdialysate NE, as well as plasma ACTH and corticosterone, and body temperature. IL-1beta also induced shivering and a prolonged depression of locomotor activity. Pretreatment with indomethacin (10 mg/kg sc) prevented the IL-1beta-induced increases in body temperature and the apparent increase in hypothalamic NE release, but only attenuated the IL-1beta-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

  8. Dibutyryl cyclic AMP induces differentiation of human neuroblastoma SH-SY5Y cells into a noradrenergic phenotype.

    PubMed

    Kume, Toshiaki; Kawato, Yuka; Osakada, Fumitaka; Izumi, Yasuhiko; Katsuki, Hiroshi; Nakagawa, Takayuki; Kaneko, Shuji; Niidome, Tetsuhiro; Takada-Takatori, Yuki; Akaike, Akinori

    2008-10-10

    Dibutyryl cyclic AMP (dbcAMP) and retinoic acid (RA) have been demonstrated to be the inducers of morphological differentiation in SH-SY5Y cells, a human catecholaminergic neuroblastoma cell line. However, it remains unclear whether morphologically differentiated SH-SY5Y cells by these compounds acquire catecholaminergic properties. We focused on the alteration of tyrosine hydroxylase (TH) expression and intracellular content of noradrenaline (NA) as the indicators of functional differentiation. Three days treatment with dbcAMP (1mM) and RA (10microM) induced morphological changes and an increase of TH-positive cells using immunocytochemical analysis in SH-SY5Y cells. The percentage of TH-expressing cells in dbcAMP (1mM) treatment was larger than that in RA (10microM) treatment. In addition, dbcAMP increased intracellular NA content, whereas RA did not. The dbcAMP-induced increase in TH-expressing cells is partially inhibited by KT5720, a protein kinase A (PKA) inhibitor. We also investigated the effect of butyrate on SH-SY5Y cells, because dbcAMP is enzymatically degraded by intracellular esterase, thereby resulting in the formation of butyrate. Butyrate induced the increase of NA content at lower concentrations than dbcAMP, although the increase in TH-expressing cells by butyrate was smaller than that by dbcAMP. The dbcAMP (1mM)- and butyrate (0.3mM)-induced increase in NA content was completely suppressed by alpha-methyl-p-tyrosine (1mM), an inhibitor of TH. These results suggest that dbcAMP induces differentiation into the noradrenergic phenotype through both PKA activation and butyrate.

  9. The involvement of cholinergic and noradrenergic systems in behavioral recovery following oxotremorine treatment to chronically stressed rats.

    PubMed

    Srikumar, B N; Raju, T R; Shankaranarayana Rao, B S

    2006-12-01

    Chronic stress in rats has been shown to impair learning and memory, and precipitate several affective disorders like depression and anxiety. The mechanisms involved in these stress-induced disorders and the possible reversal are poorly understood, thus limiting the number of drugs available for their treatment. Our earlier studies suggest cholinergic dysfunction as the underlying cause in the behavioral deficits following stress. Muscarinic cholinergic agonist, oxotremorine is demonstrated to have a beneficial effect in reversing brain injury-induced behavioral dysfunction. In this study, we have evaluated the effect of oxotremorine treatment on chronic restraint stress-induced cognitive deficits. Rats were subjected to restraint stress (6 h/day) for 21 days followed by oxotremorine treatment for 10 days. Spatial learning and memory was assessed in a partially baited eight-arm radial maze task. Stressed rats exhibited impairment in performance, with decreased percentage of correct choices and an increase in the number of reference memory errors (RMEs). Oxotremorine treatment (0.1 or 0.2 mg/kg, i.p.) to stressed rats resulted in a significant increase in the percent correct choices and a decrease in the number of RMEs compared with stress as well as the stress+vehicle-treated groups. In the retention test, oxotremorine treated rats committed less RMEs compared with the stress group. Chronic restraint stress decreased acetylcholinesterase (AChE) activity in the hippocampus, frontal cortex and septum, which was reversed by both the doses of oxotremorine. Further, oxotremorine treatment also restored the norepinephrine levels in the hippocampus and frontal cortex. Thus, this study demonstrates the potential of cholinergic muscarinic agonists and the involvement of both cholinergic and noradrenergic systems in the reversal of stress-induced learning and memory deficits.

  10. 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

  11. Effects of lesions of the dorsal noradrenergic bundle on conditioned suppression to a CS and to a contextual background stimulus.

    PubMed

    Tsaltas, E; Schugens, M M; Gray, J A

    1989-01-01

    The aim of the experiment was to determine whether the dorsal noradrenergic bundle (DB) plays a role in conditioning to context. Rats received either bilateral lesions of the DB by local injection of 6-hydroxydopamine, vehicle injections only, or sham operations. All animals were then trained to barpress for food on a variable interval (VI) schedule. Two 5-min intrusion periods were superimposed on the VI baseline during each session. An 'envelope' stimulus (flashing light) was on throughout each intrusion period. In addition, embedded in the two intrusion periods of each session, there occurred 8 presentations of a 'punctate' conditioned stimulus (CS) (a 15-s clicker), and 8 presentations of a 0.5-s footshock. Within each surgical condition rats were randomly allocated to one of three conditioning groups, receiving 100%, 50% or 0% temporal association between CS and shock. Conditioning to the punctate CS and to the context provided by the envelope stimulus was assessed by the degree of suppression of the barpress response relative to the VI baseline. Responding was most suppressed in the punctate CS in the 100 and 50% conditions, and most suppressed in the envelope stimulus in the 0% condition. DB lesions released response suppression to the punctate CS, had no effect on suppression to the envelope stimulus, and reduced sensitivity to CS-shock probability as measured by response suppression during the punctate CS. These results confirm previous reports that DB lesions alleviate response suppression to shock-associated cues, identify some of the parameters that affect this phenomenon, but fail to support a role for the DB in contextual conditioning.

  12. 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

  13. 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.

  14. Too much of a good thing: blocking noradrenergic facilitation in medial prefrontal cortex prevents the detrimental effects of chronic stress on cognition.

    PubMed

    Jett, Julianne D; Morilak, David A

    2013-03-01

    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 α(1)-, β(1)-, and β(2)-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.

  15. The antidepressant-like effect of ethynyl estradiol is mediated by both serotonergic and noradrenergic systems in the forced swimming test.

    PubMed

    Vega-Rivera, N M; López-Rubalcava, C; Estrada-Camarena, E

    2013-10-10

    17α-Ethynyl-estradiol (EE2, a synthetic steroidal estrogen) induces antidepressant-like effects in the forced swimming test (FST) similar to those induced by 5-HT and noradrenaline reuptake inhibitors (dual antidepressants). However, the precise mechanism of action of EE2 has not been studied. In the present study, the participation of estrogen receptors (ERs) and the serotonergic and the noradrenergic presynaptic sites in the antidepressant-like action of EE2 was evaluated in the FST. The effects of the ER antagonist ICI 182,780 (10 μg/rat; i.c.v.), the serotonergic and noradrenergic terminal destruction with 5,7-dihydroxytryptamine (5,7-DHT; 200 μg/rat, i.c.v.), and N-(2-chloro-ethyl)-N-ethyl-2-bromobenzylamine (DSP4; 10mg/kg, i.p.) were studied in ovariectomized rats treated with EE2 and subjected to the FST. In addition, the participation of α2-adrenergic receptors in the antidepressant-like action of EE2 was explored using the selective α2-receptor antagonist idazoxan (0.25, 0.5 and 1.0mg/kg, i.p.). EE2 induced an antidepressant-like action characterized by a decrease in immobility behavior with a concomitant increase in swimming and climbing behaviors. The ER antagonist, 5,7-DHT, DSP4, and idazoxan blocked the effects of EE2 on the immobility behavior, whereas ICI 182,780 and 5,7-DHT affected swimming behavior. The noradrenergic compound DSP4 altered climbing behavior, while Idazoxan inhibited the increase of swimming and climbing behaviors induced by EE2. Our results suggest that the antidepressant-like action of EE2 implies a complex mechanism of action on monoaminergic systems and estrogen receptors. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. Independent inputs by VGLUT2- and VGLUT3-positive glutamatergic terminals onto rat sympathetic preganglionic neurons.

    PubMed

    Nakamura, Kazuhiro; Wu, Sheng-Xi; Fujiyama, Fumino; Okamoto, Keiko; Hioki, Hiroyuki; Kaneko, Takeshi

    2004-03-01

    To characterize glutamatergic axon terminals onto sympathetic preganglionic neurons (SPNs), we visualized immunohistochemically three vesicular glutamate transporters (VGLUTs) in the intermediolateral cell column (IML) of rat thoracic spinal cord. VGLUT2 and VGLUT3 immunoreactivities but not VGLUT1 immunoreactivity were distributed in the IML and found in terminals making asymmetric synapses and apposed to dendrites immunopositive for choline acetyltransferase, an SPN marker. VGLUT2 and VGLUT3 immunoreactivities were not co-localized with each other. A population of VGLUT2-immunoreactive but not VGLUT3-immunoreactive terminals were adrenergic or noradrenergic. Some of VGLUT3-immunoreactive but not VGLUT2-immunoreactive terminals contained serotonin. These results indicate at least two independent glutamatergic terminal populations, which include a distinct monoaminergic subpopulation, making excitatory inputs onto SPNs. Copyright 2004 Lippincott Williams & Wilkins

  17. Motor Neuron Diseases

    MedlinePlus

    ... length SMN protein, which is critical for the maintenance of motor neurons. Physical and speech therapy, occupational ... length SMN protein, which is critical for the maintenance of motor neurons. Physical and speech therapy, occupational ...

  18. 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.

  19. Some lumbar sympathetic neurons develop a glutamatergic phenotype after peripheral axotomy with a note on VGLUT2-positive perineuronal baskets

    PubMed Central

    Brumovsky, Pablo R.; Seroogy, Kim B.; Lundgren, Kerstin H.; Watanabe, Masahiko; Hökfelt, Tomas; Gebhart, G. F.

    2011-01-01

    Glutamate is the main excitatory neurotransmitter in the nervous system, including in primary afferent neurons. However, to date a glutamatergic phenotype of autonomic neurons has not been described. Therefore, we explored the expression of vesicular glutamate transporters (VGLUTs) type 1, 2 and 3 in lumbar sympathetic chain (LSC) and major pelvic ganglion (MPG) of naïve BALB/C mice, as well as after pelvic nerve axotomy (PNA), using immunohistochemistry and in situ hybridization. Colocalization with activating transcription factor-3 (ATF-3), tyrosine hydroxylase (TH), vesicular acetylcholine transporter (VAChT) and calcitonin generelated peptide was also examined. Sham-PNA, sciatic nerve axotomy (SNA) or naïve mice were included. In naïve mice, VGLUT2-like immunoreactivity (LI) was only detected in fibers and varicosities in LSC and MPG; no ATF-3-immunoreactive (IR) neurons were visible. In contrast, PNA induced upregulation of VGLUT2 protein and transcript, as well as of ATF-3-LI in subpopulations of LSC neurons. Interestingly, VGLUT2-IR LSC neurons coexpressed ATF-3, and often lacked the noradrenergic marker TH. SNA only increased VGLUT2 protein and transcript in scattered LSC neurons. Neither PNA nor SNA upregulated VGLUT2 in MPG neurons. We also found perineuronal baskets immunoreactive either for VGLUT2 or the acetylcholinergic marker VAChT in non-PNA MPGs, usually around TH-IR neurons. VGLUT1-LI was restricted to some varicosities in MPGs, was absent in LSCs, and remained largely unaffected by PNA or SNA. This was confirmed by the lack of expression of VGLUT1 or VGLUT3 mRNAs in LSCs, even after PNA or SNA. Taken together, axotomy of visceral and non-visceral nerves results in a glutamatergic phenotype of some LSC neurons. In addition, we show previously non-described MPG perineuronal glutamatergic baskets. PMID:21596036

  20. Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress.

    PubMed

    Adamec, R; Muir, C; Grimes, M; Pearcey, K

    2007-05-16

    The roles of beta-NER (beta-noradrenergic receptor), GR (glucocorticoid) and mineral corticoid receptors (MR) in the consolidation of anxiogenic effects of predator stress were studied. One minute after predator stress, different groups of rats were injected (ip) with vehicle, propranolol (beta-NER blocker, 5 and 10 mg/kg), mifepristone (RU486, GR blocker, 20 mg/kg), spironolactone (MR blocker, 50 mg/kg), propranolol (5 mg/kg) plus RU486 (20 mg/kg) or the anxiolytic, chloradiazepoxide (CPZ, 10 mg/kg). One week later, rodent anxiety was assessed in elevated plus maze, hole board, light/dark box, social interaction and acoustic startle. Considering all tests except startle, propranolol dose dependently blocked consolidation of lasting anxiogenic effects of predator stress in all tests. GR receptor block alone was ineffective. However, GR block in combination with an ineffective dose of propranolol did blocked consolidation of predator stress effects in all tests, suggesting a synergism between beta-NER and GR. Surprisingly, MR block prevented consolidation of anxiogenic effects in all tests except the light/dark box. CPZ post stress was ineffective against the anxiogenic impact of predator stress. Study of startle was complicated by the fact that anxiogenic effects of stress on startle amplitude manifested as both an increase and a decrease in startle amplitude. Suppression of startle occurred in stressed plus vehicle injected groups handled three times prior to predator stress. In contrast, stressed plus vehicle rats handled five times prior to predator stress showed increases in startle, as did all predator stressed only groups. Mechanisms of consolidation of the different startle responses appear to differ. CPZ post stress blocked startle suppression but not enhancement of startle. Propranolol post stress had no effect on either suppression or enhancement of startle. GR block alone post stress prevented suppression of startle, but not enhancement. In contrast

  1. Adrenergic receptors inhibit TRPV1 activity in the dorsal root ganglion neurons of rats.

    PubMed

    Matsushita, Yumi; Manabe, Miki; Kitamura, Naoki; Shibuya, Izumi

    2018-01-01

    Transient receptor potential vanilloid type 1 (TRPV1) is a polymodal receptor channel that responds to multiple types of stimuli, such as heat, acid, mechanical pressure and some vanilloids. Capsaicin is the most commonly used vanilloid to stimulate TRPV1. TRPV1 channels are expressed in dorsal root ganglion neurons that extend to Aδ- and C-fibers and have a role in the transduction of noxious inputs to the skin into the electrical signals of the sensory nerve. Although noradrenergic nervous systems, including the descending antinociceptive system and the sympathetic nervous system, are known to modulate pain sensation, the functional association between TRPV1 and noradrenaline in primary sensory neurons has rarely been examined. In the present study, we examined the effects of noradrenaline on capsaicin-evoked currents in cultured dorsal root ganglion neurons of the rat by the whole-cell voltage clamp method. Noradrenaline at concentrations higher than 0.1 pM significantly reduced the amplitudes of the inward capsaicin currents recorded at -60 mV holding potential. This inhibitory action was reversed by either yohimbine (an α2 antagonist, 10 nM) or propranolol (a β antagonist, 10 nM). The α2 agonists, clonidine (1 pM) and dexmedetomidine (1 pM) inhibited capsaicin currents, and yohimbine (1 nM) reversed the effects of clonidine. The inhibitory action of noradrenaline was not seen in the neurons pretreated with pertussis toxin (100 μg/ml for 24 h) and the neurons dialyzed intracellularly with guanosine 5'- [β-thio] diphosphate (GDPβS, 200 μM), the catalytic subunit of protein kinase A (250 U/ml) or okadaic acid (1 μM). These results suggest that noradrenaline directly acts on dorsal root ganglion neurons to inhibit the activity of TRPV1 depending on the activation of α2-adrenoceptors followed by the inhibition of the adenylate cyclase/cAMP/protein kinase A pathway.

  2. The Medial Paralemniscal Nucleus and Its Afferent Neuronal Connections in Rat

    PubMed Central

    VARGA, TAMÁS; PALKOVITS, MIKLÓS; USDIN, TED BJÖRN; DOBOLYI, ARPÁD

    2009-01-01

    Previously, we described a cell group expressing tuberoinfundibular peptide of 39 residues (TIP39) in the lateral pontomesencephalic tegmentum, and referred to it as the medial paralemniscal nucleus (MPL). To identify this nucleus further in rat, we have now characterized the MPL cytoarchitectonically on coronal, sagittal, and horizontal serial sections. Neurons in the MPL have a columnar arrangement distinct from adjacent areas. The MPL is bordered by the intermediate nucleus of the lateral lemniscus nucleus laterally, the oral pontine reticular formation medially, and the rubrospinal tract ventrally, whereas the A7 noradrenergic cell group is located immediately mediocaudal to the MPL. TIP39-immunoreactive neurons are distributed throughout the cytoarchitectonically defined MPL and constitute 75% of its neurons as assessed by double labeling of TIP39 with a fluorescent Nissl dye or NeuN. Furthermore, we investigated the neuronal inputs to the MPL by using the retrograde tracer cholera toxin B subunit. The MPL has afferent neuronal connections distinct from adjacent brain regions including major inputs from the auditory cortex, medial part of the medial geniculate body, superior colliculus, external and dorsal cortices of the inferior colliculus, periolivary area, lateral preoptic area, hypothalamic ventromedial nucleus, lateral and dorsal hypothalamic areas, subparafascicular and posterior intralaminar thalamic nuclei, periaqueductal gray, and cuneiform nucleus. In addition, injection of the anterograde tracer biotinylated dextran amine into the auditory cortex and the hypothalamic ventromedial nucleus confirmed projections from these areas to the distinct MPL. The afferent neuronal connections of the MPL suggest its involvement in auditory and reproductive functions. PMID:18770870

  3. The medial paralemniscal nucleus and its afferent neuronal connections in rat.

    PubMed

    Varga, Tamás; Palkovits, Miklós; Usdin, Ted Björn; Dobolyi, Arpád

    2008-11-10

    Previously, we described a cell group expressing tuberoinfundibular peptide of 39 residues (TIP39) in the lateral pontomesencephalic tegmentum, and referred to it as the medial paralemniscal nucleus (MPL). To identify this nucleus further in rat, we have now characterized the MPL cytoarchitectonically on coronal, sagittal, and horizontal serial sections. Neurons in the MPL have a columnar arrangement distinct from adjacent areas. The MPL is bordered by the intermediate nucleus of the lateral lemniscus nucleus laterally, the oral pontine reticular formation medially, and the rubrospinal tract ventrally, whereas the A7 noradrenergic cell group is located immediately mediocaudal to the MPL. TIP39-immunoreactive neurons are distributed throughout the cytoarchitectonically defined MPL and constitute 75% of its neurons as assessed by double labeling of TIP39 with a fluorescent Nissl dye or NeuN. Furthermore, we investigated the neuronal inputs to the MPL by using the retrograde tracer cholera toxin B subunit. The MPL has afferent neuronal connections distinct from adjacent brain regions including major inputs from the auditory cortex, medial part of the medial geniculate body, superior colliculus, external and dorsal cortices of the inferior colliculus, periolivary area, lateral preoptic area, hypothalamic ventromedial nucleus, lateral and dorsal hypothalamic areas, subparafascicular and posterior intralaminar thalamic nuclei, periaqueductal gray, and cuneiform nucleus. In addition, injection of the anterograde tracer biotinylated dextran amine into the auditory cortex and the hypothalamic ventromedial nucleus confirmed projections from these areas to the distinct MPL. The afferent neuronal connections of the MPL suggest its involvement in auditory and reproductive functions. (c) 2008 Wiley-Liss, Inc.

  4. Neuronal Activation in the Central Nervous System of Rats in the Initial Stage of Chronic Kidney Disease-Modulatory Effects of Losartan and Moxonidine

    PubMed Central

    Palkovits, Miklós; Šebeková, Katarína; Klenovics, Kristina Simon; Kebis, Anton; Fazeli, Gholamreza; Bahner, Udo; Heidland, August

    2013-01-01

    The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances. PMID:23818940

  5. Neuronal Mechanisms of Intelligence.

    DTIC Science & Technology

    1984-11-01

    integrated activity of neuronal ircuits, that is -~ directly modified by reinforcing signals. -S. a -4 ’ p ...kinds of consequences and a supply of behavior ... which has little or no relation to (eliciting or releasing) stimuli." ( p . 501). As a consequence, the...fraction of these synapses is active" ( p . 5). Klopf’s heterostat is diagrammed as a 3-neuron assembly in Fig. 1, which shows a "reinforced" neuron and its

  6. Neurofibromin and Neuronal Apoptosis

    DTIC Science & Technology

    2006-07-01

    role of familial pheochromocytoma genes, including succinate dehydrogenase (SDH) and Nf1, in modulating neuronal apoptosis following neurotrophin...gene products, in Nf1-/- sensory and sympathetic neurons; this work will also have relevance to the biology of familial pheochromocytoma . "So what...Schlisio, S. (2005). Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer. Cancer

  7. GABAergic ventrolateral pre-optic nucleus neurons are involved in the mediation of the anesthetic hypnosis induced by propofol

    PubMed Central

    Yuan, Jie; Luo, Zhuxin; Zhang, Yu; Zhang, Yi; Wang, Yuan; Cao, Song; Fu, Bao; Yang, Hao; Zhang, Lin; Zhou, Wenjing; Yu, Tian

    2017-01-01

    Intravenous anesthetics have been used clinically to induce unconsciousness for seventeen decades, however the mechanism of anesthetic-induced unconsciousness remains to be fully elucidated. It has previously been demonstrated that anesthetics exert sedative effects by acting on endogenous sleep-arousal circuits. However, few studies focus on the ventrolateral pre-optic (VLPO) to locus coeruleus (LC) sleep-arousal pathway. The present study aimed to investigate if VLPO is involved in unconsciousness induced by propofol. The present study additionally investigated if the inhibitory effect of propofol on LC neurons was mediated by activating VLPO neurons. Microinjection, target lesion and extracellular single-unit recordings were used to study the role of the VLPO-LC pathway in propofol anesthesia. The results demonstrated that GABAA agonist (THIP) or GABAA antagonist (gabazine) microinjections into VLPO altered the time of loss of righting reflex and the time of recovery of righting reflex. Furthermore, propofol suppressed the spontaneous firing activity of LC noradrenergic neurons. There was no significant difference observed in firing activity between VLPO sham lesion and VLPO lesion rats. The findings indicate that VLPO neurons are important in propofol-induced unconsciousness, however are unlikely to contribute to the inhibitory effect of propofol on LC spontaneous firing activity. PMID:28765955

  8. Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the subcellular distribution of corticotropin releasing factor receptors.

    PubMed

    Retson, T A; Reyes, B A; Van Bockstaele, E J

    2015-01-02

    Understanding the neurobiological bases for sex differences in alcohol dependence is needed to help guide the development of individualized therapies for alcohol abuse disorders. In the present study, alcohol-induced adaptations in (1) anxiety-like behavior, (2) patterns of c-Fos activation and (3) subcellular distribution of corticotropin releasing factor receptor in locus coeruleus (LC) neurons was investigated in male and female Sprague-Dawley rats that were chronically exposed to ethanol using a liquid diet. Results confirm and extend reports by others showing that chronic ethanol exposure produces an anxiogenic-like response in both male and female subjects. Ethanol-induced sex differences were observed with increased c-Fos expression in LC neurons of female ethanol-treated subjects compared to controls or male subjects. Results also reveal sex differences in the subcellular distribution of the CRFr in LC-noradrenergic neurons with female subjects exposed to ethanol exhibiting a higher frequency of plasmalemmal CRFrs. These adaptations have implications for LC neuronal activity and its neural targets across the sexes. Considering the important role of the LC in ethanol-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis, the present results indicate important sex differences in feed-forward regulation of the HPA axis that may render alcohol dependent females more vulnerable to subsequent stress exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use

    PubMed Central

    Skelly, Mary J; Weiner, Jeff L

    2014-01-01

    Background Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Methods Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period. Results Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05). Conclusions These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a

  10. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use.

    PubMed

    Skelly, Mary J; Weiner, Jeff L

    2014-07-01

    Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period. Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05). These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.

  11. Glucocorticoid receptors participate in the opiate withdrawal-induced stimulation of rats NTS noradrenergic activity and in the somatic signs of morphine withdrawal.

    PubMed

    Navarro-Zaragoza, Javier; Hidalgo, Juana M; Laorden, M Luisa; Milanés, M Victoria

    2012-08-01

    Recent evidence suggests that glucocorticoid receptor (GR) is a major molecular substrate of addictive properties of drugs of abuse. Hence, we performed a series of experiments to further characterize the role of GR signalling in opiate withdrawal-induced physical signs of dependence, enhanced noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) phosphorylation (activation) as well as GR expression in the nucleus of the solitary tract noradrenergic cell group (NTS-A₂). The role of GR signalling was assessed by i.p. pretreatment of the selective GR antagonist, mifepristone. Rats were implanted with two morphine (or placebo) pellets. Six days later, rats were pretreated with mifepristone or vehicle 30 min before naloxone and physical signs of abstinence, NA turnover, TH activation, GR expression and the hypothalamus-pituitary-adrenocortical axis activity were measured using HPLC, immunoblotting and RIA. Mifepristone alleviated the somatic signs of naloxone-induced opiate withdrawal. Mifepristone attenuated the increase in the NA metabolite, 3-methoxy-4-hydroxyphenylethylen glycol (MHPG), in the PVN, and the enhanced NA turnover observed in morphine-withdrawn rats. Mifepristone antagonized the TH phosphorylation at Ser³¹ and the expression of c-Fos expression induced by morphine withdrawal. Finally, naloxone-precipitated morphine withdrawal induced up-regulation of GR in the NTS. These results suggest that the physical signs of opiate withdrawal, TH activation and stimulation of noradrenergic pathways innervating the PVN are modulated by GR signalling. Overall, the present data suggest that drugs targeting the GR may ameliorate stress and aversive effects associated with opiate withdrawal. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  12. 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.

  13. 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

  14. How microglia kill neurons.

    PubMed

    Brown, Guy C; Vilalta, Anna

    2015-12-02

    Microglia are resident brain macrophages that become inflammatory activated in most brain pathologies. Microglia normally protect neurons, but may accidentally kill neurons when attempting to limit infections or damage, and this may be more common with degenerative disease as there was no significant selection pressure on the aged brain in the past. A number of mechanisms by which activated microglia kill neurons have been identified, including: (i) stimulation of the phagocyte NADPH oxidase (PHOX) to produce superoxide and derivative oxidants, (ii) expression of inducible nitric oxide synthase (iNOS) producing NO and derivative oxidants, (iii) release of glutamate and glutaminase, (iv) release of TNFα, (v) release of cathepsin B, (vi) phagocytosis of stressed neurons, and (vii) decreased release of nutritive BDNF and IGF-1. PHOX stimulation contributes to microglial activation, but is not directly neurotoxic unless NO is present. NO is normally neuroprotective, but can react with superoxide to produce neurotoxic peroxynitrite, or in the presence of hypoxia inhibit mitochondrial respiration. Glutamate can be released by glia or neurons, but is neurotoxic only if the neurons are depolarised, for example as a result of mitochondrial inhibition. TNFα is normally neuroprotective, but can become toxic if caspase-8 or NF-κB activation are inhibited. If the above mechanisms do not kill neurons, they may still stress the neurons sufficiently to make them susceptible to phagocytosis by activated microglia. We review here whether microglial killing of neurons is an artefact, makes evolutionary sense or contributes in common neuropathologies and by what mechanisms. This article is part of a Special Issue entitled SI: Neuroprotection. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. The mirror neuron system.

    PubMed

    Cattaneo, Luigi; Rizzolatti, Giacomo

    2009-05-01

    Mirror neurons are a class of neurons, originally discovered in the premotor cortex of monkeys, that discharge both when individuals perform a given motor act and when they observe others perform that same motor act. Ample evidence demonstrates the existence of a cortical network with the properties of mirror neurons (mirror system) in humans. The human mirror system is involved in understanding others' actions and their intentions behind them, and it underlies mechanisms of observational learning. Herein, we will discuss the clinical implications of the mirror system.

  16. Mesmerising mirror neurons.

    PubMed

    Heyes, Cecilia

    2010-06-01

    Mirror neurons have been hailed as the key to understanding social cognition. I argue that three currents of thought-relating to evolution, atomism and telepathy-have magnified the perceived importance of mirror neurons. When they are understood to be a product of associative learning, rather than an adaptation for social cognition, mirror neurons are no longer mesmerising, but they continue to raise important questions about both the psychology of science and the neural bases of social cognition. Copyright 2010 Elsevier Inc. All rights reserved.

  17. Partitioning neuronal variability

    PubMed Central

    Goris, Robbe L.T.; Movshon, J. Anthony; Simoncelli, Eero P.

    2014-01-01

    Responses of sensory neurons differ across repeated measurements. This variability is usually treated as stochasticity arising within neurons or neural circuits. However, some portion of the variability arises from fluctuations in excitability due to factors that are not purely sensory, such as arousal, attention, and adaptation. To isolate these fluctuations, we developed a model in which spikes are generated by a Poisson process whose rate is the product of a drive that is sensory in origin, and a gain summarizing stimulus-independent modulatory influences on excitability. This model provides an accurate account of response distributions of visual neurons in macaque LGN, V1, V2, and MT, revealing that variability originates in large part from excitability fluctuations which are correlated over time and between neurons, and which increase in strength along the visual pathway. The model provides a parsimonious explanation for observed systematic dependencies of response variability and covariability on firing rate. PMID:24777419

  18. 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

  19. 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.

  20. Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons.

    PubMed

    Li, Ai-Jun; Wang, Qing; Dinh, Thu T; Powers, Bethany R; Ritter, Sue

    2014-02-15

    Previous work has shown that hindbrain catecholamine neurons are required components of the brain's glucoregulatory circuitry. However, the mechanisms and circuitry underlying their glucoregulatory functions are poorly understood. Here we examined three drugs, glucosamine (GcA), phloridzin (Phl) and 5-thio-d-glucose (5TG), that stimulate food intake but interfere in different ways with cellular glucose utilization or transport. We examined feeding and blood glucose responses to each drug in male rats previously injected into the hypothalamic paraventricular nucleus with anti-dopamine-β-hydroxylase conjugated to saporin (DSAP), a retrogradely transported immunotoxin that selectively lesions noradrenergic and adrenergic neurons, or with unconjugated saporin (SAP) control. Our major findings were 1) that GcA, Phl, and 5TG all stimulated feeding in SAP controls whether injected into the lateral or fourth ventricle (LV or 4V), 2) that each drug's potency was similar for both LV and 4V injections, 3) that neither LV or 4V injection of these drugs evoked feeding in DSAP-lesioned rats, and 4) that only 5TG, which blocks glycolysis, stimulated a blood glucose response. The antagonist of the MEK/ERK signaling cascade, U0126, attenuated GcA-induced feeding, but not Phl- or 5TG-induced feeding. Thus GcA, Phl, and 5TG, although differing in mechanism and possibly activating different neural populations, stimulate feeding in a catecholamine-dependent manner. Although results do not exclude the possibility that catecholamine neurons possess glucose-sensing mechanisms responsive to all of these agents, currently available evidence favors the possibility that the feeding effects result from convergent neural circuits in which catecholamine neurons are a required component.

  1. Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons

    PubMed Central

    Wang, Qing; Dinh, Thu T.; Powers, Bethany R.; Ritter, Sue

    2013-01-01

    Previous work has shown that hindbrain catecholamine neurons are required components of the brain's glucoregulatory circuitry. However, the mechanisms and circuitry underlying their glucoregulatory functions are poorly understood. Here we examined three drugs, glucosamine (GcA), phloridzin (Phl) and 5-thio-d-glucose (5TG), that stimulate food intake but interfere in different ways with cellular glucose utilization or transport. We examined feeding and blood glucose responses to each drug in male rats previously injected into the hypothalamic paraventricular nucleus with anti-dopamine-β-hydroxylase conjugated to saporin (DSAP), a retrogradely transported immunotoxin that selectively lesions noradrenergic and adrenergic neurons, or with unconjugated saporin (SAP) control. Our major findings were 1) that GcA, Phl, and 5TG all stimulated feeding in SAP controls whether injected into the lateral or fourth ventricle (LV or 4V), 2) that each drug's potency was similar for both LV and 4V injections, 3) that neither LV or 4V injection of these drugs evoked feeding in DSAP-lesioned rats, and 4) that only 5TG, which blocks glycolysis, stimulated a blood glucose response. The antagonist of the MEK/ERK signaling cascade, U0126, attenuated GcA-induced feeding, but not Phl- or 5TG-induced feeding. Thus GcA, Phl, and 5TG, although differing in mechanism and possibly activating different neural populations, stimulate feeding in a catecholamine-dependent manner. Although results do not exclude the possibility that catecholamine neurons possess glucose-sensing mechanisms responsive to all of these agents, currently available evidence favors the possibility that the feeding effects result from convergent neural circuits in which catecholamine neurons are a required component. PMID:24381177

  2. 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.

  3. Anti-NGF monoclonal antibody muMab 911 does not deplete neurons in the superior cervical ganglia of young or old adult rats.

    PubMed

    Marcek, John; Okerberg, Carlin; Liu, Chang-Ning; Potter, David; Butler, Paul; Boucher, Magalie; Zorbas, Mark; Mouton, Peter; Nyengaard, Jens R; Somps, Chris

    2016-10-01

    Nerve growth factor (NGF) blocking therapies are an emerging and effective approach to pain management. However, concerns about the potential for adverse effects on the structure and function of the peripheral nervous system have slowed their development. Early studies using NGF antisera in adult rats reported effects on the size and number of neurons in the sympathetic chain ganglia. In the work described here, both young adult (6-8 week) and fully mature (7-8 month) rats were treated with muMab 911, a selective, murine, anti-NGF monoclonal antibody, to determine if systemic exposures to pharmacologically active levels of antibody for 1 month cause loss of neurons in the sympathetic superior cervical ganglia (SCG). State-of-the-art, unbiased stereology performed by two independent laboratories was used to determine the effects of muMab 911 on SCG neuronal number and size, as well as ganglion size. Following muMab 911 treatment, non-statistically significant trends toward smaller ganglia, and smaller and fewer neurons, were seen when routine, nonspecific stains were used in stereologic assessments. However, when noradrenergic neurons were identified using tyrosine hydroxylase (TH) immunoreactivity, trends toward fewer neurons observed with routine stains were not apparent. The only statistically significant effects detected were lower SCG weights in muMab 911-treated rats, and a smaller volume of TH immunoreactivity in neurons from younger rats treated with muMab 911. These results indicate that therapeutically relevant exposures to the anti-NGF monoclonal antibody muMab 911 for 1 month have no effect on neuron numbers within the SCG from young or old adult rats. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Neurons of human nucleus accumbens.

    PubMed

    Sazdanović, Maja; Sazdanović, Predrag; Zivanović-Macuzić, Ivana; Jakovljević, Vladimir; Jeremić, Dejan; Peljto, Amir; Tosevski, Jovo

    2011-08-01

    Nucleus accumbens is a part of the ventral striatum also known as a drug active brain region, especially related with drug addiction. The aim of the study was to investigate the Golgi morphology of the nucleus accumbens neurons. The study was performed on the frontal and sagittal sections of 15 human brains by the Golgi Kopsch method. We classified neurons in the human nucleus accumbens according to their morphology and size into four types: type I--fusiform neurons; type II--fusiform neurons with lateral dendrite, arising from a part of the cell body; type III--pyramidal-like neuron; type IV--multipolar neuron. The medium spiny neurons, which are mostly noted regarding to the drug addictive conditions of the brain, correspond to the type IV--multipolar neurons. Two regions of human nucleus accumbens could be clearly recognized on Nissl and Golgi preparations each containing different predominant neuronal types. Central part of nucleus accumbens, core region, has a low density of impregnated neurons with predominant type III, pyramidal-like neurons, with spines on secondary branches and rare type IV, multipolar neurons. Contrary to the core, peripheral region, shell of nucleus, has a high density of impregnated neurons predominantly contained of type I and type IV--multipolar neurons, which all are rich in spines on secondary and tertiary dendritic branches. Our results indicate great morphological variability of human nucleus accumbens neurons. This requires further investigations and clarifying clinical significance of this important brain region.

  5. Neuronal avalanches and learning

    NASA Astrophysics Data System (ADS)

    de Arcangelis, Lucilla

    2011-05-01

    Networks of living neurons represent one of the most fascinating systems of biology. If the physical and chemical mechanisms at the basis of the functioning of a single neuron are quite well understood, the collective behaviour of a system of many neurons is an extremely intriguing subject. Crucial ingredient of this complex behaviour is the plasticity property of the network, namely the capacity to adapt and evolve depending on the level of activity. This plastic ability is believed, nowadays, to be at the basis of learning and memory in real brains. Spontaneous neuronal activity has recently shown features in common to other complex systems. Experimental data have, in fact, shown that electrical information propagates in a cortex slice via an avalanche mode. These avalanches are characterized by a power law distribution for the size and duration, features found in other problems in the context of the physics of complex systems and successful models have been developed to describe their behaviour. In this contribution we discuss a statistical mechanical model for the complex activity in a neuronal network. The model implements the main physiological properties of living neurons and is able to reproduce recent experimental results. Then, we discuss the learning abilities of this neuronal network. Learning occurs via plastic adaptation of synaptic strengths by a non-uniform negative feedback mechanism. The system is able to learn all the tested rules, in particular the exclusive OR (XOR) and a random rule with three inputs. The learning dynamics exhibits universal features as function of the strength of plastic adaptation. Any rule could be learned provided that the plastic adaptation is sufficiently slow.

  6. 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.

  7. 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.

  8. 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.

  9. Noradrenergic neurotransmission within the bed nucleus of the stria terminalis modulates the retention of immobility in the rat forced swimming test.

    PubMed

    Nagai, Michelly M; Gomes, Felipe V; Crestani, Carlos C; Resstel, Leonardo B M; Joca, Sâmia R L

    2013-06-01

    The bed nucleus of the stria terminalis (BNST) is a limbic structure that has a direct influence on the autonomic, neuroendocrine, and behavioral responses to stress. It was recently reported that reversible inactivation of synaptic transmission within this structure causes antidepressant-like effects, indicating that activation of the BNST during stressful situations would facilitate the development of behavioral changes related to the neurobiology of depression. Moreover, noradrenergic neurotransmission is abundant in the BNST and has an important role in the regulation of emotional processes related to the stress response. Thus, this study aimed to test the hypothesis that activation of adrenoceptors within the BNST facilitates the development of behavioral consequences of stress. To investigate this hypothesis, male Wistar rats were stressed (forced swimming, 15 min) and 24 h later received intra-BNST injections of vehicle, WB4101, RX821002, CGP20712, or ICI118,551, which are selective α(1), α(2), β(1), and β(2) adrenoceptor antagonists, respectively, 10 min before a 5-min forced swimming test. It was observed that administration of WB4101 (10 and 15 nmol), CGP20712 (5 and 10 nmol), or ICI118,551 (5 nmol) into the BNST reduced the immobility time of rats subjected to forced swimming test, indicating an antidepressant-like effect. These findings suggest that activation of α(1), β(1), and β(2) adrenoceptors in the BNST could be involved in the development of the behavioral consequences of stress. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

  10. 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

  11. Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study.

    PubMed

    Gallopin, Thierry; Luppi, Pierre-Hervé; Rambert, Francis A; Frydman, Armand; Fort, Patrice

    2004-02-01

    The pharmacologic profile of modafinil, an increasingly popular wake-promoting drug for narcolepsy treatment, differs from those of classic psychostimulants such as amphetamine. However, its brain targets are still a matter of debate. We hypothesized that modafinil could increase waking by inhibiting the sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such action could be direct or indirect via the potentiation of inhibition mediated by waking neurotransmitters. We thus studied the effect of modafinil on the membrane potential and firing rate of VLPO neurons recorded in rat-brain slices. We further determined whether pretreatment with modafinil modifies the effect of noradrenaline, carbachol, serotonin, histamine, dopamine, or clonidine. Pretreatment with modafinil specifically increased the inhibition of VLPO neurons induced by noradrenaline but had no effect when applied alone or in combination with other substances. Pretreatment with nisoxetine, a selective noradrenaline reuptake blocker, similarly increased the noradrenaline-induced inhibition of VLPO cells. Further, the potentiation by modafinil was minimized when modafinil and nisoxetine were applied together. These results suggest that modafinil blocks the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons from the VLPO. Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.

  12. Neuronal Mechanisms of Intelligence

    DTIC Science & Technology

    1987-11-01

    1984). Calcium-dependent protein kinases and neuronal function. Trends in PharmacologicaL Sciences, 5, 188-192. Schwartzkroin , P . A . (1981). To...arding electrical stimulus. Animals with nucleus •’• a ~CCumbens electrodes were wtraied in one-hour daily sesions to nose-poke for C p ! L. Stein & J.D...D O FILE. COR a AFOSR Grant #84-0325 Final Technical Report November 1987 AFOSR.T- 88-02. Cn’ NEURONAL MECHANISMS OF INTELLIGENCE DEPARTMENT OF

  13. The Reliability of Neurons

    PubMed Central

    Bullock, Theodore Holmes

    1970-01-01

    The prevalent probabilistic view is virtually untestable; it remains a plausible belief. The cases usually cited can not be taken as evidence for it. Several grounds for this conclusion are developed. Three issues are distinguished in an attempt to clarify a murky debate: (a) the utility of probabilistic methods in data reduction, (b) the value of models that assume indeterminacy, and (c) the validity of the inference that the nervous system is largely indeterministic at the neuronal level. No exception is taken to the first two; the second is a private heuristic question. The third is the issue to which the assertion in the first two sentences is addressed. Of the two kinds of uncertainty, statistical mechanical (= practical unpredictability) as in a gas, and Heisenbergian indeterminancy, the first certainly exists, the second is moot at the neuronal level. It would contribute to discussion to recognize that neurons perform with a degree of reliability. Although unreliability is difficult to establish, to say nothing of measure, evidence that some neurons have a high degree of reliability, in both connections and activity is increasing greatly. An example is given from sternarchine electric fish. PMID:5462670

  14. The neuron classification problem

    PubMed Central

    Bota, Mihail; Swanson, Larry W.

    2007-01-01

    A systematic account of neuron cell types is a basic prerequisite for determining the vertebrate nervous system global wiring diagram. With comprehensive lineage and phylogenetic information unavailable, a general ontology based on structure-function taxonomy is proposed and implemented in a knowledge management system, and a prototype analysis of select regions (including retina, cerebellum, and hypothalamus) presented. The supporting Brain Architecture Knowledge Management System (BAMS) Neuron ontology is online and its user interface allows queries about terms and their definitions, classification criteria based on the original literature and “Petilla Convention” guidelines, hierarchies, and relations—with annotations documenting each ontology entry. Combined with three BAMS modules for neural regions, connections between regions and neuron types, and molecules, the Neuron ontology provides a general framework for physical descriptions and computational modeling of neural systems. The knowledge management system interacts with other web resources, is accessible in both XML and RDF/OWL, is extendible to the whole body, and awaits large-scale data population requiring community participation for timely implementation. PMID:17582506

  15. Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

    PubMed Central

    Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika

    2014-01-01

    The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically

  16. 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 ...

  17. Vasculo-Neuronal Coupling: Retrograde Vascular Communication to Brain Neurons.

    PubMed

    Kim, Ki Jung; Ramiro Diaz, Juan; Iddings, Jennifer A; Filosa, Jessica A

    2016-12-14

    Continuous cerebral blood flow is essential for neuronal survival, but whether vascular tone influences resting neuronal function is not known. Using a multidisciplinary approach in both rat and mice brain slices, we determined whether flow/pressure-evoked increases or decreases in parenchymal arteriole vascular tone, which result in arteriole constriction and dilation, respectively, altered resting cortical pyramidal neuron activity. We present evidence for intercellular communication in the brain involving a flow of information from vessel to astrocyte to neuron, a direction opposite to that of classic neurovascular coupling and referred to here as vasculo-neuronal coupling (VNC). Flow/pressure increases within parenchymal arterioles increased vascular tone and simultaneously decreased resting pyramidal neuron firing activity. On the other hand, flow/pressure decreases evoke parenchymal arteriole dilation and increased resting pyramidal neuron firing activity. In GLAST-CreERT2; R26-lsl-GCaMP3 mice, we demonstrate that increased parenchymal arteriole tone significantly increased intracellular calcium in perivascular astrocyte processes, the onset of astrocyte calcium changes preceded the inhibition of cortical pyramidal neuronal firing activity. During increases in parenchymal arteriole tone, the pyramidal neuron response was unaffected by blockers of nitric oxide, GABA A , glutamate, or ecto-ATPase. However, VNC was abrogated by TRPV4 channel, GABA B , as well as an adenosine A 1 receptor blocker. Differently to pyramidal neuron responses, increases in flow/pressure within parenchymal arterioles increased the firing activity of a subtype of interneuron. Together, these data suggest that VNC is a complex constitutive active process that enables neurons to efficiently adjust their resting activity according to brain perfusion levels, thus safeguarding cellular homeostasis by preventing mismatches between energy supply and demand. We present evidence for vessel-to-neuron

  18. Neurogenic differentiation of dental pulp stem cells to neuron-like cells in dopaminergic and motor neuronal inductive media.

    PubMed

    Chang, Chia-Chieh; Chang, Kai-Chun; Tsai, Shang-Jye; Chang, Hao-Hueng; Lin, Chun-Pin

    2014-12-01

    Dental pulp stem cells (DPSCs) have been proposed as a promising source of stem cells in nerve regeneration due to their close embryonic origin and ease of harvest. The aim of this study was to evaluate the efficacy of dopaminergic and motor neuronal inductive media on transdifferentiation of human DPSCs (hDPSCs) into neuron-like cells. Isolation, cultivation, and identification of hDPSCs were performed with morphological analyses and flow cytometry. The proliferation potential of DPSCs was evaluated with an XTT [(2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide)] assay. Media for the induction of dopaminergic and spinal motor neuronal differentiation were prepared. The efficacy of neural induction was evaluated by detecting the expression of neuron cell-specific cell markers in DPSCs by immunocytochemistry and quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). In the XTT assay, there was a 2.6- or 2-fold decrease in DPSCs cultured in dopaminergic or motor neuronal inductive media, respectively. The proportions of βIII-tubulin (βIII-tub), glial fibrillary acidic protein (GFAP), and oligodendrocyte (O1)-positive cells were significantly higher in DPSCs cultured in both neuronal inductive media compared with those cultured in control media. Furthermore, hDPSC-derived dopaminergic and spinal motor neuron cells after induction expressed a higher density of neuron cell markers than those before induction. These findings suggest that in response to the neuronal inductive stimuli, a greater proportion of DPSCs stop proliferation and acquire a phenotype resembling mature neurons. Such neural crest-derived adult DPSCs may provide an alternative stem cell source for therapy-based treatments of neuronal disorders and injury. Copyright © 2014. Published by Elsevier B.V.

  19. 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.

  20. Effects of single and simultaneous lesions of serotonergic and noradrenergic pathways on open-space and bright-space anxiety-like behavior in two animal models.

    PubMed

    Sziray, Nóra; Kuki, Zsófia; Nagy, Katalin M; Markó, Bernadett; Kompagne, Hajnalka; Lévay, György

    2010-05-01

    The objective of the present study is to investigate the effects of single and simultaneous lesions of the noradrenergic and serotonergic pathways (NA-X, 5-HT-X and XX, respectively) by intracerebroventricular administration of selective neurotoxins N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine-HCl (DSP-4) and 5,7-dihydroxytryptamine (5,7-DHT) on anxiety-like behavior in rats. To evaluate the effects of the various lesions, animals were tested in elevated plus-maze (EPM) and light-dark (LD) paradigms. In EPM, single lesions produced strong, statistically significant increase (p<0.001) of both time spent in the open arms (OT) and number of entries into the open arms (OE) compared to sham-lesioned animals. Simultaneous lesion further strengthened this anxiolytic effect causing an approximate 500% elevation of OT compared to sham-lesioned animals. In LD, 5-HT lesion caused a significant (p<0.05) increase in both light movement time and light horizontal activity parameters compared to intact, sham, and NA-lesioned groups. Neither of the lesions caused any change in the spontaneous locomotor activity of the animals up to 15min as measured in activity meter. These findings suggest that single and simultaneous lesions of 5-HT- and NA-pathways modify anxiety-related state of experimental animals to different extents and these modifications alter the behavior of animals differently in the two models used: NA-X and 5-HT-X reduce open space anxiety-like behavior and XX further strengthens this effect in the EPM, while only 5-HT-X is resulting in reduced bright-space anxiety-like behavior leaving the performance of NA-X and XX animals unchanged.

  1. Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis: effects on anxiety behavior in postpartum and virgin female rats.

    PubMed

    Smith, Carl D; Piasecki, Christopher C; Weera, Marcus; Olszewicz, Joshua; Lonstein, Joseph S

    2013-08-01

    Emotional hyperreactivity can inhibit maternal responsiveness in female rats and other animals. Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral bed nucleus of the stria terminalis (BSTv) with the α2-autoreceptor antagonist, yohimbine, or the more selective α2-autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine or idazoxan. It was further assessed if the α2-autoreceptor agonist clonidine (which decreases norepinephrine release) would, conversely, reduce dams' anxiety. Groups of diestrous virgins were also examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related behavior in postpartum females. However, BSTv infusion of idazoxan did not reproduce yohimbine's anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv clonidine. Because yohimbine is a weak 5HT1A receptor agonist, other groups of females received BSTv infusion of the 5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related behavior. Lastly, levels of norepinephrine and serotonin in tissue punches from the BSTv did not differ between postpartum and diestrous rats, but serotonin turnover was lower in mothers. These results suggest that the impaired maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both be readily explained by an increase in dams' anxiety, and that BSTv α2-autoreceptor modulation alone has little influence on anxiety-related behaviors in postpartum or diestrous rats.

  2. Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis – effects on anxiety behavior in postpartum and virgin female rats

    PubMed Central

    Smith, Carl D.; Piasecki, Christopher C.; Weera, Marcus; Olszewicz, Joshua; Lonstein, Joseph S.

    2014-01-01

    Emotional hyper-reactivity can inhibit maternal responsiveness in female rats and other animals. Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral bed nucleus of the stria terminalis (BSTv) with the α2-autoreceptor antagonist, yohimbine, or the more selective α2-autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine or idazoxan. It was further assessed if the α2-autoreceptor agonist clonidine (which decreases norepinephrine release) would, conversely, reduce dams’ anxiety. Groups of diestrous virgins were also examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related behavior in postpartum females. However, BSTv infusion of idazoxan did not reproduce yohimbine’s anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv clonidine. Because yohimbine is a weak 5HT1A receptor agonist, other groups of females received BSTv infusion of the 5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related behavior. Lastly, levels of norepinephrine and serotonin in tissue punches from the BSTv did not differ between postpartum and diestrous rats, but serotonin turnover was lower in mothers. These results suggest that the impaired maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both be readily explained by an increase in dams’ anxiety, and that BSTv α2-autoreceptor modulation alone has little influence anxiety-related behaviors in postpartum or diestrous rats. PMID:23796237

  3. 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.

  4. 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.

  5. Measurement of endogenous noradrenaline release in the rat cerebral cortex in vivo by transcortical dialysis: effects of drugs affecting noradrenergic transmission.

    PubMed

    L'Heureux, R; Dennis, T; Curet, O; Scatton, B

    1986-06-01

    The release of endogenous noradrenaline was measured in the cerebral cortex of the halothane-anesthetized rat by using the technique of brain dialysis coupled to a radioenzymatic assay. A thin dialysis tube was inserted transversally in the cerebral cortex (transcortical dialysis) and perfused with Ringer medium (2 microliter min-1). Under basal conditions, the cortical output of noradrenaline was stable over a period of at least 6 h and amounted to 8.7 pg/20 min (not corrected for recovery). Histological control of the perfused area revealed very little damage and normal morphology in the vicinity of the dialysis tube. Omission of calcium from the perfusion medium caused a marked drop in cortical noradrenaline output. Bilateral electrical stimulation (for 10 min) of the ascending noradrenergic pathways in the medial forebrain bundle caused a frequency-dependent increase in cortical noradrenaline output over the range 5-20 Hz. Stimulation at a higher frequency (50 Hz) resulted in a levelling off of the increase in cortical noradrenaline release. Systemic administration of the dopamine-beta-hydroxylase inhibitor bis-(4-methyl-1-homopiperazinylthiocarbonyl) disulfide (FLA 63) (25 mg/kg i.p.) markedly reduced, whereas injection of the monoamine oxidase inhibitor pargyline (75 mg/kg i.p.) resulted in a progressive increase in, cortical noradrenaline output. d-Amphetamine (2 mg/kg i.p.) provoked a sharp increase in cortical noradrenaline release (+450% over basal values within 40 min). Desmethylimipramine (10 mg/kg i.p.) produced a twofold increase of cortical noradrenaline release. Finally, idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.), respectively, increased and decreased the release of noradrenaline from the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Neuronal synchrony: Peculiarity and generality

    PubMed Central

    Nowotny, Thomas; Huerta, Ramon; Rabinovich, Mikhail I.

    2008-01-01

    Synchronization in neuronal systems is a new and intriguing application of dynamical systems theory. Why are neuronal systems different as a subject for synchronization? (1) Neurons in themselves are multidimensional nonlinear systems that are able to exhibit a wide variety of different activity patterns. Their “dynamical repertoire” includes regular or chaotic spiking, regular or chaotic bursting, multistability, and complex transient regimes. (2) Usually, neuronal oscillations are the result of the cooperative activity of many synaptically connected neurons (a neuronal circuit). Thus, it is necessary to consider synchronization between different neuronal circuits as well. (3) The synapses that implement the coupling between neurons are also dynamical elements and their intrinsic dynamics influences the process of synchronization or entrainment significantly. In this review we will focus on four new problems: (i) the synchronization in minimal neuronal networks with plastic synapses (synchronization with activity dependent coupling), (ii) synchronization of bursts that are generated by a group of nonsymmetrically coupled inhibitory neurons (heteroclinic synchronization), (iii) the coordination of activities of two coupled neuronal networks (partial synchronization of small composite structures), and (iv) coarse grained synchronization in larger systems (synchronization on a mesoscopic scale). PMID:19045493

  7. Criticality in Neuronal Networks

    NASA Astrophysics Data System (ADS)

    Friedman, Nir; Ito, Shinya; Brinkman, Braden A. W.; Shimono, Masanori; Deville, R. E. Lee; Beggs, John M.; Dahmen, Karin A.; Butler, Tom C.

    2012-02-01

    In recent years, experiments detecting the electrical firing patterns in slices of in vitro brain tissue have been analyzed to suggest the presence of scale invariance and possibly criticality in the brain. Much of the work done however has been limited in two ways: 1) the data collected is from local field potentials that do not represent the firing of individual neurons; 2) the analysis has been primarily limited to histograms. In our work we examine data based on the firing of individual neurons (spike data), and greatly extend the analysis by considering shape collapse and exponents. Our results strongly suggest that the brain operates near a tuned critical point of a highly distinctive universality class.

  8. Single neuron modeling and data assimilation in BNST neurons

    NASA Astrophysics Data System (ADS)

    Farsian, Reza

    Neurons, although tiny in size, are vastly complicated systems, which are responsible for the most basic yet essential functions of any nervous system. Even the most simple models of single neurons are usually high dimensional, nonlinear, and contain many parameters and states which are unobservable in a typical neurophysiological experiment. One of the most fundamental problems in experimental neurophysiology is the estimation of these parameters and states, since knowing their values is essential in identification, model construction, and forward prediction of biological neurons. Common methods of parameter and state estimation do not perform well for neural models due to their high dimensionality and nonlinearity. In this dissertation, two alternative approaches for parameters and state estimation of biological neurons have been demonstrated: dynamical parameter estimation (DPE) and a Markov Chain Monte Carlo (MCMC) method. The first method uses elements of chaos control and synchronization theory for parameter and state estimation. MCMC is a statistical approach which uses a path integral formulation to evaluate a mean and an error bound for these unobserved parameters and states. These methods have been applied to biological system of neurons in Bed Nucleus of Stria Termialis neurons (BNST) of rats. State and parameters of neurons in both systems were estimated, and their value were used for recreating a realistic model and predicting the behavior of the neurons successfully. The knowledge of biological parameters can ultimately provide a better understanding of the internal dynamics of a neuron in order to build robust models of neuron networks.

  9. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents.

    PubMed

    Papakostas, George I; Thase, Michael E; Fava, Maurizio; Nelson, J Craig; Shelton, Richard C

    2007-12-01

    Recent studies suggest that the treatment of major depressive disorder (MDD) with newer antidepressant drugs that simultaneously enhance norepinephrine and serotonin neurotransmission might result in higher response and remission rates than the selective serotonin reuptake inhibitors (SSRIs). The goal of our work was to compare response rates among patients with MDD treated with either of these two broad categories of antidepressant drugs. Medline/Pubmed, EMBase, clinical trial registries, program syllabi from major psychiatric meetings held since 1995, and documents from relevant pharmaceutical companies were searched for double-blind, randomized trials comparing a newer serotonergic-noradrenergic antidepressant drug (venlafaxine, duloxetine, milnacipran, mirtazapine, mianserin, or moclobemide) with an SSRI for MDD. Ninety-three trials (n = 17,036) were combined using a random-effects model. Treatment with serotonergic + noradrenergic antidepressant drugs was more likely to result in clinical response than the SSRIs (risk ratio [RR] = 1.059; response rates 63.6% versus 59.3%; p = .003). There was no evidence for heterogeneity among studies combined (p = 1.0). Excluding each individual agent did not significantly alter the pooled RR. With the exception of duloxetine (.985), RRs for response for each individual serotonergic + noradrenergic antidepressant drug were within the 95% confidence interval of the pooled RR (1.019-1.101). Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage compared with SSRIs in MDD. With the Number Needed to Treat (NNT) statistic as one indicator of clinical significance, nearly 24 patients would need to be treated with dual-action antidepressant drugs instead of SSRIs in order to obtain one additional responder. This difference falls well below the mark of NNT = 10 suggested by the United Kingdom's National Institute of Clinical Excellence but nonetheless might be of public health relevance given the

  10. Vesicular glutamate transporter DNPI/VGLUT2 is expressed by both C1 adrenergic and nonaminergic presympathetic vasomotor neurons of the rat medulla.

    PubMed

    Stornetta, Ruth L; Sevigny, Charles P; Schreihofer, Ann M; Rosin, Diane L; Guyenet, Patrice G

    2002-03-12

    The main source of excitatory drive to the sympathetic preganglionic neurons that control blood pressure is from neurons located in the rostral ventrolateral medulla (RVLM). This monosynaptic input includes adrenergic (C1), peptidergic, and noncatecholaminergic neurons. Some of the cells in this pathway are suspected to be glutamatergic, but conclusive evidence is lacking. In the present study we sought to determine whether these presympathetic neurons express the vesicular glutamate transporter BNPI/VGLUT1 or the closely related gene DNPI, the rat homolog of the mouse vesicular glutamate transporter VGLUT2. Both BNPI/VGLUT1 and DNPI/VGLUT2 mRNAs were detected in the medulla oblongata by in situ hybridization, but only DNPI/VGLUT2 mRNA was present in the RVLM. Moreover, BNPI immunoreactivity was absent from the thoracic spinal cord lateral horn. DNPI/VGLUT2 mRNA was present in many medullary cells retrogradely labeled with Fluoro-Gold from the spinal cord (T2; four rats). Within the RVLM, 79% of the bulbospinal C1 cells contained DNPI/VGLUT2 mRNA. Bulbospinal noradrenergic A5 neurons did not contain DNPI/VGLUT2 mRNA. The RVLM of six unanesthetized rats subjected to 2 hours of hydralazine-induced hypotension contained tenfold more c-Fos-ir DNPI/VGLUT2 neurons than that of six saline-treated controls. c-Fos-ir DNPI/VGLUT2 neurons included C1 and non-C1 neurons (3:2 ratio). In seven barbiturate-anesthetized rats, 16 vasomotor presympathetic neurons were filled with biotinamide and analyzed for the presence of tyrosine hydroxylase immunoreactivity and/or DNPI/VGLUT2 mRNA. Biotinamide-labeled neurons included C1 and non-C1 cells. Most non-C1 (9/10) and C1 presympathetic cells (5/6) contained DNPI/VGLUT2 mRNA. In conclusion, DNPI/VGLUT2 is expressed by most blood pressure-regulating presympathetic cells of the RVLM. The data suggest that these neurons may be glutamatergic and that the C1 adrenergic phenotype is one of several secondary phenotypes that are differentially

  11. State-dependent interactions between excitatory neuromodulators in the neuronal control of breathing

    PubMed Central

    Doi, Atsushi; Ramirez, Jan-Marino

    2010-01-01

    All neuronal networks are modulated by multiple neuropeptides and biogenic amines. Yet, few studies investigate how different modulators interact to regulate network activity. Here we explored the state-dependent functional interactions between three excitatory neuromodulators acting on neurokinin1 (NK1), alpha1 noradrenergic (α1 NE) and 5-HT2 serotonin receptors (5-HT2) within the Pre-Bötzinger complex (pre-BötC), an area critical for the generation of breathing. In anesthetized, in vivo mice the reliance on endogenous NK1 activation depended on spontaneous breathing frequency and the modulatory state of the animal. Endogenous NK1 activation had no significant respiratory effect when stimulating raphe magnus and/or locus ceruleus, but became critical, when α1 NE and 5-HT2 receptors were pharmacologically blocked. The dependence of the centrally generated respiratory rhythm on NK1 activation was blunted in the presence of α1 NE and 5-HT2 agonists as demonstrated in slices containing the pre-BötC. We conclude that a modulators’ action is determined by the concurrent modulation and interaction with other neuromodulators. Deficiencies in one neuromodulator are immediately compensated by the action of other neuromodulators. This interplay could play a role in the state-dependency of certain breathing disorders. PMID:20554877

  12. 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

  13. 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

  14. Metabolic reprogramming during neuronal differentiation.

    PubMed

    Agostini, M; Romeo, F; Inoue, S; Niklison-Chirou, M V; Elia, A J; Dinsdale, D; Morone, N; Knight, R A; Mak, T W; Melino, G

    2016-09-01

    Newly generated neurons pass through a series of well-defined developmental stages, which allow them to integrate into existing neuronal circuits. After exit from the cell cycle, postmitotic neurons undergo neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. Lack of a global metabolic analysis during early cortical neuronal development led us to explore the role of cellular metabolism and mitochondrial biology during ex vivo differentiation of primary cortical neurons. Unexpectedly, we observed a huge increase in mitochondrial biogenesis. Changes in mitochondrial mass, morphology and function were correlated with the upregulation of the master regulators of mitochondrial biogenesis, TFAM and PGC-1α. Concomitant with mitochondrial biogenesis, we observed an increase in glucose metabolism during neuronal differentiation, which was linked to an increase in glucose uptake and enhanced GLUT3 mRNA expression and platelet isoform of phosphofructokinase 1 (PFKp) protein expression. In addition, glutamate-glutamine metabolism was also increased during the differentiation of cortical neurons. We identified PI3K-Akt-mTOR signalling as a critical regulator role of energy metabolism in neurons. Selective pharmacological inhibition of these metabolic pathways indicate existence of metabolic checkpoint that need to be satisfied in order to allow neuronal differentiation.

  15. Metabolic reprogramming during neuronal differentiation

    PubMed Central

    Agostini, M; Romeo, F; Inoue, S; Niklison-Chirou, M V; Elia, A J; Dinsdale, D; Morone, N; Knight, R A; Mak, T W; Melino, G

    2016-01-01

    Newly generated neurons pass through a series of well-defined developmental stages, which allow them to integrate into existing neuronal circuits. After exit from the cell cycle, postmitotic neurons undergo neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. Lack of a global metabolic analysis during early cortical neuronal development led us to explore the role of cellular metabolism and mitochondrial biology during ex vivo differentiation of primary cortical neurons. Unexpectedly, we observed a huge increase in mitochondrial biogenesis. Changes in mitochondrial mass, morphology and function were correlated with the upregulation of the master regulators of mitochondrial biogenesis, TFAM and PGC-1α. Concomitant with mitochondrial biogenesis, we observed an increase in glucose metabolism during neuronal differentiation, which was linked to an increase in glucose uptake and enhanced GLUT3 mRNA expression and platelet isoform of phosphofructokinase 1 (PFKp) protein expression. In addition, glutamate–glutamine metabolism was also increased during the differentiation of cortical neurons. We identified PI3K–Akt–mTOR signalling as a critical regulator role of energy metabolism in neurons. Selective pharmacological inhibition of these metabolic pathways indicate existence of metabolic checkpoint that need to be satisfied in order to allow neuronal differentiation. PMID:27058317

  16. Neuroprotective, Neurogenic, and Amyloid Beta Reducing Effect of a Novel Alpha 2-Adrenoblocker, Mesedin, on Astroglia and Neuronal Progenitors upon Hypoxia and Glutamate Exposure

    PubMed Central

    Melkonyan, Magda M.; Hunanyan, Lilit; Lourhmati, Ali; Layer, Nikolas; Beer-Hammer, Sandra; Yenkoyan, Konstantin; Schwab, Matthias; Danielyan, Lusine

    2017-01-01

    Locus coeruleus-noradrenergic system dysfunction is known to contribute to the progression of Alzheimer’s disease (AD). Besides a variety of reports showing the involvement of norepinephrine and its receptor systems in cognition, amyloid β (Aβ) metabolism, neuroinflammation, and neurogenesis, little is known about the contribution of the specific receptors to these actions. Here, we investigated the neurogenic and neuroprotective properties of a new α2 adrenoblocker, mesedin, in astroglial primary cultures (APC) from C57BL/6 and 3×Tg-AD mice. Our results demonstrate that mesedin rescues neuronal precursors and young neurons, and reduces the lactate dehydrogenase (LDH) release from astroglia under hypoxic and normoxic conditions. Mesedin also increased choline acetyltransferase, postsynaptic density marker 95 (PSD95), and Aβ-degrading enzyme neprilysin in the wild type APC, while in the 3×Tg-AD APC exposed to glutamate, it decreased the intracellular content of Aβ and enhanced the survival of synaptophysin-positive astroglia and neurons. These effects in APC can at least partially be attributed to the mesedin’s ability of increasing the expression of Interleukine(IL)-10, which is a potent anti-inflammatory, neuroprotective neurogenic, and Aβ metabolism enhancing factor. In summary, our data identify the neurogenic, neuroprotective, and anti-amyloidogenic action of mesedin in APC. Further in vivo studies are needed to estimate the therapeutic value of mesedin for AD. PMID:29267189

  17. [Effect of non-selective alpha-adrenergic receptor antagonist nicergoline on the activity of neurons in the ventral lateral thalamic nucleus].

    PubMed

    Lukhanina, O P; Pil'kevych, N A

    2005-01-01

    In experiments on rats microionophoretic administration of nicergoline mainly showed the dual effect on the background activity of the ventrolateral thalamic nucleus (VL) neurons and their reactions evoked by the superior cerebellum peduncle stimulation: inhibitory under weak (2-10 nA) and excitatory under stronger (20-40 nA) currents. Microionophoresis (25 nA) of nicergoline led to decrease of the postexcitatory inhibitory processes during paired stimulation of the cerebellum fibers. Paired-pulse ratio (number of spikes in the short-latency neuronal responses elicited by the second pulse/number of spikes by the first pulse) increased, which support a presynaptic mode of drug action. Hence excitatory effect of nicergoline may be related to the blockade of the presynaptic alpha2-receptors, while inhibitory effect by the blockade of the postsynaptic alphal-receptors. Present data reveal the essential participation of the alpha-adrenoreceptor system in the modulation of background and evoked neuronal activity of the motor thalamus. The possible role of noradrenergic denervation in the development of movement disorders accompanying Parkinson's disease is discussed.

  18. The biophysics of neuronal growth

    NASA Astrophysics Data System (ADS)

    Franze, Kristian; Guck, Jochen

    2010-09-01

    For a long time, neuroscience has focused on biochemical, molecular biological and electrophysiological aspects of neuronal physiology and pathology. However, there is a growing body of evidence indicating the importance of physical stimuli for neuronal growth and development. In this review we briefly summarize the historical background of neurobiophysics and give an overview over the current understanding of neuronal growth from a physics perspective. We show how biophysics has so far contributed to a better understanding of neuronal growth and discuss current inconsistencies. Finally, we speculate how biophysics may contribute to the successful treatment of lesions to the central nervous system, which have been considered incurable until very recently.

  19. Hypersensitivity of prediabetic JCR:LA-cp rats to fine airborne combustion particle-induced direct and noradrenergic-mediated vascular contraction.

    PubMed

    Proctor, Spencer D; Dreher, Kevin L; Kelly, Sandra E; Russell, James C

    2006-04-01

    Particulate matter with mean aerodynamic diameter < or =2.5 microm (PM(2.5)), from diesel exhaust, coal or residual oil burning, and from industrial plants, is a significant component of airborne pollution. Type 2 diabetes is associated with enhanced risk of adverse cardiovascular events following exposure to PM(2.5). Particle properties, sources, and pathophysiological mechanisms responsible are unknown. We studied effects of residual oil fly ash (ROFA) from a large U.S. powerplant on vascular function in a prediabetic, hyperinsulinemic model, the JCR:LA-cp rat. Residual oil fly ash leachate (ROFA-L) was studied using aortic rings from young-adult, obese, insulin-resistant rats and lean normal rats in vitro. Contractile response to phenylephrine and relaxant response to acetylcholine were determined in the presence and absence of L-NAME (N(G)-nitro-L-arginine methyl ester). In a separate series of studies, the direct contractile effects of ROFA-L on repeated exposure were determined. ROFA-L (12.5 microg ml(-1)) increased phenylephrine-mediated contraction in obese (p < 0.05), but not in lean rat aortae, with the effect being exacerbated by L-NAME, and it reduced acetylcholine-mediated relaxation of both obese and lean aortae (p < 0.0001). Initial exposure of aortae to ROFA-L caused a small contractile response (<0.05 g), which was markedly greater on second exposure in the obese (approximately 0.6 g, p < 0.0001) aortae but marginal in lean (approximately 0.1 g) aortae. Our data demonstrate that bioavailable constituents of oil combustion particles enhance noradrenergic-mediated vascular contraction, impair endothelium-mediated relaxation, and induce direct vasocontraction in prediabetic rats. These observations provide the first direct evidence of the causal properties of PM(2.5) and identify the pathophysiological role of the early prediabetic state in susceptibility to environmentally induced cardiovascular disease. These are important implications for public

  20. Neurochemical excitation of propriospinal neurons facilitates locomotor command signal transmission in the lesioned spinal cord.

    PubMed

    Zaporozhets, Eugene; Cowley, Kristine C; Schmidt, Brian J

    2011-06-01

    Previous studies of the in vitro neonatal rat brain stem-spinal cord showed that propriospinal relays contribute to descending transmission of a supraspinal command signal that is capable of activating locomotion. Using the same preparation, the present series examines whether enhanced excitation of thoracic propriospinal neurons facilitates propagation of the locomotor command signal in the lesioned spinal cord. First, we identified neurotransmitters contributing to normal endogenous propriospinal transmission of the locomotor command signal by testing the effect of receptor antagonists applied to cervicothoracic segments during brain stem-induced locomotor-like activity. Spinal cords were either intact or contained staggered bilateral hemisections located at right T1/T2 and left T10/T11 junctions designed to abolish direct long-projecting bulbospinal axons. Serotonergic, noradrenergic, dopaminergic, and glutamatergic, but not cholinergic, receptor antagonists blocked locomotor-like activity. Approximately 73% of preparations with staggered bilateral hemisections failed to generate locomotor-like activity in response to electrical stimulation of the brain stem alone; such preparations were used to test the effect of neuroactive substances applied to thoracic segments (bath barriers placed at T3 and T9) during brain stem stimulation. The percentage of preparations developing locomotor-like activity was as follows: 5-HT (43%), 5-HT/N-methyl-D-aspartate (NMDA; 33%), quipazine (42%), 8-hydroxy-2-(di-n-propylamino)tetralin (20%), methoxamine (45%), and elevated bath K(+) concentration (29%). Combined norepinephrine and dopamine increased the success rate (67%) compared with the use of either agent alone (4 and 7%, respectively). NMDA, Mg(2+) ion removal, clonidine, and acetylcholine were ineffective. The results provide proof of principle that artificial excitation of thoracic propriospinal neurons can improve supraspinal control over hindlimb locomotor networks in the

  1. β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

    PubMed Central

    Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

    2010-01-01

    Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

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

    PubMed Central

    Gonzalez, M. M. C.; Aston-Jones, G.

    2008-01-01

    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. PMID:18347342

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

    PubMed

    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 β 1 - and not α 1 - or α 2 -adrenergic receptor stimulation. Activation of β 1 -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 β 1 -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 β 1 -adrenergic receptors, which in turn activate HCN channels via a signaling pathway involving the

  4. 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

  5. ReNeuron Group plc.

    PubMed

    Sinden, John D

    2006-01-01

    ReNeuron is a UK-based pioneer in stem cell research and development. The Company has leading edge, proprietary somatic stem cell technologies from which it is developing groundbreaking cell therapy products. ReNeuron's focus is on cell therapy treatments designed to reverse the effects of major diseases such as stroke, diabetes and diseases of the eye.

  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. 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…

  8. 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

  9. Phenotypic Checkpoints Regulate Neuronal Development

    PubMed Central

    Ben-Ari, Yehezkel; Spitzer, Nicholas C.

    2010-01-01

    Nervous system development proceeds by sequential gene expression mediated by cascades of transcription factors in parallel with sequences of patterned network activity driven by receptors and ion channels. These sequences are cell type- and developmental stage-dependent and modulated by paracrine actions of substances released by neurons and glia. How and to what extent these sequences interact to enable neuronal network development is not understood. Recent evidence demonstrates that CNS development requires intermediate stages of differentiation providing functional feedback that influences gene expression. We suggest that embryonic neuronal functions constitute a series of phenotypic checkpoint signatures; neurons failing to express these functions are delayed or developmentally arrested. Such checkpoints are likely to be a general feature of neuronal development and may constitute presymptomatic signatures of neurological disorders when they go awry. PMID:20864191

  10. MRI findings of neuronal ceroid lipofuscinosis in a cat

    PubMed Central

    White, Crystal; Mortier, Jeremy; Verin, Ranieri; Maddox, Thomas; Goncalves, Rita; Sanchez-Masian, Daniel

    2018-01-01

    Case summary A 2-year-old male domestic shorthair cat presented to the University of Liverpool Small Animal Teaching Hospital with a 2 week history of altered mentation, blindness and focal epileptic seizures. MRI examination revealed generalised cerebral and cerebellar atrophy, diffuse T2-weighted hyperintensity of the white matter and meningeal thickening. Neuronal ceroid lipofuscinosis was confirmed on post-mortem examination. Relevance and novel information This is the first report of the MRI findings of neuronal ceroid lipofuscinosis in a cat. PMID:29531776

  11. 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

  12. 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

  13. 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.

  14. Neuronal pathway finding: from neurons to initial neural networks.

    PubMed

    Roscigno, Cecelia I

    2004-10-01

    Neuronal pathway finding is crucial for structured cellular organization and development of neural circuits within the nervous system. Neuronal pathway finding within the visual system has been extensively studied and therefore is used as a model to review existing knowledge regarding concepts of this developmental process. General principles of neuron pathway finding throughout the nervous system exist. Comprehension of these concepts guides neuroscience nurses in gaining an understanding of the developmental course of action, the implications of different anomalies, as well as the theoretical basis and nursing implications of some provocative new therapies being proposed to treat neurodegenerative diseases and neurologic injuries. These therapies have limitations in light of current ethical, developmental, and delivery modes and what is known about the development of neuronal pathways.

  15. Biosynthesis of Astrocytic Trehalose Regulates Neuronal Arborization in Hippocampal Neurons.

    PubMed

    Martano, Giuseppe; Gerosa, Laura; Prada, Ilaria; Garrone, Giulia; Krogh, Vittorio; Verderio, Claudia; Passafaro, Maria

    2017-09-20

    Trehalose is a nonreducing disaccharide that has recently attracted much attention because of its ability to inhibit protein aggregation, induce autophagy, and protect against dissections and strokes. In vertebrates, the biosynthesis of trehalose was long considered absent due to the lack of annotated genes involved in this process. In contrast, trehalase (TreH), which is an enzyme required for the cleavage of trehalose, is known to be conserved and expressed. Here, we show that trehalose is present as an endogenous metabolite in the rodent hippocampus. We found that primary astrocytes were able to synthesize trehalose and release it into the extracellular space. Notably, the TreH enzyme was observed only in the soma of neurons, which are the exclusive users of this substrate. A statistical analysis of the metabolome during different stages of maturation indicated that this metabolite is implicated in neuronal maturation. A morphological analysis of primary neurons confirmed that trehalose is required for neuronal arborization.

  16. Glial tumors with neuronal differentiation.

    PubMed

    Park, Chul-Kee; Phi, Ji Hoon; Park, Sung-Hye

    2015-01-01

    Immunohistochemical studies for neuronal differentiation in glial tumors revealed subsets of tumors having both characteristics of glial and neuronal lineages. Glial tumors with neuronal differentiation can be observed with diverse phenotypes and histologic grades. The rosette-forming glioneuronal tumor of the fourth ventricle and papillary glioneuronal tumor have been newly classified as distinct disease entities. There are other candidates for classification, such as the glioneuronal tumor without pseudopapillary architecture, glioneuronal tumor with neuropil-like islands, and the malignant glioneuronal tumor. The clinical significance of these previously unclassified tumors should be confirmed. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Mechanosensing in hypothalamic osmosensory neurons.

    PubMed

    Prager-Khoutorsky, Masha

    2017-11-01

    Osmosensory neurons are specialized cells activated by increases in blood osmolality to trigger thirst, secretion of the antidiuretic hormone vasopressin, and elevated sympathetic tone during dehydration. In addition to multiple extrinsic factors modulating their activity, osmosensory neurons are intrinsically osmosensitive, as they are activated by increased osmolality in the absence of neighboring cells or synaptic contacts. This intrinsic osmosensitivity is a mechanical process associated with osmolality-induced changes in cell volume. This review summarises recent findings revealing molecular mechanisms underlying the mechanical activation of osmosensory neurons and highlighting important roles of microtubules, actin, and mechanosensitive ion channels in this process. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Simulating synchronization in neuronal networks

    NASA Astrophysics Data System (ADS)

    Fink, Christian G.

    2016-06-01

    We discuss several techniques used in simulating neuronal networks by exploring how a network's connectivity structure affects its propensity for synchronous spiking. Network connectivity is generated using the Watts-Strogatz small-world algorithm, and two key measures of network structure are described. These measures quantify structural characteristics that influence collective neuronal spiking, which is simulated using the leaky integrate-and-fire model. Simulations show that adding a small number of random connections to an otherwise lattice-like connectivity structure leads to a dramatic increase in neuronal synchronization.

  19. 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/

  20. Neurons on the couch.

    PubMed

    Marić, Nadja P; Jašović-Gašić, Miroslava

    2010-12-01

    A hundred years after psychoanalysis was introduced, neuroscience has taken a giant step forward. It seems nowadays that effects of psychotherapy could be monitored and measured by state-of-the art brain imaging techniques. Today, the psychotherapy is considered as a strategic and purposeful environmental influence intended to enhance learning. Since gene expression is regulated by environmental influences throughout life and these processes create brain architecture and influence the strength of synaptic connections, psychotherapy (as a kind of learning) should be explored in the context of aforementioned paradigm. In other words, when placing a client on the couch, therapist actually placed client's neuronal network; while listening and talking, expressing and analyzing, experiencing transference and counter transference, therapist tends to stabilize synaptic connections and influence dendritic growth by regulating gene-transcriptional activity. Therefore, we strongly believe that, in the near future, an increasing knowledge on cellular and molecular interactions and mechanisms of action of different psycho- and pharmaco-therapeutic procedures will enable us to tailor a sophisticated therapeutic approach toward a person, by combining major therapeutic strategies in psychiatry on the basis of rational goals and evidence-based therapeutic expectations.

  1. 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.

  2. 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

  3. 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

  4. Neuronal boost to evolutionary dynamics.

    PubMed

    de Vladar, Harold P; Szathmáry, Eörs

    2015-12-06

    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.

  5. Bayesian Networks Predict Neuronal Transdifferentiation.

    PubMed

    Ainsworth, Richard I; Ai, Rizi; Ding, Bo; Li, Nan; Zhang, Kai; Wang, Wei

    2018-05-30

    We employ the language of Bayesian networks to systematically construct gene-regulation topologies from deep-sequencing single-nucleus RNA-Seq data for human neurons. From the perspective of the cell-state potential landscape, we identify attractors that correspond closely to different neuron subtypes. Attractors are also recovered for cell states from an independent data set confirming our models accurate description of global genetic regulations across differing cell types of the neocortex (not included in the training data). Our model recovers experimentally confirmed genetic regulations and community analysis reveals genetic associations in common pathways. Via a comprehensive scan of all theoretical three-gene perturbations of gene knockout and overexpression, we discover novel neuronal trans-differrentiation recipes (including perturbations of SATB2, GAD1, POU6F2 and ADARB2) for excitatory projection neuron and inhibitory interneuron subtypes. Copyright © 2018, G3: Genes, Genomes, Genetics.

  6. Neuronal control of energy homeostasis

    PubMed Central

    Gao, Qian; Horvath, Tamas L.

    2013-01-01

    Neuronal control of body energy homeostasis is the key mechanism by which animals and humans regulate their long-term energy balance. Various hypothalamic neuronal circuits (which include the hypothalamic melanocortin, midbrain dopamine reward and caudal brainstem autonomic feeding systems) control energy intake and expenditure to maintain body weight within a narrow range for long periods of a life span. Numerous peripheral metabolic hormones and nutrients target these structures providing feedback signals that modify the default “settings” of neuronal activity to accomplish this balance. A number of molecular genetic tools for manipulating individual components of brain energy homeostatic machineries, in combination with anatomical, electrophysiological, pharmacological and behavioral techniques, have been developed, which provide a means for elucidating the complex molecular and cellular mechanisms of feeding behavior and metabolism. This review will highlight some of these advancements and focus on the neuronal circuitries of energy homeostasis. PMID:18061579

  7. Do enteric neurons make hypocretin?

    PubMed

    Baumann, Christian R; Clark, Erika L; Pedersen, Nigel P; Hecht, Jonathan L; Scammell, Thomas E

    2008-04-10

    Hypocretins (orexins) are wake-promoting neuropeptides produced by hypothalamic neurons. These hypocretin-producing cells are lost in people with narcolepsy, possibly due to an autoimmune attack. Prior studies described hypocretin neurons in the enteric nervous system, and these cells could be an additional target of an autoimmune process. We sought to determine whether enteric hypocretin neurons are lost in narcoleptic subjects. Even though we tried several methods (including whole mounts, sectioned tissue, pre-treatment of mice with colchicine, and the use of various primary antisera), we could not identify hypocretin-producing cells in enteric nervous tissue collected from mice or normal human subjects. These results raise doubts about whether enteric neurons produce hypocretin.

  8. Imitation, mirror neurons and autism.

    PubMed

    Williams, J H; Whiten, A; Suddendorf, T; Perrett, D I

    2001-06-01

    Various deficits in the cognitive functioning of people with autism have been documented in recent years but these provide only partial explanations for the condition. We focus instead on an imitative disturbance involving difficulties both in copying actions and in inhibiting more stereotyped mimicking, such as echolalia. A candidate for the neural basis of this disturbance may be found in a recently discovered class of neurons in frontal cortex, 'mirror neurons' (MNs). These neurons show activity in relation both to specific actions performed by self and matching actions performed by others, providing a potential bridge between minds. MN systems exist in primates without imitative and 'theory of mind' abilities and we suggest that in order for them to have become utilized to perform social cognitive functions, sophisticated cortical neuronal systems have evolved in which MNs function as key elements. Early developmental failures of MN systems are likely to result in a consequent cascade of developmental impairments characterised by the clinical syndrome of autism.

  9. Neuronal substrates of sleep homeostasis; lessons from flies, rats and mice.

    PubMed

    Donlea, Jeffrey M; Alam, Md Noor; Szymusiak, Ronald

    2017-06-01

    Sleep homeostasis is a fundamental property of vigilance state regulation that is highly conserved across species. Neuronal systems and circuits that underlie sleep homeostasis are not well understood. In Drosophila, a neuronal circuit involving neurons in the ellipsoid body and in the dorsal Fan-shaped body is a candidate for both tracing sleep need during waking and translating it to increased sleep drive and expression. Sleep homeostasis in rats and mice involves multiple neuromodulators acting on multiple wake- and sleep-promoting neuronal systems. A functional central homeostat emerges from A 1 receptor mediated actions of adenosine on wake-promoting neurons in the basal forebrain and hypothalamus, and A 2A adenosine receptor-mediated actions on sleep-promoting neurons in the preoptic hypothalamus and nucleus accumbens. Copyright © 2017. Published by Elsevier Ltd.

  10. Network synchronization in hippocampal neurons.

    PubMed

    Penn, Yaron; Segal, Menahem; Moses, Elisha

    2016-03-22

    Oscillatory activity is widespread in dynamic neuronal networks. The main paradigm for the origin of periodicity consists of specialized pacemaking elements that synchronize and drive the rest of the network; however, other models exist. Here, we studied the spontaneous emergence of synchronized periodic bursting in a network of cultured dissociated neurons from rat hippocampus and cortex. Surprisingly, about 60% of all active neurons were self-sustained oscillators when disconnected, each with its own natural frequency. The individual neuron's tendency to oscillate and the corresponding oscillation frequency are controlled by its excitability. The single neuron intrinsic oscillations were blocked by riluzole, and are thus dependent on persistent sodium leak currents. Upon a gradual retrieval of connectivity, the synchrony evolves: Loose synchrony appears already at weak connectivity, with the oscillators converging to one common oscillation frequency, yet shifted in phase across the population. Further strengthening of the connectivity causes a reduction in the mean phase shifts until zero-lag is achieved, manifested by synchronous periodic network bursts. Interestingly, the frequency of network bursting matches the average of the intrinsic frequencies. Overall, the network behaves like other universal systems, where order emerges spontaneously by entrainment of independent rhythmic units. Although simplified with respect to circuitry in the brain, our results attribute a basic functional role for intrinsic single neuron excitability mechanisms in driving the network's activity and dynamics, contributing to our understanding of developing neural circuits.

  11. New Features for Neuron Classification.

    PubMed

    Hernández-Pérez, Leonardo A; Delgado-Castillo, Duniel; Martín-Pérez, Rainer; Orozco-Morales, Rubén; Lorenzo-Ginori, Juan V

    2018-04-28

    This paper addresses the problem of obtaining new neuron features capable of improving results of neuron classification. Most studies on neuron classification using morphological features have been based on Euclidean geometry. Here three one-dimensional (1D) time series are derived from the three-dimensional (3D) structure of neuron instead, and afterwards a spatial time series is finally constructed from which the features are calculated. Digitally reconstructed neurons were separated into control and pathological sets, which are related to three categories of alterations caused by epilepsy, Alzheimer's disease (long and local projections), and ischemia. These neuron sets were then subjected to supervised classification and the results were compared considering three sets of features: morphological, features obtained from the time series and a combination of both. The best results were obtained using features from the time series, which outperformed the classification using only morphological features, showing higher correct classification rates with differences of 5.15, 3.75, 5.33% for epilepsy and Alzheimer's disease (long and local projections) respectively. The morphological features were better for the ischemia set with a difference of 3.05%. Features like variance, Spearman auto-correlation, partial auto-correlation, mutual information, local minima and maxima, all related to the time series, exhibited the best performance. Also we compared different evaluators, among which ReliefF was the best ranked.

  12. 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

  13. 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

  14. Communication among neurons.

    PubMed

    Marner, Lisbeth

    2012-04-01

    The communication among neurons is the prerequisite for the working brain. To understand the cellular, neurochemical, and structural basis of this communication, and the impacts of aging and disease on brain function, quantitative measures are necessary. This thesis evaluates several quantitative neurobiological methods with respect to possible bias and methodological issues. Stereological methods are suited for the unbiased estimation of number, length, and volumes of components of the nervous system. Stereological estimates of the total length of myelinated nerve fibers were made in white matter of post mortem brains, and the impact of aging and diseases as Schizophrenia and Alzheimer's disease were evaluated. Although stereological methods are in principle unbiased, shrinkage artifacts are difficult to account for. Positron emission tomography (PET) recordings, in conjunction with kinetic modeling, permit the quantitation of radioligand binding in brain. The novel serotonin 5-HT4 antagonist [11C]SB207145 was used as an example of the validation process for quantitative PET receptor imaging. Methods based on reference tissue as well as methods based on an arterial plasma input function were evaluated with respect to precision and accuracy. It was shown that [11C]SB207145 binding had high sensitivity to occupancy by unlabeled ligand, necessitating high specific activity in the radiosynthesis to avoid bias. The established serotonin 5-HT2A ligand [18F]altanersin was evaluated in a two-year follow-up study in elderly subjects. Application of partial volume correction of the PET data diminished the reliability of the measures, but allowed for the correct distinction between changes due to brain atrophy and receptor availability. Furthermore, a PET study of patients with Alzheimer's disease with the serotonin transporter ligand [11C]DASB showed relatively preserved serotonergic projections, despite a marked decrease in 5-HT2A receptor binding. Possible confounders are

  15. Fatty acids increase neuronal hypertrophy of Pten knockdown neurons

    PubMed Central

    Fricano, Catherine J.; DeSpenza, Tyrone; Frazel, Paul W.; Li, Meijie; O'Malley, A. James; Westbrook, Gary L.; Luikart, Bryan W.

    2014-01-01

    Phosphatase and tensin homolog (Pten) catalyzes the reverse reaction of PI3K by dephosphorylating PIP3 to PIP2. This negatively regulates downstream Akt/mTOR/S6 signaling resulting in decreased cellular growth and proliferation. Co-injection of a lentivirus knocking Pten down with a control lentivirus allows us to compare the effects of Pten knockdown between individual neurons within the same animal. We find that knockdown of Pten results in neuronal hypertrophy by 21 days post-injection. This neuronal hypertrophy is correlated with increased p-S6 and p-mTOR in individual neurons. We used this system to test whether an environmental factor that has been implicated in cellular hypertrophy could influence the severity of the Pten knockdown-induced hypertrophy. Implantation of mini-osmotic pumps delivering fatty acids results in increased neuronal hypertrophy and p-S6/p-mTOR staining. These hypertrophic effects were reversed in response to rapamycin treatment. However, we did not observe a similar increase in hypertrophy in response to dietary manipulations of fatty acids. Thus, we conclude that by driving growth signaling with fatty acids and knocking down a critical regulator of growth, Pten, we are able to observe an additive morphological phenotype of increased soma size mediated by the mTOR pathway. PMID:24795563

  16. 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).

  17. The mirror-neuron system.

    PubMed

    Rizzolatti, Giacomo; Craighero, Laila

    2004-01-01

    A category of stimuli of great importance for primates, humans in particular, is that formed by actions done by other individuals. If we want to survive, we must understand the actions of others. Furthermore, without action understanding, social organization is impossible. In the case of humans, there is another faculty that depends on the observation of others' actions: imitation learning. Unlike most species, we are able to learn by imitation, and this faculty is at the basis of human culture. In this review we present data on a neurophysiological mechanism--the mirror-neuron mechanism--that appears to play a fundamental role in both action understanding and imitation. We describe first the functional properties of mirror neurons in monkeys. We review next the characteristics of the mirror-neuron system in humans. We stress, in particular, those properties specific to the human mirror-neuron system that might explain the human capacity to learn by imitation. We conclude by discussing the relationship between the mirror-neuron system and language.

  18. 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.

  19. Trafficking of presynaptic AMPA receptors mediating neurotransmitter release: neuronal selectivity and relationships with sensitivity to cyclothiazide.

    PubMed

    Pittaluga, Anna; Feligioni, Marco; Longordo, Fabio; Luccini, Elisa; Raiteri, Maurizio

    2006-03-01

    Postsynaptic glutamate AMPA receptors (AMPARs) can recycle between plasma membrane and intracellular pools. In contrast, trafficking of presynaptic AMPARs has not been investigated. AMPAR surface expression involves interactions between the GluR2 carboxy tail and various proteins including glutamate receptor-interacting protein (GRIP), AMPA receptor-binding protein (ABP), protein interacting with C kinase 1 (PICK1), N-ethyl-maleimide-sensitive fusion protein (NSF). Here, peptides known to selectively block the above interactions were entrapped into synaptosomes to study the effects on the AMPA-evoked release of [3H]noradrenaline ([3H]NA) and [3H]acetylcholine ([3H]ACh) from rat hippocampal and cortical synaptosomes, respectively. Internalization of pep2-SVKI to prevent GluR2-GRIP/ABP/PICK1 interactions potentiated the AMPA-evoked release of [3H]NA but left unmodified that of [3H]ACh. Similar potentiation was caused by pep2-AVKI, the blocker of GluR2-PICK1 interaction. Conversely, a decrease in the AMPA-evoked release of [3H]NA, but not of [3H]ACh, was caused by pep2m, a selective blocker of the GluR2-NSF interaction. In the presence of pep2-SVKI the presynaptic AMPARs on noradrenergic terminals lost sensitivity to cyclothiazide. AMPARs releasing [3H]ACh, but not those releasing [3H]NA, were sensitive to spermine, suggesting that they are GluR2-lacking AMPARs. To conclude: (i) release-regulating presynaptic AMPARs constitutively cycle in isolated nerve terminals; (ii) the process exhibits neuronal selectivity; (iii) AMPAR trafficking and desensitization may be interrelated.

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

    PubMed

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

    2016-08-01

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

  1. The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons.

    PubMed

    Gervasi, Noreen M; Scott, Shane S; Aschrafi, Armaz; Gale, Jenna; Vohra, Sanah N; MacGibeny, Margaret A; Kar, Amar N; Gioio, Anthony E; Kaplan, Barry B

    2016-06-01

    Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3'UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal. Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  2. Simulation of Code Spectrum and Code Flow of Cultured Neuronal Networks.

    PubMed

    Tamura, Shinichi; Nishitani, Yoshi; Hosokawa, Chie; Miyoshi, Tomomitsu; Sawai, Hajime

    2016-01-01

    It has been shown that, in cultured neuronal networks on a multielectrode, pseudorandom-like sequences (codes) are detected, and they flow with some spatial decay constant. Each cultured neuronal network is characterized by a specific spectrum curve. That is, we may consider the spectrum curve as a "signature" of its associated neuronal network that is dependent on the characteristics of neurons and network configuration, including the weight distribution. In the present study, we used an integrate-and-fire model of neurons with intrinsic and instantaneous fluctuations of characteristics for performing a simulation of a code spectrum from multielectrodes on a 2D mesh neural network. We showed that it is possible to estimate the characteristics of neurons such as the distribution of number of neurons around each electrode and their refractory periods. Although this process is a reverse problem and theoretically the solutions are not sufficiently guaranteed, the parameters seem to be consistent with those of neurons. That is, the proposed neural network model may adequately reflect the behavior of a cultured neuronal network. Furthermore, such prospect is discussed that code analysis will provide a base of communication within a neural network that will also create a base of natural intelligence.

  3. 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.

  4. Unconventional secretory processing diversifies neuronal ion channel properties

    PubMed Central

    Hanus, Cyril; Geptin, Helene; Tushev, Georgi; Garg, Sakshi; Alvarez-Castelao, Beatriz; Sambandan, Sivakumar; Kochen, Lisa; Hafner, Anne-Sophie; Langer, Julian D; Schuman, Erin M

    2016-01-01

    N-glycosylation – the sequential addition of complex sugars to adhesion proteins, neurotransmitter receptors, ion channels and secreted trophic factors as they progress through the endoplasmic reticulum and the Golgi apparatus – is one of the most frequent protein modifications. In mammals, most organ-specific N-glycosylation events occur in the brain. Yet, little is known about the nature, function and regulation of N-glycosylation in neurons. Using imaging, quantitative immunoblotting and mass spectrometry, we show that hundreds of neuronal surface membrane proteins are core-glycosylated, resulting in the neuronal membrane displaying surprisingly high levels of glycosylation profiles that are classically associated with immature intracellular proteins. We report that while N-glycosylation is generally required for dendritic development and glutamate receptor surface expression, core-glycosylated proteins are sufficient to sustain these processes, and are thus functional. This atypical glycosylation of surface neuronal proteins can be attributed to a bypass or a hypo-function of the Golgi apparatus. Core-glycosylation is regulated by synaptic activity, modulates synaptic signaling and accelerates the turnover of GluA2-containing glutamate receptors, revealing a novel mechanism that controls the composition and sensing properties of the neuronal membrane. DOI: http://dx.doi.org/10.7554/eLife.20609.001 PMID:27677849

  5. Dynamics of moment neuronal networks.

    PubMed

    Feng, Jianfeng; Deng, Yingchun; Rossoni, Enrico

    2006-04-01

    A theoretical framework is developed for moment neuronal networks (MNNs). Within this framework, the behavior of the system of spiking neurons is specified in terms of the first- and second-order statistics of their interspike intervals, i.e., the mean, the variance, and the cross correlations of spike activity. Since neurons emit and receive spike trains which can be described by renewal--but generally non-Poisson--processes, we first derive a suitable diffusion-type approximation of such processes. Two approximation schemes are introduced: the usual approximation scheme (UAS) and the Ornstein-Uhlenbeck scheme. It is found that both schemes approximate well the input-output characteristics of spiking models such as the IF and the Hodgkin-Huxley models. The MNN framework is then developed according to the UAS scheme, and its predictions are tested on a few examples.

  6. Neuronal clues to vascular guidance.

    PubMed

    Suchting, Steven; Bicknell, Roy; Eichmann, Anne

    2006-03-10

    The development of the vertebrate vascular system into a highly ordered and stereotyped network requires precise control over the branching and growth of new vessels. Recent research has highlighted the important role of genetic programs in regulating vascular patterning and in particular has established a crucial role for families of molecules previously described in controlling neuronal guidance. Like neurons, new vessels are guided along the correct path by integrating attractive and repulsive cues from the external environment. This is achieved by specialised endothelial cells at the leading tip of vessel sprouts which express receptor proteins that couple extracellular guidance signals with the cytoskeletal changes necessary to alter cell direction. Here, we review the genetic and in vitro evidence implicating four families of ligand-receptor signalling systems common to both neuronal and vessel guidance: the Ephrins and Eph receptors; Semaphorins, Neuropilins and Plexin receptors; Netrin and Unc5 receptors; and Slits and Robo receptors.

  7. 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.

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

    PubMed

    Kim, Ji-Il; Cho, Hye-Yeon; Han, Jin-Hee; Kaang, Bong-Kiun

    2016-04-01

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

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

    PubMed Central

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

    2016-01-01

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

  10. Uncovering Neuronal Networks Defined by Consistent Between-Neuron Spike Timing from Neuronal Spike Recordings

    PubMed Central

    2018-01-01

    Abstract It is widely assumed that distributed neuronal networks are fundamental to the functioning of the brain. Consistent spike timing between neurons is thought to be one of the key principles for the formation of these networks. This can involve synchronous spiking or spiking with time delays, forming spike sequences when the order of spiking is consistent. Finding networks defined by their sequence of time-shifted spikes, denoted here as spike timing networks, is a tremendous challenge. As neurons can participate in multiple spike sequences at multiple between-spike time delays, the possible complexity of networks is prohibitively large. We present a novel approach that is capable of (1) extracting spike timing networks regardless of their sequence complexity, and (2) that describes their spiking sequences with high temporal precision. We achieve this by decomposing frequency-transformed neuronal spiking into separate networks, characterizing each network’s spike sequence by a time delay per neuron, forming a spike sequence timeline. These networks provide a detailed template for an investigation of the experimental relevance of their spike sequences. Using simulated spike timing networks, we show network extraction is robust to spiking noise, spike timing jitter, and partial occurrences of the involved spike sequences. Using rat multineuron recordings, we demonstrate the approach is capable of revealing real spike timing networks with sub-millisecond temporal precision. By uncovering spike timing networks, the prevalence, structure, and function of complex spike sequences can be investigated in greater detail, allowing us to gain a better understanding of their role in neuronal functioning. PMID:29789811

  11. [The ontogeny of the mirror neuron system].

    PubMed

    Myowa-Yamakoshi, Masako

    2014-06-01

    Abstract Humans utilize the mirror neuron system to understand and predict others' actions. However, the ontogeny of the mirror neuron system remains unknown. Whether mirror neuron function is an innate trait or whether mirror neurons acquire their sensorimotor matching properties ontogenetically remains to be clarified. In this paper, I review the ontogenetic theory of the mirror neuron system. I then discuss the functioning of the mirror neuron system in the context of social cognitive abilities, which are unique to humans. Recently, some researchers argue that it is too early to interpret the function of mirror neurons as an understanding of the underlying psychological states of others. They imply that such functioning would require inferential cognitive processes that are known to involve areas outside the mirror neuron system. Filling in this missing link may be the key to elucidating the unique ability of humans to understand others' actions.

  12. The Neuronal Infrastructure of Speaking

    ERIC Educational Resources Information Center

    Menenti, Laura; Segaert, Katrien; Hagoort, Peter

    2012-01-01

    Models of speaking distinguish producing meaning, words and syntax as three different linguistic components of speaking. Nevertheless, little is known about the brain's integrated neuronal infrastructure for speech production. We investigated semantic, lexical and syntactic aspects of speaking using fMRI. In a picture description task, we…

  13. 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

  14. Hypothalamic neurones governing glucose homeostasis.

    PubMed

    Coppari, R

    2015-06-01

    The notion that the brain directly controls the level of glucose in the blood (glycaemia) independent of its known action on food intake and body weight has been known ever since 1849. That year, the French physiologist Dr Claude Bernard reported that physical puncture of the floor of the fourth cerebral ventricle rapidly leads to an increased level of sugar in the blood (and urine) in rabbits. Despite this important discovery, it took approximately 150 years before significant efforts aimed at understanding the underlying mechanism of brain-mediated control of glucose metabolism were made. Technological developments allowing for genetically-mediated manipulation of selected molecular pathways in a neurone-type-specific fashion unravelled the importance of specific molecules in specific neuronal populations. These neuronal pathways govern glucose metabolism in the presence and even in the absence of insulin. Also, a peculiarity of these pathways is that certain biochemically-defined neurones govern glucose metabolism in a tissue-specific fashion. © 2015 British Society for Neuroendocrinology.

  15. 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

  16. 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.

  17. Spiking neuron network Helmholtz machine.

    PubMed

    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.

  18. 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

  19. Neuronal imprinting of human values.

    PubMed

    Delgado, J M

    2000-03-01

    In the 21st century, psychophysiology will face the challenge of establishing ethical principles and practical means for the genetic and social influencing of the development of human beings. Neuronal imprinting of beliefs and morality within infantile minds will be necessary for the peaceful coexistence of races and cultures. This process requires study and consideration, among others, of the following psychophysiological facts: (1) Genes do not transmit moral values. (2) Material support of physiological activities is necessary for the existence and development of mental functions. (3) Imprinting of human values is based on material changes within neuronal structures. (4) Early neuronal imprinting is performed without personal awareness or consent of the individual and depends on sensory inputs, mainly from the social structure of the group. (5) Biological structures lack values. Personal and social antagonisms do not depend on genes, but on cultural indoctrination. (6) Pleasure and punishment (positive and negative reinforcement) are the two main elements, which regulate animal and human behavior. (7) Values must be chosen by adults, who decide the questions 'why'? 'when'? 'which ones'?, 'who should teach'?, 'what?' and 'how'? (8) Many biological imperatives are shared by all animals and by all people. Human beings may be considered the 'crickets of the Universe', unable to understand the mysteries of nature because of our insufficient neuronal capacity. (9) Our emotional life is mainly related to the structure of the limbic system controlled by the neocortex. (10) New theories based on the integration of physics, chemistry, biology and other specific areas of knowledge, as proposed by the General Theory of Systems, will avoid 'opposites', favoring the acceptance of complementary aspects of reality. (11) Early education will promote preferential learning which depends on both genetic endowment and neuronal development influenced by experience. It is the

  20. Prospective Coding by Spiking Neurons

    PubMed Central

    Brea, Johanni; Gaál, Alexisz Tamás; Senn, Walter

    2016-01-01

    Animals learn to make predictions, such as associating the sound of a bell with upcoming feeding or predicting a movement that a motor command is eliciting. How predictions are realized on the neuronal level and what plasticity rule underlies their learning is not well understood. Here we propose a biologically plausible synaptic plasticity rule to learn predictions on a single neuron level on a timescale of seconds. The learning rule allows a spiking two-compartment neuron to match its current firing rate to its own expected future discounted firing rate. For instance, if an originally neutral event is repeatedly followed by an event that elevates the firing rate of a neuron, the originally neutral event will eventually also elevate the neuron’s firing rate. The plasticity rule is a form of spike timing dependent plasticity in which a presynaptic spike followed by a postsynaptic spike leads to potentiation. Even if the plasticity window has a width of 20 milliseconds, associations on the time scale of seconds can be learned. We illustrate prospective coding with three examples: learning to predict a time varying input, learning to predict the next stimulus in a delayed paired-associate task and learning with a recurrent network to reproduce a temporally compressed version of a sequence. We discuss the potential role of the learning mechanism in classical trace conditioning. In the special case that the signal to be predicted encodes reward, the neuron learns to predict the discounted future reward and learning is closely related to the temporal difference learning algorithm TD(λ). PMID:27341100

  1. 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.

  2. Purification of Immature Neuronal Cells from Neural Stem Cell Progeny

    PubMed Central

    Azari, Hassan; Osborne, Geoffrey W.; Yasuda, Takahiro; Golmohammadi, Mohammad G.; Rahman, Maryam; Deleyrolle, Loic P.; Esfandiari, Ebrahim; Adams, David J.; Scheffler, Bjorn; Steindler, Dennis A.; Reynolds, Brent A.

    2011-01-01

    Large-scale proliferation and multi-lineage differentiation capabilities make neural stem cells (NSCs) a promising renewable source of cells for therapeutic applications. However, the practical application for neuronal cell replacement is limited by heterogeneity of NSC progeny, relatively low yield of neurons, predominance of astrocytes, poor survival of donor cells following transplantation and the potential for uncontrolled proliferation of precursor cells. To address these impediments, we have developed a method for the generation of highly enriched immature neurons from murine NSC progeny. Adaptation of the standard differentiation procedure in concert with flow cytometry selection, using scattered light and positive fluorescent light selection based on cell surface antibody binding, provided a near pure (97%) immature neuron population. Using the purified neurons, we screened a panel of growth factors and found that bone morphogenetic protein-4 (BMP-4) demonstrated a strong survival effect on the cells in vitro, and enhanced their functional maturity. This effect was maintained following transplantation into the adult mouse striatum where we observed a 2-fold increase in the survival of the implanted cells and a 3-fold increase in NeuN expression. Additionally, based on the neural-colony forming cell assay (N-CFCA), we noted a 64 fold reduction of the bona fide NSC frequency in neuronal cell population and that implanted donor cells showed no signs of excessive or uncontrolled proliferation. The ability to provide defined neural cell populations from renewable sources such as NSC may find application for cell replacement therapies in the central nervous system. PMID:21687800

  3. 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.

  4. 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

  5. Foxp2 regulates neuronal differentiation and neuronal subtype specification.

    PubMed

    Chiu, Yi-Chi; Li, Ming-Yang; Liu, Yuan-Hsuan; Ding, Jing-Ya; Yu, Jenn-Yah; Wang, Tsu-Wei

    2014-07-01

    Mutations of the transcription factor FOXP2 in humans cause a severe speech and language disorder. Disruption of Foxp2 in songbirds or mice also leads to deficits in song learning or ultrasonic vocalization, respectively. These data suggest that Foxp2 plays important roles in the developing nervous system. However, the mechanism of Foxp2 in regulating neural development remains elusive. In the current study, we found that Foxp2 increased neuronal differentiation without affecting cell proliferation and cell survival in primary neural progenitors from embryonic forebrains. Foxp2 induced the expression of platelet-derived growth factor receptor α, which mediated the neurognic effect of Foxp2. In addition, Foxp2 positively regulated the differentiation of medium spiny neurons derived from the lateral ganglionic eminence and negatively regulated the formation of interneurons derived from dorsal medial ganglionic eminence by interacting with the Sonic hedgehog pathway. Taken together, our results suggest that Foxp2 regulates multiple aspects of neuronal development in the embryonic forebrain. © 2014 Wiley Periodicals, Inc.

  6. Trigeminal Medullary Dorsal Horn Neurons Activated by Nasal Stimulation Coexpress AMPA, NMDA, and NK1 Receptors

    PubMed Central

    McCulloch, P. F.; DiNovo, K. M.; Westerhaus, D. J.; Vizinas, T. A.; Peevey, J. F.; Lach, M. A.; Czarnocki, P.

    2013-01-01

    Afferent information initiating the cardiorespiratory responses during nasal stimulation projects from the nasal passages to neurons within the trigeminal medullary dorsal horn (MDH) via the anterior ethmoidal nerve (AEN). Central AEN terminals are thought to release glutamate to activate the MDH neurons. This study was designed to determine which neurotransmitter receptors (AMPA, kainate, or NMDA glutamate receptor subtypes or the Substance P receptor NK1) are expressed by these activated MDH neurons. Fos was used as a neuronal marker of activated neurons, and immunohistochemistry combined with epifluorescent microscopy was used to determine which neurotransmitter receptor subunits were coexpressed by activated MDH neurons. Results indicate that, during nasal stimulation with ammonia vapors in urethane-anesthetized Sprague-Dawley rats, activated neurons within the superficial MDH coexpress the AMPA glutamate receptor subunits GluA1 (95.8%) and GluA2/3 (88.2%), the NMDA glutamate receptor subunits GluN1 (89.1%) and GluN2A (41.4%), and NK1 receptors (64.0%). It is therefore likely that during nasal stimulation the central terminals of the AEN release glutamate and substance P that then produces activation of these MDH neurons. The involvement of AMPA and NMDA receptors may mediate fast and slow neurotransmission, respectively, while NK1 receptor involvement may indicate activation of a nociceptive pathway. PMID:24967301

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

    PubMed

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

    2012-08-22

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

  9. Cardiac neuronal hierarchy in health and disease.

    PubMed

    Armour, J Andrew

    2004-08-01

    The cardiac neuronal hierarchy can be represented as a redundant control system made up of spatially distributed cell stations comprising afferent, efferent, and interconnecting neurons. Its peripheral and central neurons are in constant communication with one another such that, for the most part, it behaves as a stochastic control system. Neurons distributed throughout this hierarchy interconnect via specific linkages such that each neuronal cell station is involved in temporally dependent cardio-cardiac reflexes that control overlapping, spatially organized cardiac regions. Its function depends primarily, but not exclusively, on inputs arising from afferent neurons transducing the cardiovascular milieu to directly or indirectly (via interconnecting neurons) modify cardiac motor neurons coordinating regional cardiac behavior. As the function of the whole is greater than that of its individual parts, stable cardiac control occurs most of the time in the absence of direct cause and effect. During altered cardiac status, its redundancy normally represents a stabilizing feature. However, in the presence of regional myocardial ischemia, components within the intrinsic cardiac nervous system undergo pathological change. That, along with any consequent remodeling of the cardiac neuronal hierarchy, alters its spatially and temporally organized reflexes such that populations of neurons, acting in isolation, may destabilize efferent neuronal control of regional cardiac electrical and/or mechanical events.

  10. Dendrites of medial olivocochlear neurons in mouse.

    PubMed

    Brown, M C; Levine, J L

    2008-06-12

    Stains for acetylcholinesterase (AChE) and retrograde labeling with Fluorogold (FG) were used to study olivocochlear neurons and their dendritic patterns in mice. The two methods gave similar results for location and number of somata. The total number of medial olivocochlear (MOC) neurons in the ventral nucleus of the trapezoid body (VNTB) is about 170 per side. An additional dozen large olivocochlear neurons are located in the dorsal periolivary nucleus (DPO). Dendrites of all of these neurons are long and extend in all directions from the cell bodies, a pattern that contrasts with the sharp frequency tuning of their responses. For VNTB neurons, there were greater numbers of dendrites directed medially than laterally and those directed medially were longer (on average, 25-50% longer). Dendrite extensions were most pronounced for neurons located in the rostral portion of the VNTB. When each dendrite from a single neuron was represented as a vector, and all the vectors summed, the result was also skewed toward the medial direction. DPO neurons, however, had more symmetric dendrites that projected into more dorsal parts of the trapezoid body, suggesting that this small group of olivocochlear neurons has very different physiological properties. Dendrites of both types of neurons were somewhat elongated rostrally, about 20% longer than those directed caudally. These results can be interpreted as extensions of dendrites of olivocochlear neurons toward their synaptic inputs: medially to meet crossing fibers from the cochlear nucleus that are part of the MOC reflex pathway, and rostrally to meet descending inputs from higher centers.

  11. Neuronal Allocation to a Hippocampal Engram

    PubMed Central

    Park, Sungmo; Kramer, Emily E; Mercaldo, Valentina; Rashid, Asim J; Insel, Nathan; Frankland, Paul W; Josselyn, Sheena A

    2016-01-01

    The dentate gyrus (DG) is important for encoding contextual memories, but little is known about how a population of DG neurons comes to encode and support a particular memory. One possibility is that recruitment into an engram depends on a neuron's excitability. Here, we manipulated excitability by overexpressing CREB in a random population of DG neurons and examined whether this biased their recruitment to an engram supporting a contextual fear memory. To directly assess whether neurons overexpressing CREB at the time of training became critical components of the engram, we examined memory expression while the activity of these neurons was silenced. Chemogenetically (hM4Di, an inhibitory DREADD receptor) or optogenetically (iC++, a light-activated chloride channel) silencing the small number of CREB-overexpressing DG neurons attenuated memory expression, whereas silencing a similar number of random neurons not overexpressing CREB at the time of training did not. As post-encoding reactivation of the activity patterns present during initial experience is thought to be important in memory consolidation, we investigated whether post-training silencing of neurons allocated to an engram disrupted subsequent memory expression. We found that silencing neurons 5 min (but not 24 h) following training disrupted memory expression. Together these results indicate that the rules of neuronal allocation to an engram originally described in the lateral amygdala are followed in different brain regions including DG, and moreover, that disrupting the post-training activity pattern of these neurons prevents memory consolidation. PMID:27187069

  12. Neuronal Allocation to a Hippocampal Engram.

    PubMed

    Park, Sungmo; Kramer, Emily E; Mercaldo, Valentina; Rashid, Asim J; Insel, Nathan; Frankland, Paul W; Josselyn, Sheena A

    2016-12-01

    The dentate gyrus (DG) is important for encoding contextual memories, but little is known about how a population of DG neurons comes to encode and support a particular memory. One possibility is that recruitment into an engram depends on a neuron's excitability. Here, we manipulated excitability by overexpressing CREB in a random population of DG neurons and examined whether this biased their recruitment to an engram supporting a contextual fear memory. To directly assess whether neurons overexpressing CREB at the time of training became critical components of the engram, we examined memory expression while the activity of these neurons was silenced. Chemogenetically (hM4Di, an inhibitory DREADD receptor) or optogenetically (iC++, a light-activated chloride channel) silencing the small number of CREB-overexpressing DG neurons attenuated memory expression, whereas silencing a similar number of random neurons not overexpressing CREB at the time of training did not. As post-encoding reactivation of the activity patterns present during initial experience is thought to be important in memory consolidation, we investigated whether post-training silencing of neurons allocated to an engram disrupted subsequent memory expression. We found that silencing neurons 5 min (but not 24 h) following training disrupted memory expression. Together these results indicate that the rules of neuronal allocation to an engram originally described in the lateral amygdala are followed in different brain regions including DG, and moreover, that disrupting the post-training activity pattern of these neurons prevents memory consolidation.

  13. How to make spinal motor neurons.

    PubMed

    Davis-Dusenbery, Brandi N; Williams, Luis A; Klim, Joseph R; Eggan, Kevin

    2014-02-01

    All muscle movements, including breathing, walking, and fine motor skills rely on the function of the spinal motor neuron to transmit signals from the brain to individual muscle groups. Loss of spinal motor neuron function underlies several neurological disorders for which treatment has been hampered by the inability to obtain sufficient quantities of primary motor neurons to perform mechanistic studies or drug screens. Progress towards overcoming this challenge has been achieved through the synthesis of developmental biology paradigms and advances in stem cell and reprogramming technology, which allow the production of motor neurons in vitro. In this Primer, we discuss how the logic of spinal motor neuron development has been applied to allow generation of motor neurons either from pluripotent stem cells by directed differentiation and transcriptional programming, or from somatic cells by direct lineage conversion. Finally, we discuss methods to evaluate the molecular and functional properties of motor neurons generated through each of these techniques.

  14. Large-scale recording of neuronal ensembles.

    PubMed

    Buzsáki, György

    2004-05-01

    How does the brain orchestrate perceptions, thoughts and actions from the spiking activity of its neurons? Early single-neuron recording research treated spike pattern variability as noise that needed to be averaged out to reveal the brain's representation of invariant input. Another view is that variability of spikes is centrally coordinated and that this brain-generated ensemble pattern in cortical structures is itself a potential source of cognition. Large-scale recordings from neuronal ensembles now offer the opportunity to test these competing theoretical frameworks. Currently, wire and micro-machined silicon electrode arrays can record from large numbers of neurons and monitor local neural circuits at work. Achieving the full potential of massively parallel neuronal recordings, however, will require further development of the neuron-electrode interface, automated and efficient spike-sorting algorithms for effective isolation and identification of single neurons, and new mathematical insights for the analysis of network properties.

  15. Mirror neurons and motor intentionality.

    PubMed

    Rizzolatti, Giacomo; Sinigaglia, Corrado

    2007-01-01

    Our social life rests to a large extent on our ability to understand the intentions of others. What are the bases of this ability? A very influential view is that we understand the intentions of others because we are able to represent them as having mental states. Without this meta-representational (mind-reading) ability their behavior would be meaningless to us. Over the past few years this view has been challenged by neurophysiological findings and, in particular, by the discovery of mirror neurons. The functional properties of these neurons indicate that intentional understanding is based primarily on a mechanism that directly matches the sensory representation of the observed actions with one's own motor representation of those same actions. These findings reveal how deeply motor and intentional components of action are intertwined, suggesting that both can be fully comprehended only starting from a motor approach to intentionality.

  16. Neuronal network models of epileptogenesis

    PubMed Central

    Abdullahi, Aminu T.; Adamu, Lawan H.

    2017-01-01

    Epilepsy is a chronic neurological condition, following some trigger, transforming a normal brain to one that produces recurrent unprovoked seizures. In the search for the mechanisms that best explain the epileptogenic process, there is a growing body of evidence suggesting that the epilepsies are network level disorders. In this review, we briefly describe the concept of neuronal networks and highlight 2 methods used to analyse such networks. The first method, graph theory, is used to describe general characteristics of a network to facilitate comparison between normal and abnormal networks. The second, dynamic causal modelling, is useful in the analysis of the pathways of seizure spread. We concluded that the end results of the epileptogenic process are best understood as abnormalities of neuronal circuitry and not simply as molecular or cellular abnormalities. The network approach promises to generate new understanding and more targeted treatment of epilepsy. PMID:28416779

  17. 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

  18. Unbalanced neuronal circuits in addiction.

    PubMed

    Volkow, Nora D; Wang, Gen-Jack; Tomasi, Dardo; Baler, Ruben D

    2013-08-01

    Through sequential waves of drug-induced neurochemical stimulation, addiction co-opts the brain's neuronal circuits that mediate reward, motivation to behavioral inflexibility and a severe disruption of self-control and compulsive drug intake. Brain imaging technologies have allowed neuroscientists to map out the neural landscape of addiction in the human brain and to understand how drugs modify it. Published by Elsevier Ltd.

  19. DNA Damage Induced Neuronal Death

    DTIC Science & Technology

    1999-10-01

    heterozygous for the DNA repair genes Os-methylguanine methyltransferase (Mgmt), 3-methyladenine DNA glycosylase (Aag) , and xeroderma pigmentosum ...mice by human 06-alkylguanine-DNA alkyltransferase. Science 1993; 259: 219-222. 4. Enokido Y, Inamura N, Araki T, et al: Loss of the xeroderma ... pigmentosum group A gene (XPA) enhances apoptosis of cultured cerebellar neurons induced by UV but not by low-K+ medium. J Neurochem 199; 69: 246-251. 5

  20. Neurochemical phenotypes of cardiorespiratory neurons.

    PubMed

    Pilowsky, Paul M

    2008-12-10

    Interactions between the cardiovascular and respiratory systems have been known for many years but the functional significance of the interactions is still widely debated. Here I discuss the possible role of metabotropic receptors in regulating cardiorespiratory neurons in the brainstem and spinal cord. It is clear that, although much has been discovered, cardiorespiratory regulation is certainly one area that still has a long way to go before its secrets are fully divulged and their function in controlling circulatory and respiratory function is revealed.

  1. Guiding neuronal growth with light

    PubMed Central

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

    2002-01-01

    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. PMID:12456879

  2. 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

  3. Neuronal Responses to Physiological Stress

    PubMed Central

    Kagias, Konstantinos; Nehammer, Camilla; Pocock, Roger

    2012-01-01

    Physiological stress can be defined as any external or internal condition that challenges the homeostasis of a cell or an organism. It can be divided into three different aspects: environmental stress, intrinsic developmental stress, and aging. Throughout life all living organisms are challenged by changes in the environment. Fluctuations in oxygen levels, temperature, and redox state for example, trigger molecular events that enable an organism to adapt, survive, and reproduce. In addition to external stressors, organisms experience stress associated with morphogenesis and changes in inner chemistry during normal development. For example, conditions such as intrinsic hypoxia and oxidative stress, due to an increase in tissue mass, have to be confronted by developing embryos in order to complete their development. Finally, organisms face the challenge of stochastic accumulation of molecular damage during aging that results in decline and eventual death. Studies have shown that the nervous system plays a pivotal role in responding to stress. Neurons not only receive and process information from the environment but also actively respond to various stresses to promote survival. These responses include changes in the expression of molecules such as transcription factors and microRNAs that regulate stress resistance and adaptation. Moreover, both intrinsic and extrinsic stresses have a tremendous impact on neuronal development and maintenance with implications in many diseases. Here, we review the responses of neurons to various physiological stressors at the molecular and cellular level. PMID:23112806

  4. Results on a binding neuron model and their implications for modified hourglass model for neuronal network.

    PubMed

    Arunachalam, Viswanathan; Akhavan-Tabatabaei, Raha; Lopez, Cristina

    2013-01-01

    The classical models of single neuron like Hodgkin-Huxley point neuron or leaky integrate and fire neuron assume the influence of postsynaptic potentials to last till the neuron fires. Vidybida (2008) in a refreshing departure has proposed models for binding neurons in which the trace of an input is remembered only for a finite fixed period of time after which it is forgotten. The binding neurons conform to the behaviour of real neurons and are applicable in constructing fast recurrent networks for computer modeling. This paper develops explicitly several useful results for a binding neuron like the firing time distribution and other statistical characteristics. We also discuss the applicability of the developed results in constructing a modified hourglass network model in which there are interconnected neurons with excitatory as well as inhibitory inputs. Limited simulation results of the hourglass network are presented.

  5. Single-cell axotomy of cultured hippocampal neurons integrated in neuronal circuits.

    PubMed

    Gomis-Rüth, Susana; Stiess, Michael; Wierenga, Corette J; Meyn, Liane; Bradke, Frank

    2014-05-01

    An understanding of the molecular mechanisms of axon regeneration after injury is key for the development of potential therapies. Single-cell axotomy of dissociated neurons enables the study of the intrinsic regenerative capacities of injured axons. This protocol describes how to perform single-cell axotomy on dissociated hippocampal neurons containing synapses. Furthermore, to axotomize hippocampal neurons integrated in neuronal circuits, we describe how to set up coculture with a few fluorescently labeled neurons. This approach allows axotomy of single cells in a complex neuronal network and the observation of morphological and molecular changes during axon regeneration. Thus, single-cell axotomy of mature neurons is a valuable tool for gaining insights into cell intrinsic axon regeneration and the plasticity of neuronal polarity of mature neurons. Dissociation of the hippocampus and plating of hippocampal neurons takes ∼2 h. Neurons are then left to grow for 2 weeks, during which time they integrate into neuronal circuits. Subsequent axotomy takes 10 min per neuron and further imaging takes 10 min per neuron.

  6. DeepNeuron: an open deep learning toolbox for neuron tracing.

    PubMed

    Zhou, Zhi; Kuo, Hsien-Chi; Peng, Hanchuan; Long, Fuhui

    2018-06-06

    Reconstructing three-dimensional (3D) morphology of neurons is essential for understanding brain structures and functions. Over the past decades, a number of neuron tracing tools including manual, semiautomatic, and fully automatic approaches have been developed to extract and analyze 3D neuronal structures. Nevertheless, most of them were developed based on coding certain rules to extract and connect structural components of a neuron, showing limited performance on complicated neuron morphology. Recently, deep learning outperforms many other machine learning methods in a wide range of image analysis and computer vision tasks. Here we developed a new Open Source toolbox, DeepNeuron, which uses deep learning networks to learn features and rules from data and trace neuron morphology in light microscopy images. DeepNeuron provides a family of modules to solve basic yet challenging problems in neuron tracing. These problems include but not limited to: (1) detecting neuron signal under different image conditions, (2) connecting neuronal signals into tree(s), (3) pruning and refining tree morphology, (4) quantifying the quality of morphology, and (5) classifying dendrites and axons in real time. We have tested DeepNeuron using light microscopy images including bright-field and confocal images of human and mouse brain, on which DeepNeuron demonstrates robustness and accuracy in neuron tracing.

  7. Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans

    PubMed Central

    Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Mód, László; Szocsics, Péter; Silva, Afonso C.; Maglóczky, Zsófia; Morales, Marisela

    2016-01-01

    The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease. PMID:27477243

  8. Neuronal Differentiation Modulated by Polymeric Membrane Properties.

    PubMed

    Morelli, Sabrina; Piscioneri, Antonella; Drioli, Enrico; De Bartolo, Loredana

    2017-01-01

    In this study, different collagen-blend membranes were successfully constructed by blending collagen with chitosan (CHT) or poly(lactic-co-glycolic acid) (PLGA) to enhance their properties and thus create new biofunctional materials with great potential use for neuronal tissue engineering and regeneration. Collagen blending strongly affected membrane properties in the following ways: (i) it improved the surface hydrophilicity of both pure CHT and PLGA membranes, (ii) it reduced the stiffness of CHT membranes, but (iii) it did not modify the good mechanical properties of PLGA membranes. Then, we investigated the effect of the different collagen concentrations on the neuronal behavior of the membranes developed. Morphological observations, immunocytochemistry, and morphometric measures demonstrated that the membranes developed, especially CHT/Col30, PLGA, and PLGA/Col1, provided suitable microenvironments for neuronal growth owing to their enhanced properties. The most consistent neuronal differentiation was obtained in neurons cultured on PLGA-based membranes, where a well-developed neuronal network was achieved due to their improved mechanical properties. Our findings suggest that tensile strength and elongation at break are key material parameters that have potential influence on both axonal elongation and neuronal structure and organization, which are of fundamental importance for the maintenance of efficient neuronal growth. Hence, our study has provided new insights regarding the effects of membrane mechanical properties on neuronal behavior, and thus it may help to design and improve novel instructive biomaterials for neuronal tissue engineering. © 2017 S. Karger AG, Basel.

  9. Optimization Methods for Spiking Neurons and Networks

    PubMed Central

    Russell, Alexander; Orchard, Garrick; Dong, Yi; Mihalaş, Ştefan; Niebur, Ernst; Tapson, Jonathan; Etienne-Cummings, Ralph

    2011-01-01

    Spiking neurons and spiking neural circuits are finding uses in a multitude of tasks such as robotic locomotion control, neuroprosthetics, visual sensory processing, and audition. The desired neural output is achieved through the use of complex neuron models, or by combining multiple simple neurons into a network. In either case, a means for configuring the neuron or neural circuit is required. Manual manipulation of parameters is both time consuming and non-intuitive due to the nonlinear relationship between parameters and the neuron’s output. The complexity rises even further as the neurons are networked and the systems often become mathematically intractable. In large circuits, the desired behavior and timing of action potential trains may be known but the timing of the individual action potentials is unknown and unimportant, whereas in single neuron systems the timing of individual action potentials is critical. In this paper, we automate the process of finding parameters. To configure a single neuron we derive a maximum likelihood method for configuring a neuron model, specifically the Mihalas–Niebur Neuron. Similarly, to configure neural circuits, we show how we use genetic algorithms (GAs) to configure parameters for a network of simple integrate and fire with adaptation neurons. The GA approach is demonstrated both in software simulation and hardware implementation on a reconfigurable custom very large scale integration chip. PMID:20959265

  10. Synaptic Circuit Organization of Motor Corticothalamic Neurons

    PubMed Central

    Yamawaki, Naoki

    2015-01-01

    Corticothalamic (CT) neurons in layer 6 constitute a large but enigmatic class of cortical projection neurons. How they are integrated into intracortical and thalamo-cortico-thalamic circuits is incompletely understood, especially outside of sensory cortex. Here, we investigated CT circuits in mouse forelimb motor cortex (M1) using multiple circuit-analysis methods. Stimulating and recording from CT, intratelencephalic (IT), and pyramidal tract (PT) projection neurons, we found strong CT↔ CT and CT↔ IT connections; however, CT→IT connections were limited to IT neurons in layer 6, not 5B. There was strikingly little CT↔ PT excitatory connectivity. Disynaptic inhibition systematically accompanied excitation in these pathways, scaling with the amplitude of excitation according to both presynaptic (class-specific) and postsynaptic (cell-by-cell) factors. In particular, CT neurons evoked proportionally more inhibition relative to excitation (I/E ratio) than IT neurons. Furthermore, the amplitude of inhibition was tuned to match the amount of excitation at the level of individual neurons; in the extreme, neurons receiving no excitation received no inhibition either. Extending these studies to dissect the connectivity between cortex and thalamus, we found that M1-CT neurons and thalamocortical neurons in the ventrolateral (VL) nucleus were remarkably unconnected in either direction. Instead, VL axons in the cortex excited both IT and PT neurons, and CT axons in the thalamus excited other thalamic neurons, including those in the posterior nucleus, which additionally received PT excitation. These findings, which contrast in several ways with previous observations in sensory areas, illuminate the basic circuit organization of CT neurons within M1 and between M1 and thalamus. PMID:25653383

  11. The balance between the pro-inflammatory effect of plasma noradrenaline and the anti-inflammatory effect of neuronal noradrenaline determines the peripheral effects of noradrenaline.

    PubMed

    Crotty, T P

    2015-11-01

    Experiments on canine lateral saphenous vein segments have shown that noradrenaline causes potent, flow dependent effects, at a threshold concentration comparable to that of plasma noradrenaline, when it stimulates a segment by diffusion from its microcirculation (vasa vasorum). The effects it causes contrast with those neuronal noradrenaline causes in vivo and that, in the light of the principle that all information is transmitted in patterns that need contrast to be detected - star patterns need darkness, sound patterns, quietness - has generated the hypothesis that plasma noradrenaline provides the obligatory contrast tissues need to detect and respond to the regulatory information encrypted in the diffusion pattern of neuronal noradrenaline. Based on the implications of that hypothesis, the controlled variable of the peripheral noradrenergic system is believed to be the maintenance of a set point balance between the contrasting effects of plasma and neuronal noradrenaline on a tissue. The hypothalamic sympathetic centres are believed to monitor that balance through the level of afferent sympathetic traffic they receive from a tissue and to correct any deviation it detects in the balance by adjusting the level of efferent sympathetic input it projects to the tissue. The failure of the centres to maintain the correct balance is believed to be responsible for inflammatory and genetic disorders. When the failure causes the balance to be polarised in favour of the effect of plasma noradrenaline that is believed to cause inflammatory diseases like dilator cardiac failure, renal hypertension, varicose veins and aneurysms; when it causes it to be polarised in favour of the effect of neuronal noradrenaline that is believed to cause genetic diseases like hypertrophic cardiopathy, pulmonary hypertension and stenoses and when, in pregnancy, a factor causes the polarity to favour plasma noradrenaline in all the maternal tissues except the uterus and conceptus, where it

  12. Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats.

    PubMed

    Li, Ai-Jun; Wang, Qing; Elsarelli, Megan M; Brown, R Lane; Ritter, Sue

    2015-08-01

    Hindbrain catecholamine neurons are required for elicitation of feeding responses to glucose deficit, but the forebrain circuitry required for these responses is incompletely understood. Here we examined interactions of catecholamine and orexin neurons in eliciting glucoprivic feeding. Orexin neurons, located in the perifornical lateral hypothalamus (PeFLH), are heavily innervated by hindbrain catecholamine neurons, stimulate food intake, and increase arousal and behavioral activation. Orexin neurons may therefore contribute importantly to appetitive responses, such as food seeking, during glucoprivation. Retrograde tracing results showed that nearly all innervation of the PeFLH from the hindbrain originated from catecholamine neurons and some raphe nuclei. Results also suggested that many catecholamine neurons project collaterally to the PeFLH and paraventricular hypothalamic nucleus. Systemic administration of the antiglycolytic agent, 2-deoxy-D-glucose, increased food intake and c-Fos expression in orexin neurons. Both responses were eliminated by a lesion of catecholamine neurons innervating orexin neurons using the retrogradely transported immunotoxin, anti-dopamine-β-hydroxylase saporin, which is specifically internalized by dopamine-β-hydroxylase-expressing catecholamine neurons. Using designer receptors exclusively activated by designer drugs in transgenic rats expressing Cre recombinase under the control of tyrosine hydroxylase promoter, catecholamine neurons in cell groups A1 and C1 of the ventrolateral medulla were activated selectively by peripheral injection of clozapine-N-oxide. Clozapine-N-oxide injection increased food intake and c-Fos expression in PeFLH orexin neurons as well as in paraventricular hypothalamic nucleus neurons. In summary, catecholamine neurons are required for the activation of orexin neurons during glucoprivation. Activation of orexin neurons may contribute to appetitive responses required for glucoprivic feeding.

  13. Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro

    PubMed Central

    Perez-Alcazar, Marta; Culley, Georgia; Lyckenvik, Tim; Mobarrez, Kristoffer; Bjorefeldt, Andreas; Wasling, Pontus; Seth, Henrik; Asztely, Frederik; Harrer, Andrea; Iglseder, Bernhard; Aigner, Ludwig; Hanse, Eric; Illes, Sebastian

    2016-01-01

    For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling. PMID:26973467

  14. 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.

  15. 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

  16. C. elegans model of neuronal aging

    PubMed Central

    Peng, Chiu-Ying; Chen, Chun-Hao; Hsu, Jiun-Min

    2011-01-01

    Aging of the nervous system underlies the behavioral and cognitive decline associated with senescence. Understanding the molecular and cellular basis of neuronal aging will therefore contribute to the development of effective treatments for aging and age-associated neurodegenerative disorders. Despite this pressing need, there are surprisingly few animal models that aim at recapitulating neuronal aging in a physiological context. We recently developed a C. elegans model of neuronal aging, and showed that age-dependent neuronal defects are regulated by insulin signaling. We identified electrical activity and epithelial attachment as two critical factors in the maintenance of structural integrity of C. elegans touch receptor neurons. These findings open a new avenue for elucidating the molecular mechanisms that maintain neuronal structures during the course of aging. PMID:22446530

  17. 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).

  18. 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

  19. New Insights into Microglia-Neuron Interactions: A Neuron's Perspective.

    PubMed

    Pósfai, Balázs; Cserép, Csaba; Orsolits, Barbara; Dénes, Ádám

    2018-05-19

    Microglia are the primary immune cells of the central nervous system. However, recent data indicate that microglia also contribute to diverse physiological and pathophysiological processes that extend beyond immune-related functions and there is a growing interest to understand the mechanisms through which microglia interact with other cells in the brain. In particular, the molecular processes that contribute to microglia-neuron communication in the healthy brain and their role in common brain diseases have been intensively studied during the last decade. In line with this, fate-mapping studies, genetic models and novel pharmacological approaches have revealed the origin of microglial progenitors, demonstrated the role of self-maintaining microglial populations during brain development or in adulthood, and identified the unexpectedly long lifespan of microglia that may profoundly change our view about senescence and age-related human diseases. Despite the exponentially increasing knowledge about microglia, the role of these cells in health and disease is still extremely controversial and the precise molecular targets for intervention are not well defined. This is in part due to the lack of microglia-specific manipulation approaches until very recently and to the high level of complexity of the interactions between microglia and other cells in the brain that occur at different temporal and spatial scales. In this review, we briefly summarize the known physiological roles of microglia-neuron interactions in brain homeostasis and attempt to outline some major directions and challenges of future microglia research. Copyright © 2018. Published by Elsevier Ltd.

  20. 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

  1. Shockwaves Cause Synaptic Degeneration in Cultured Neurons

    DTIC Science & Technology

    2009-11-02

    constructed of delrin. A piezoresistive pressure sensor (Endevco Model 8530C) was mounted flush with the plate, coaxial with the center of the gene gun ...biolostic gene gun to deliver shockwaves to cultured hippocampal or cortical neurons. These cultured cells form abundant synapses in vitro, and after a 24-48...neurons, we used a biolostic gene gun to deliver shockwaves to cultured hippocampal or cortical neurons. These cultured cells form abundant synapses in

  2. Spike timing precision of neuronal circuits.

    PubMed

    Kilinc, Deniz; Demir, Alper

    2018-06-01

    Spike timing is believed to be a key factor in sensory information encoding and computations performed by the neurons and neuronal circuits. However, the considerable noise and variability, arising from the inherently stochastic mechanisms that exist in the neurons and the synapses, degrade spike timing precision. Computational modeling can help decipher the mechanisms utilized by the neuronal circuits in order to regulate timing precision. In this paper, we utilize semi-analytical techniques, which were adapted from previously developed methods for electronic circuits, for the stochastic characterization of neuronal circuits. These techniques, which are orders of magnitude faster than traditional Monte Carlo type simulations, can be used to directly compute the spike timing jitter variance, power spectral densities, correlation functions, and other stochastic characterizations of neuronal circuit operation. We consider three distinct neuronal circuit motifs: Feedback inhibition, synaptic integration, and synaptic coupling. First, we show that both the spike timing precision and the energy efficiency of a spiking neuron are improved with feedback inhibition. We unveil the underlying mechanism through which this is achieved. Then, we demonstrate that a neuron can improve on the timing precision of its synaptic inputs, coming from multiple sources, via synaptic integration: The phase of the output spikes of the integrator neuron has the same variance as that of the sample average of the phases of its inputs. Finally, we reveal that weak synaptic coupling among neurons, in a fully connected network, enables them to behave like a single neuron with a larger membrane area, resulting in an improvement in the timing precision through cooperation.

  3. Design of memristive interface between electronic neurons

    NASA Astrophysics Data System (ADS)

    Gerasimova, S. A.; Mikhaylov, A. N.; Belov, A. I.; Korolev, D. S.; Guseinov, D. V.; Lebedeva, A. V.; Gorshkov, O. N.; Kazantsev, V. B.

    2018-05-01

    Nonlinear dynamics of two electronic oscillators coupled via a memristive device has been investigated. Such model mimics the interaction between synaptically coupled brain neurons with the memristive device imitating neuron axon. The synaptic connection is provided by the adaptive behavior of memristive device that changes its resistance under the action of spike-like activity. Mathematical model of such a memristive interface has been developed to describe and predict the experimentally observed regularities of forced synchronization of neuron-like oscillators.

  4. Optimization of Neuronal-Computer Interface

    DTIC Science & Technology

    2009-06-23

    for the inhibitory neurotransmitter gamma-aminobutyric acid ( GABA ) receptor subunit as a general marker of inhibitory neurons (Beck et al., 1993...These analyses confirmed the presence of GABA -positive neurons (Fig. 4). Fig 4: Cultures contain inhibitory neurons. Cultures were subjected to double...immunofluorescent analyses for neurofilaments (anti-NF) using monoclonal antibody SMI-32 and a polyclonal antibody directed against the GABA receptor

  5. Acute lower motor neuron tetraparesis.

    PubMed

    Añor, Sònia

    2014-11-01

    Flaccid nonambulatory tetraparesis or tetraplegia is an infrequent neurologic presentation; it is characteristic of neuromuscular disease (lower motor neuron [LMN] disease) rather than spinal cord disease. Paresis beginning in the pelvic limbs and progressing to the thoracic limbs resulting in flaccid tetraparesis or tetraplegia within 24 to 72 hours is a common presentation of peripheral nerve or neuromuscular junction disease. Complete body flaccidity develops with severe decrease or complete loss of spinal reflexes in pelvic and thoracic limbs. Animals with acute generalized LMN tetraparesis commonly show severe motor dysfunction in all limbs and severe generalized weakness in all muscles. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. Nrf2 promotes neuronal cell differentiation.

    PubMed

    Zhao, Fei; Wu, Tongde; Lau, Alexandria; Jiang, Tao; Huang, Zheping; Wang, Xiao-Jun; Chen, Weimin; Wong, Pak Kin; Zhang, Donna D

    2009-09-15

    The transcription factor Nrf2 has emerged as a master regulator of the endogenous antioxidant response, which is critical in defending cells against environmental insults and in maintaining intracellular redox balance. However, whether Nrf2 has any role in neuronal cell differentiation is largely unknown. In this report, we have examined the effects of Nrf2 on cell differentiation using a neuroblastoma cell line, SH-SY5Y. Retinoic acid (RA) and 12-O-tetradecanoylphorbol 13-acetate, two well-studied inducers of neuronal differentiation, are able to induce Nrf2 and its target gene NAD(P)H quinone oxidoreductase 1 in a dose- and time-dependent manner. RA-induced Nrf2 up-regulation is accompanied by neurite outgrowth and an induction of two neuronal differentiation markers, neurofilament-M and microtubule-associated protein 2. Overexpression of Nrf2 in SH-SY5Y cells promotes neuronal differentiation, whereas inhibition of endogenous Nrf2 expression inhibited neuronal differentiation. More remarkably, the positive role of Nrf2 in neuronal differentiation was verified ex vivo in primary neuron culture. Primary neurons isolated from Nrf2-null mice showed a retarded progress in differentiation, compared to those from wild-type mice. Collectively, our data demonstrate a novel role for Nrf2 in promoting neuronal cell differentiation, which will open new perspectives for therapeutic uses of Nrf2 activators in patients with neurodegenerative diseases.

  11. Beyond Critical Exponents in Neuronal Avalanches

    NASA Astrophysics Data System (ADS)

    Friedman, Nir; Butler, Tom; Deville, Robert; Beggs, John; Dahmen, Karin

    2011-03-01

    Neurons form a complex network in the brain, where they interact with one another by firing electrical signals. Neurons firing can trigger other neurons to fire, potentially causing avalanches of activity in the network. In many cases these avalanches have been found to be scale independent, similar to critical phenomena in diverse systems such as magnets and earthquakes. We discuss models for neuronal activity that allow for the extraction of testable, statistical predictions. We compare these models to experimental results, and go beyond critical exponents.

  12. Neurochemistry of olivocochlear neurons in the hamster.

    PubMed

    Reuss, Stefan; Disque-Kaiser, Ursula; Antoniou-Lipfert, Patricia; Gholi, Maryam Najaf; Riemann, Elke; Riemann, Randolf

    2009-04-01

    The present study was conducted to characterize the superior olivary complex (SOC) of the lower brain stem in the pigmented Djungarian hamster Phodopus sungorus. Using Nissl-stained serial cryostat sections from fresh-frozen brains, we determined the borders of the SOC nuclei. We also identified olivocochlear (OC) neurons by retrograde neuronal tracing upon injection of Fluoro-Gold into the scala tympani. To evaluate the SOC as a putative source of neuronal nitric oxide synthase (nNOS), arginine-vasopressin (AVP), oxytocin (OT), vasoactive intestinal polypeptide (VIP), or pituitary adenylate cyclase-activating polypeptide (PACAP) that were all found in the cochlea, we conducted immunohistochemistry on sections exhibiting retrogradely labeled neurons. We did not observe AVP-, OT-, or VIP-immunoreactivity, neither in OC neurons nor in the SOC at all, revealing that cochlear AVP, OT, and VIP are of nonolivary origin. However, we found nNOS, the enzyme responsible for nitric oxide synthesis in neurons, and PACAP in neuronal perikarya of the SOC. Retrogradely labeled neurons of the lateral olivocochlear (LOC) system in the lateral superior olive did not contain PACAP and were only infrequently nNOS-immunoreactive. In contrast, some shell neurons and some of the medial OC (MOC) system exhibited immunofluorescence for either substance. Our data obtained from the dwarf hamster Phodopus sungorus confirm previous observations that a part of the LOC system is nitrergic. They further demonstrate that the medial olivocochlear system is partly nitrergic and use PACAP as neurotransmitter or modulator.

  13. 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

  14. Life-long stability of neurons: a century of research on neurogenesis, neuronal death and neuron quantification in adult CNS.

    PubMed

    Turlejski, Kris; Djavadian, Ruzanna

    2002-01-01

    In this chapter we provide an extensive review of 100 years of research on the stability of neurons in the mammalian brain, with special emphasis on humans. Although Cajal formulated the Neuronal Doctrine, he was wrong in his beliefs that adult neurogenesis did not occur and adult neurons are dying throughout life. These two beliefs became accepted "common knowledge" and have shaped much of neuroscience research and provided much of the basis for clinical treatment of age-related brain diseases. In this review, we consider adult neurogenesis from a historical and evolutionary perspective. It is concluded, that while adult neurogenesis is a factor in the dynamics of the dentate gyrus and olfactory bulb, it is probably not a major factor during the life-span in most brain areas. Likewise, the acceptance of neuronal death as an explanation for normal age-related senility is challenged with evidence collected over the last fifty years. Much of the problem in changing this common belief of dying neurons was the inadequacies of neuronal counting methods. In this review we discuss in detail implications of recent improvements in neuronal quantification. We conclude: First, age-related neuronal atrophy is the major factor in functional deterioration of existing neurons and could be slowed down, or even reversed by various pharmacological interventions. Second, in most cases neuronal degeneration during aging is a pathology that in principle may be avoided. Third, loss of myelin and of the white matter is more frequent and important than the limited neuronal death in normal aging.

  15. 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

  16. A low cost, modular, and physiologically inspired electronic neuron

    NASA Astrophysics Data System (ADS)

    Sitt, J. D.; Campetella, F.; Aliaga, J.

    2010-12-01

    We describe a low cost design of an electronic neuron, which is designed to represent the dynamical properties of the membrane potential of biological neurons by modeling the states of the membrane channels. This electronic neuron can be used to study the nonlinear properties of the membrane voltage dynamics and to develop and analyze small neuronal circuits using electronic neurons as building blocks.

  17. 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.

  18. 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.

  19. 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.

  20. Functional Interactions between Newborn and Mature Neurons Leading to Integration into Established Neuronal Circuits.

    PubMed

    Boulanger-Weill, Jonathan; Candat, Virginie; Jouary, Adrien; Romano, Sebastián A; Pérez-Schuster, Verónica; Sumbre, Germán

    2017-06-19

    From development up to adulthood, the vertebrate brain is continuously supplied with newborn neurons that integrate into established mature circuits. However, how this process is coordinated during development remains unclear. Using two-photon imaging, GCaMP5 transgenic zebrafish larvae, and sparse electroporation in the larva's optic tectum, we monitored spontaneous and induced activity of large neuronal populations containing newborn and functionally mature neurons. We observed that the maturation of newborn neurons is a 4-day process. Initially, newborn neurons showed undeveloped dendritic arbors, no neurotransmitter identity, and were unresponsive to visual stimulation, although they displayed spontaneous calcium transients. Later on, newborn-labeled neurons began to respond to visual stimuli but in a very variable manner. At the end of the maturation period, newborn-labeled neurons exhibited visual tuning curves (spatial receptive fields and direction selectivity) and spontaneous correlated activity with neighboring functionally mature neurons. At this developmental stage, newborn-labeled neurons presented complex dendritic arbors and neurotransmitter identity (excitatory or inhibitory). Removal of retinal inputs significantly perturbed the integration of newborn neurons into the functionally mature tectal network. Our results provide a comprehensive description of the maturation of newborn neurons during development and shed light on potential mechanisms underlying their integration into a functionally mature neuronal circuit. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  1. 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.

  2. [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.

  3. 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

  4. 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.

  5. 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.

  6. Increase of histaminergic tuberomammillary neurons in narcolepsy.

    PubMed

    Valko, Philipp O; Gavrilov, Yury V; Yamamoto, Mihoko; Reddy, Hasini; Haybaeck, Johannes; Mignot, Emmanuel; Baumann, Christian R; Scammell, Thomas E

    2013-12-01

    Narcolepsy is caused by loss of the hypothalamic neurons producing the orexin/hypocretin neuropeptides. One key target of the orexin system is the histaminergic neurons of the tuberomammillary nucleus (TMN), an essential wake-promoting system. As cerebrospinal fluid histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in 2 mouse models of narcolepsy. We counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone, and histamine in 7 narcolepsy patients and 12 control subjects using stereological techniques. We identified histaminergic neurons using immunostaining for histidine decarboxylase. We also examined these systems in 6 wild-type mice, 6 orexin/ataxin-3 transgenic mice, and 5 orexin ligand knockout mice. Compared to controls, narcolepsy patients had 94% more histaminergic TMN neurons (233,572 ± 49,476 vs 120,455 ± 10,665, p < 0.001). This increase was higher in 5 narcolepsy patients with >90% orexin neuron loss than in 2 patients with ≤75% orexin neuron loss (252,279 ± 46,264 vs 186,804 ± 1,256, p = 0.03). Similarly, the number of histaminergic TMN neurons was increased 53% in orexin ligand knockout mice compared to wild-type mice, whereas orexin/ataxin-3 transgenic mice showed an intermediate 28% increase. This surprising increase in histaminergic neurons in narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons and may contribute to some of the symptoms of narcolepsy such as preserved consciousness during cataplexy and fragmented nighttime sleep. In addition, this finding may have therapeutic implications, as medications that enhance histamine signaling are now under development. © 2013 American Neurological Association.

  7. 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

  8. 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

  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. 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

  11. 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…

  12. 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.

  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. Where do mirror neurons come from?

    PubMed

    Heyes, Cecilia

    2010-03-01

    Debates about the evolution of the 'mirror neuron system' imply that it is an adaptation for action understanding. Alternatively, mirror neurons may be a byproduct of associative learning. Here I argue that the adaptation and associative hypotheses both offer plausible accounts of the origin of mirror neurons, but the associative hypothesis has three advantages. First, it provides a straightforward, testable explanation for the differences between monkeys and humans that have led some researchers to question the existence of a mirror neuron system. Second, it is consistent with emerging evidence that mirror neurons contribute to a range of social cognitive functions, but do not play a dominant, specialised role in action understanding. Finally, the associative hypothesis is supported by recent data showing that, even in adulthood, the mirror neuron system can be transformed by sensorimotor learning. The associative account implies that mirror neurons come from sensorimotor experience, and that much of this experience is obtained through interaction with others. Therefore, if the associative account is correct, the mirror neuron system is a product, as well as a process, of social interaction. (c) 2009 Elsevier Ltd. All rights reserved.

  15. IGF-1: elixir for motor neuron diseases.

    PubMed

    Papanikolaou, Theodora; Ellerby, Lisa M

    2009-08-13

    Modulation of testosterone levels is a therapeutic approach for spinal and bulbar muscular atrophy (SBMA), a polyglutamine disorder that affects the motor neurons. The article by Palazzolo et al. in this issue of Neuron provides compelling evidence that the expression of insulin growth hormone is a potential therapeutic for SBMA.

  16. Calcium Phosphate Transfection of Primary Hippocampal Neurons

    PubMed Central

    DiBona, Victoria L.; Wu, Qian; Zhang, Huaye

    2013-01-01

    Calcium phosphate precipitation is a convenient and economical method for transfection of cultured cells. With optimization, it is possible to use this method on hard-to-transfect cells like primary neurons. Here we describe our detailed protocol for calcium phosphate transfection of hippocampal neurons cocultured with astroglial cells. PMID:24300106

  17. Calcium phosphate transfection of primary hippocampal neurons.

    PubMed

    Sun, Miao; Bernard, Laura P; Dibona, Victoria L; Wu, Qian; Zhang, Huaye

    2013-11-12

    Calcium phosphate precipitation is a convenient and economical method for transfection of cultured cells. With optimization, it is possible to use this method on hard-to-transfect cells like primary neurons. Here we describe our detailed protocol for calcium phosphate transfection of hippocampal neurons cocultured with astroglial cells.

  18. 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

  19. Reflections on mirror neurons and speech perception.

    PubMed

    Lotto, Andrew J; Hickok, Gregory S; Holt, Lori L

    2009-03-01

    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.

  20. 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

  1. 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.

  2. 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.

  3. Mirror Neurons through the Lens of Epigenetics

    PubMed Central

    Ferrari, Pier F.; Tramacere, Antonella; Simpson, Elizabeth A.; Iriki, Atsushi

    2013-01-01

    The consensus view in mirror neuron research is that mirror neurons comprise a uniform, stable execution-observation matching system. In this article, we argue that, in light of recent evidence, this is, at best, an incomplete and oversimplified view of mirror neurons, whose activity is actually quite 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 extant associative and genetic accounts fail to consider the complexity of genetic and non-genetic interactions, we propose a new Evo-Devo perspective, which predicts that environmental differences early in development, or through sensorimotor training, should produce variations in mirror neuron response patterns, tuning them to the social environment. PMID:23953747

  4. Pheromone detection by mammalian vomeronasal neurons.

    PubMed

    Zufall, Frank; Kelliher, Kevin R; Leinders-Zufall, Trese

    2002-08-01

    The vomeronasal organ (VNO) of mammals plays an essential role in the perception of chemical stimuli of social nature including pheromone-like signals but direct evidence for the transduction of pheromones by vomeronasal sensory neurons has been lacking. The recent development of electrophysiological and optical imaging methods using confocal microscopy has enabled researchers to systematically analyze sensory responses in large populations of mouse vomeronasal neurons. These experiments revealed that vomeronasal neurons are surprisingly sensitive and highly discriminative detectors of volatile, urinary metabolites that have pheromonal activity in recipient mice. Functional mapping studies of pheromone receptor activation have uncovered the basic principles of sensory processing by vomeronasal neurons and revealed striking differences in the neural mechanisms by which chemosensory information is detected by receptor neurons in the VNO and the main olfactory epithelium. These advances offer the opportunity to decipher the logic of mammalian pheromonal communication. Copyright 2002 Wiley-Liss, Inc.

  5. Revealing degree distribution of bursting neuron networks.

    PubMed

    Shen, Yu; Hou, Zhonghuai; Xin, Houwen

    2010-03-01

    We present a method to infer the degree distribution of a bursting neuron network from its dynamics. Burst synchronization (BS) of coupled Morris-Lecar neurons has been studied under the weak coupling condition. In the BS state, all the neurons start and end bursting almost simultaneously, while the spikes inside the burst are incoherent among the neurons. Interestingly, we find that the spike amplitude of a given neuron shows an excellent linear relationship with its degree, which makes it possible to estimate the degree distribution of the network by simple statistics of the spike amplitudes. We demonstrate the validity of this scheme on scale-free as well as small-world networks. The underlying mechanism of such a method is also briefly discussed.

  6. Central auditory neurons have composite receptive fields.

    PubMed

    Kozlov, Andrei S; Gentner, Timothy Q

    2016-02-02

    High-level neurons processing complex, behaviorally relevant signals are sensitive to conjunctions of features. Characterizing the receptive fields of such neurons is difficult with standard statistical tools, however, and the principles governing their organization remain poorly understood. Here, we demonstrate multiple distinct receptive-field features in individual high-level auditory neurons in a songbird, European starling, in response to natural vocal signals (songs). We then show that receptive fields with similar characteristics can be reproduced by an unsupervised neural network trained to represent starling songs with a single learning rule that enforces sparseness and divisive normalization. We conclude that central auditory neurons have composite receptive fields that can arise through a combination of sparseness and normalization in neural circuits. Our results, along with descriptions of random, discontinuous receptive fields in the central olfactory neurons in mammals and insects, suggest general principles of neural computation across sensory systems and animal classes.

  7. 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.

  8. Neuronal Vacuolization in Feline Panleukopenia Virus Infection.

    PubMed

    Pfankuche, Vanessa M; Jo, Wendy K; van der Vries, Erhard; Jungwirth, Nicole; Lorenzen, Stephan; Osterhaus, Albert D M E; Baumgärtner, Wolfgang; Puff, Christina

    2018-03-01

    Feline panleukopenia virus (FPV) infections are typically associated with anorexia, vomiting, diarrhea, neutropenia, and lymphopenia. In cases of late prenatal or early neonatal infections, cerebellar hypoplasia is reported in kittens. In addition, single cases of encephalitis are described. FPV replication was recently identified in neurons, although it is mainly found in cells with high mitotic activity. A female cat, 2 months old, was submitted to necropsy after it died with neurologic deficits. Besides typical FPV intestinal tract changes, multifocal, randomly distributed intracytoplasmic vacuoles within neurons of the thoracic spinal cord were found histologically. Next-generation sequencing identified FPV-specific sequences within the central nervous system. FPV antigen was detected within central nervous system cells, including the vacuolated neurons, via immunohistochemistry. In situ hybridization confirmed the presence of FPV DNA within the vacuolated neurons. Thus, FPV should be considered a cause for neuronal vacuolization in cats presenting with ataxia.

  9. 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

  10. A computational model of motor neuron degeneration.

    PubMed

    Le Masson, Gwendal; Przedborski, Serge; Abbott, L F

    2014-08-20

    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. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. 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.

  12. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

    PubMed Central

    Suh, Sang Won; Gum, Elizabeth T.; Hamby, Aaron M.; Chan, Pak H.; Swanson, Raymond A.

    2007-01-01

    Hypoglycemic coma and brain injury are potential complications of insulin therapy. Certain neurons in the hippocampus and cerebral cortex are uniquely vulnerable to hypoglycemic cell death, and oxidative stress is a key event in this cell death process. Here we show that hypoglycemia-induced oxidative stress and neuronal death are attributable primarily to the activation of neuronal NADPH oxidase during glucose reperfusion. Superoxide production and neuronal death were blocked by the NADPH oxidase inhibitor apocynin in both cell culture and in vivo models of insulin-induced hypoglycemia. Superoxide production and neuronal death were also blocked in studies using mice or cultured neurons deficient in the p47phox subunit of NADPH oxidase. Chelation of zinc with calcium disodium EDTA blocked both the assembly of the neuronal NADPH oxidase complex and superoxide production. Inhibition of the hexose monophosphate shunt, which utilizes glucose to regenerate NADPH, also prevented superoxide formation and neuronal death, suggesting a mechanism linking glucose reperfusion to superoxide formation. Moreover, the degree of superoxide production and neuronal death increased with increasing glucose concentrations during the reperfusion period. These results suggest that high blood glucose concentrations following hypoglycemic coma can initiate neuronal death by a mechanism involving extracellular zinc release and activation of neuronal NADPH oxidase. PMID:17404617

  13. Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons

    PubMed Central

    Vong, Linh; Ye, Chianping; Yang, Zongfang; Choi, Brian; Chua, Streamson; Lowell, Bradford B.

    2011-01-01

    SUMMARY Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part due to incomplete knowledge regarding first order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first order neurons. While functionally relevant neurons have been identified, the observed effects have been small suggesting that most first order neurons remain unidentified. Here we take an alternative approach and test whether first order neurons are inhibitory (GABAergic, VGAT+) or excitatory (glutamatergic, VGLUT2+). Remarkably, the vast majority of leptin’s anti-obesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons likely mediates, at least in part, leptin’s anti-obesity effects. PMID:21745644

  14. 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.

  15. Dynamical estimation of neuron and network properties III: network analysis using neuron spike times.

    PubMed

    Knowlton, Chris; Meliza, C Daniel; Margoliash, Daniel; Abarbanel, Henry D I

    2014-06-01

    Estimating the behavior of a network of neurons requires accurate models of the individual neurons along with accurate characterizations of the connections among them. Whereas for a single cell, measurements of the intracellular voltage are technically feasible and sufficient to characterize a useful model of its behavior, making sufficient numbers of simultaneous intracellular measurements to characterize even small networks is infeasible. This paper builds on prior work on single neurons to explore whether knowledge of the time of spiking of neurons in a network, once the nodes (neurons) have been characterized biophysically, can provide enough information to usefully constrain the functional architecture of the network: the existence of synaptic links among neurons and their strength. Using standardized voltage and synaptic gating variable waveforms associated with a spike, we demonstrate that the functional architecture of a small network of model neurons can be established.

  16. The Sensory Neurons of Touch

    PubMed Central

    Abraira, Victoria E.; Ginty, David D.

    2013-01-01

    The somatosensory system decodes a wide range of tactile stimuli and thus endows us with a remarkable capacity for object recognition, texture discrimination, sensory-motor feedback and social exchange. The first step leading to perception of innocuous touch is activation of cutaneous sensory neurons called low-threshold mechanoreceptors (LTMRs). Here, we review the properties and functions of LTMRs, emphasizing the unique tuning properties of LTMR subtypes and the organizational logic of their peripheral and central axonal projections. We discuss the spinal cord neurophysiological representation of complex mechanical forces acting upon the skin and current views of how tactile information is processed and conveyed from the spinal cord to the brain. An integrative model in which ensembles of impulses arising from physiologically distinct LTMRs are integrated and processed in somatotopically aligned mechanosensory columns of the spinal cord dorsal horn underlies the nervous system’s enormous capacity for perceiving the richness of the tactile world. PMID:23972592

  17. 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.

  18. 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

  19. [Synesthesia as a neuronal palimpsest].

    PubMed

    Hupé, Jean-Michel

    2012-01-01

    Synesthetes, a small fraction of the population, experience systematic, additional associations. For example, they may arbitrarily associate a specific color to each letter or number. Synesthesia has offered for the last ten years to cognitive science a unique opportunity to study the neural bases of subjective experience, drawing on individual differences just like in neuropsychology, but with healthy people. Here we review the current knowledge and propose a new theory, the "palimpsest hypothesis", a variant of the recycling hypothesis for reading. The neural development of written language expertise (a recent cultural invention acquired without any genetic modification) requires indeed the recycling of brain regions predisposed to expertise acquisition into reading regions. The palimpsest hypothesis supposes that for synesthetes recycling involves neuronal networks that were already specialized for color perception. Synesthetic colors would be the remains of this former expertise. © 2012 médecine/sciences – Inserm / SRMS.

  20. 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

  1. 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.

  2. Responses of neurons to extreme osmomechanical stress.

    PubMed

    Wan, X; Harris, J A; Morris, C E

    1995-05-01

    Neurons are often regarded as fragile cells, easily destroyed by mechanical and osmotic insult. The results presented here demonstrate that this perception needs revision. Using extreme osmotic swelling, we show that molluscan neurons are astonishingly robust. In distilled water, a heterogeneous population of Lymnaea stagnalis CNS neurons swelled to several times their initial volume, yet had a ST50 (survival time for 50% of cells) > 60 min. Cells that were initially bigger survived longer. On return to normal medium, survivors were able, over the next 24 hr, to rearborize. Reversible membrane capacitance changes corresponding to about 0.7 muF/cm2 of apparent surface area accompanied neuronal swelling and shrinking in hypo- and hyperosmotic solutions; reversible changes in cell surface area evidently contributed to the neurons' ability to accommodate hydrostatic pressures then recover. The reversible membrane area/capacitance changes were not dependent on extracellular Ca2+. Neurons were monitored for potassium currents during direct mechanical inflation and during osmotically driven inflation. The latter but not the former stimulus routinely elicited small potassium currents, suggesting that tension increases activate the currents only if additional disruption of the cortex has occurred. Under stress in distilled water, a third of the neurons displayed a quite unexpected behavior: prolonged writhing of peripheral regions of the soma. This suggested that a plasma membrane-linked contractile machinery (presumably actomyosin) might contribute to the neurons' mechano-osmotic robustness by restricting water influx. Consistent with this possibility, 1 mM N-ethyl-maleimide, which inhibits myosin ATPase, decreased the ST50 to 18 min, rendered the survival time independent of initial size, and abolished writhing activity. For neurons, active mechanical resistance of the submembranous cortex, along with the mechanical compliance supplied by insertion or eversion of membrane

  3. Death of Neurons following Injury Requires Conductive Neuronal Gap Junction Channels but Not a Specific Connexin

    PubMed Central

    Fontes, Joseph D.; Ramsey, Jon; Polk, Jeremy M; Koop, Andre; Denisova, Janna V.; Belousov, Andrei B.

    2015-01-01

    Pharmacological blockade or genetic knockout of neuronal connexin 36 (Cx36)-containing gap junctions reduces neuronal death caused by ischemia, traumatic brain injury and NMDA receptor (NMDAR)-mediated excitotoxicity. However, whether Cx36 gap junctions contribute to neuronal death via channel-dependent or channel-independent mechanism remains an open question. To address this, we manipulated connexin protein expression via lentiviral transduction of mouse neuronal cortical cultures and analyzed neuronal death twenty-four hours following administration of NMDA (a model of NMDAR excitotoxicity) or oxygen-glucose deprivation (a model of ischemic injury). In cultures prepared from wild-type mice, over-expression and knockdown of Cx36-containing gap junctions augmented and prevented, respectively, neuronal death from NMDAR-mediated excitotoxicity and ischemia. In cultures obtained form from Cx36 knockout mice, re-expression of functional gap junction channels, containing either neuronal Cx36 or non-neuronal Cx43 or Cx31, resulted in increased neuronal death following insult. In contrast, the expression of communication-deficient gap junctions (containing mutated connexins) did not have this effect. Finally, the absence of ethidium bromide uptake in non-transduced wild-type neurons two hours following NMDAR excitotoxicity or ischemia suggested the absence of active endogenous hemichannels in those neurons. Taken together, these results suggest a role for neuronal gap junctions in cell death via a connexin type-independent mechanism that likely relies on channel activities of gap junctional complexes among neurons. A possible contribution of gap junction channel-permeable death signals in neuronal death is discussed. PMID:26017008

  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. Cell death cascade and molecular therapy in ADAR2-deficient motor neurons of ALS.

    PubMed

    Yamashita, Takenari; Kwak, Shin

    2018-06-23

    TAR DNA-binding protein (TDP-43) pathology in the motor neurons is the most reliable pathological hallmark of amyotrophic lateral sclerosis (ALS), and motor neurons bearing TDP-43 pathology invariably exhibit failure in RNA editing at the GluA2 glutamine/arginine (Q/R) site due to down-regulation of adenosine deaminase acting on RNA 2 (ADAR2). Conditional ADAR2 knockout (AR2) mice display ALS-like phenotype, including progressive motor dysfunction due to loss of motor neurons. Motor neurons devoid of ADAR2 express Q/R site-unedited GluA2, and AMPA receptors with unedited GluA2 in their subunit assembly are abnormally permeable to Ca 2+ , which results in progressive neuronal death. Moreover, analysis of AR2 mice has demonstrated that exaggerated Ca 2+ influx through the abnormal AMPA receptors overactivates calpain, a Ca 2+ -dependent protease, that cleaves TDP-43 into aggregation-prone fragments, which serve as seeds for TDP-43 pathology. Activated calpain also disrupts nucleo-cytoplasmic transport and gene expression by cleaving molecules involved in nucleocytoplasmic transport, including nucleoporins. These lines of evidence prompted us to develop molecular targeting therapy for ALS by normalization of disrupted intracellular environment due to ADAR2 down-regulation. In this review, we have summarized the work from our group on the cell death cascade in sporadic ALS and discussed a potential therapeutic strategy for ALS. Copyright © 2018 Elsevier Ireland Ltd and the Japan Neuroscience Society. 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. Differentiation-Dependent Energy Production and Metabolite Utilization: A Comparative Study on Neural Stem Cells, Neurons, and Astrocytes

    PubMed Central

    Jády, Attila Gy.; Nagy, Ádám M.; Kőhidi, Tímea; Ferenczi, Szilamér; Tretter, László

    2016-01-01

    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. PMID:27116891

  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. Staufen2 regulates neuronal target RNAs.

    PubMed

    Heraud-Farlow, Jacki E; Sharangdhar, Tejaswini; Li, Xiao; Pfeifer, Philipp; Tauber, Stefanie; Orozco, Denise; Hörmann, Alexandra; Thomas, Sabine; Bakosova, Anetta; Farlow, Ashley R; Edbauer, Dieter; Lipshitz, Howard D; Morris, Quaid D; Bilban, Martin; Doyle, Michael; Kiebler, Michael A

    2013-12-26

    RNA-binding proteins play crucial roles in directing RNA translation to neuronal synapses. Staufen2 (Stau2) has been implicated in both dendritic RNA localization and synaptic plasticity in mammalian neurons. Here, we report the identification of functionally relevant Stau2 target mRNAs in neurons. The majority of Stau2-copurifying mRNAs expressed in the hippocampus are present in neuronal processes, further implicating Stau2 in dendritic mRNA regulation. Stau2 targets are enriched for secondary structures similar to those identified in the 3' UTRs of Drosophila Staufen targets. Next, we show that Stau2 regulates steady-state levels of many neuronal RNAs and that its targets are predominantly downregulated in Stau2-deficient neurons. Detailed analysis confirms that Stau2 stabilizes the expression of one synaptic signaling component, the regulator of G protein signaling 4 (Rgs4) mRNA, via its 3' UTR. This study defines the global impact of Stau2 on mRNAs in neurons, revealing a role in stabilization of the levels of synaptic targets. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Taotie neurons regulate appetite in Drosophila

    PubMed Central

    Zhan, Yin Peng; Liu, Li; Zhu, Yan

    2016-01-01

    The brain has an essential role in maintaining a balance between energy intake and expenditure of the body. Deciphering the processes underlying the decision-making for timely feeding of appropriate amounts may improve our understanding of physiological and psychological disorders related to feeding control. Here, we identify a group of appetite-enhancing neurons in a behavioural screen for flies with increased appetite. Manipulating the activity of these neurons, which we name Taotie neurons, induces bidirectional changes in feeding motivation. Long-term stimulation of Taotie neurons results in flies with highly obese phenotypes. Furthermore, we show that the in vivo activity of Taotie neurons in the neuroendocrine region reflects the hunger/satiety states of un-manipulated animals, and that appetitive-enhancing Taotie neurons control the secretion of insulin, a known regulator of feeding behaviour. Thus, our study reveals a new set of neurons regulating feeding behaviour in the high brain regions that represents physiological hunger states and control feeding behaviour in Drosophila. PMID:27924813

  12. Forced neuronal interactions cause poor communication.

    PubMed

    Krzisch, Marine; Toni, Nicolas

    2017-01-01

    Post-natal hippocampal neurogenesis plays a role in hippocampal function, and neurons born post-natally participate to spatial memory and mood control. However, a great proportion of granule neurons generated in the post-natal hippocampus are eliminated during the first 3 weeks of their maturation, a mechanism that depends on their synaptic integration. In a recent study, we examined the possibility of enhancing the synaptic integration of neurons born post-natally, by specifically overexpressing synaptic cell adhesion molecules in these cells. Synaptic cell adhesion molecules are transmembrane proteins mediating the physical connection between pre- and post-synaptic neurons at the synapse, and their overexpression enhances synapse formation. Accordingly, we found that overexpressing synaptic adhesion molecules increased the synaptic integration and survival of newborn neurons. Surprisingly, the synaptic adhesion molecule with the strongest effect on new neurons' survival, Neuroligin-2A, decreased memory performances in a water maze task. We present here hypotheses explaining these surprising results, in the light of the current knowledge of the mechanisms of synaptic integration of new neurons in the post-natal hippocampus.

  13. Stochastic multiresonance in coupled excitable FHN neurons

    NASA Astrophysics Data System (ADS)

    Li, Huiyan; Sun, Xiaojuan; Xiao, Jinghua

    2018-04-01

    In this paper, effects of noise on Watts-Strogatz small-world neuronal networks, which are stimulated by a subthreshold signal, have been investigated. With the numerical simulations, it is surprisingly found that there exist several optimal noise intensities at which the subthreshold signal can be detected efficiently. This indicates the occurrence of stochastic multiresonance in the studied neuronal networks. Moreover, it is revealed that the occurrence of stochastic multiresonance has close relationship with the period of subthreshold signal Te and the noise-induced mean period of the neuronal networks T0. In detail, we find that noise could induce the neuronal networks to generate stochastic resonance for M times if Te is not very large and falls into the interval ( M × T 0 , ( M + 1 ) × T 0 ) with M being a positive integer. In real neuronal system, subthreshold signal detection is very meaningful. Thus, the obtained results in this paper could give some important implications on detecting subthreshold signal and propagating neuronal information in neuronal systems.

  14. Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro.

    PubMed

    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

    2015-05-19

    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.

  15. 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

  16. From induction to conduction: how intrinsic transcriptional priming of extrinsic neuronal connectivity shapes neuronal identity.

    PubMed

    Russ, Jeffrey B; Kaltschmidt, Julia A

    2014-10-01

    Every behaviour of an organism relies on an intricate and vastly diverse network of neurons whose identity and connectivity must be specified with extreme precision during development. Intrinsically, specification of neuronal identity depends heavily on the expression of powerful transcription factors that direct numerous features of neuronal identity, including especially properties of neuronal connectivity, such as dendritic morphology, axonal targeting or synaptic specificity, ultimately priming the neuron for incorporation into emerging circuitry. As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics. As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners. Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming.

  17. Parkin Mutations Reduce the Complexity of Neuronal Processes in iPSC-derived Human Neurons

    PubMed Central

    Ren, Yong; Jiang, Houbo; Hu, Zhixing; Fan, Kevin; Wang, Jun; Janoschka, Stephen; Wang, Xiaomin; Ge, Shaoyu; Feng, Jian

    2015-01-01

    Parkinson’s disease (PD) is characterized by the degeneration of nigral dopaminergic (DA) neurons and non-DA neurons in many parts of the brain. Mutations of parkin, an E3 ubiquitin ligase that strongly binds to microtubules, are the most frequent cause of recessively inherited Parkinson’s disease. The lack of robust PD phenotype in parkin knockout mice suggests a unique vulnerability of human neurons to parkin mutations. Here, we show that the complexity of neuronal processes as measured by total neurite length, number of terminals, number of branch points and Sholl analysis, was greatly reduced in induced pluripotent stem cell (iPSC)-derived TH+ or TH− neurons from PD patients with parkin mutations. Consistent with these, microtubule stability was significantly decreased by parkin mutations in iPSC-derived neurons. Overexpression of parkin, but not its PD-linked mutant nor GFP, restored the complexity of neuronal processes and the stability of microtubules. Consistent with these, the microtubule-depolymerizing agent colchicine mimicked the effect of parkin mutations by decreasing neurite length and complexity in control neurons while the microtubule-stabilizing drug taxol mimicked the effect of parkin overexpression by enhancing the morphology of parkin-deficient neurons. The results suggest that parkin maintains the morphological complexity of human neurons by stabilizing microtubules. PMID:25332110

  18. Glass promotes the differentiation of neuronal and non-neuronal cell types in the Drosophila eye

    PubMed Central

    Morrison, Carolyn A.; Chen, Hao; Cook, Tiffany; Brown, Stuart

    2018-01-01

    Transcriptional regulators can specify different cell types from a pool of equivalent progenitors by activating distinct developmental programs. The Glass transcription factor is expressed in all progenitors in the developing Drosophila eye, and is maintained in both neuronal and non-neuronal cell types. Glass is required for neuronal progenitors to differentiate as photoreceptors, but its role in non-neuronal cone and pigment cells is unknown. To determine whether Glass activity is limited to neuronal lineages, we compared the effects of misexpressing it in neuroblasts of the larval brain and in epithelial cells of the wing disc. Glass activated overlapping but distinct sets of genes in these neuronal and non-neuronal contexts, including markers of photoreceptors, cone cells and pigment cells. Coexpression of other transcription factors such as Pax2, Eyes absent, Lozenge and Escargot enabled Glass to induce additional genes characteristic of the non-neuronal cell types. Cell type-specific glass mutations generated in cone or pigment cells using somatic CRISPR revealed autonomous developmental defects, and expressing Glass specifically in these cells partially rescued glass mutant phenotypes. These results indicate that Glass is a determinant of organ identity that acts in both neuronal and non-neuronal cells to promote their differentiation into functional components of the eye. PMID:29324767

  19. Mesodermal and neuronal retinoids regulate the induction and maintenance of limb innervating spinal motor neurons.

    PubMed

    Ji, Sheng-Jian; Zhuang, BinQuan; Falco, Crystal; Schneider, André; Schuster-Gossler, Karin; Gossler, Achim; Sockanathan, Shanthini

    2006-09-01

    During embryonic development, the generation, diversification and maintenance of spinal motor neurons depend upon extrinsic signals that are tightly regulated. Retinoic acid (RA) is necessary for specifying the fates of forelimb-innervating motor neurons of the Lateral Motor Column (LMC), and the specification of LMC neurons into medial and lateral subtypes. Previous studies implicate motor neurons as the relevant source of RA for specifying lateral LMC fates at forelimb levels. However, at the time of LMC diversification, a significant amount of retinoids in the spinal cord originates from the adjacent paraxial mesoderm. Here we employ mouse genetics to show that RA derived from the paraxial mesoderm is required for lateral LMC induction at forelimb and hindlimb levels, demonstrating that mesodermally synthesized RA functions as a second source of signals to specify lateral LMC identity. Furthermore, reduced RA levels in postmitotic motor neurons result in a decrease of medial and lateral LMC neurons, and abnormal axonal projections in the limb; invoking additional roles for neuronally synthesized RA in motor neuron maintenance and survival. These findings suggest that during embryogenesis, mesodermal and neuronal retinoids act coordinately to establish and maintain appropriate cohorts of spinal motor neurons that innervate target muscles in the limb.

  20. 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.

  1. 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 morphologic