Skip to main content

Advertisement

SpringerLink
Log in

Transcription Factors Phox2a/2b Upregulate Expression of Noradrenergic and Dopaminergic Phenotypes in Aged Rat Brains

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

The present study investigated the effects of forced overexpression of Phox2a/2b, two transcription factors, in the locus coeruleus (LC) of aged rats on noradrenergic and dopaminergic phenotypes in brains. Results showed that a significant increase in Phox2a/2b mRNA levels in the LC region was paralleled by marked enhancement in expression of DBH and TH per se. Furthermore, similar increases in TH protein levels were observed in the substantial nigra and striatum, as well as in the hippocampus and frontal cortex. Overexpression of Phox2 genes also significantly increased BrdU-positive cells in the hippocampal dentate gyrus and NE levels in the striatum. Moreover, this manipulation significantly improved the cognition behavior. The in vitro experiments revealed that norepinephrine treatments may increase the transcription of TH gene through the epigenetic action on the TH promoter. The results indicate that Phox2 genes may play an important role in improving the function of the noradrenergic and dopaminergic neurons in aged animals, and regulation of Phox2 gene expression may have therapeutic utility in aging or disorders involving degeneration of noradrenergic neurons.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

BrdU:

5-Bromo-2-deoxyuridine

ChIP:

Chromatin immunoprecipitation assay

DA:

Dopamine

DBH:

Dopamine-β-hydroxylase

DG:

Dentate gyrus

ECL:

Enhanced chemiluminescence

FBS:

Fetal bovine serum

FC:

Frontal cortex

GCL:

Granule cell layer

HPLC:

High-performance liquid chromatography

HP:

Hippocampus

LC:

Locus coeruleus

MWM:

Morris water maze

NE:

Norepinephrine

PBS:

Phosphate-buffer saline

PD:

Parkinson’s disease

qPCR:

Quantitative real-time polymerase chain reaction

SDS:

Sodium lauryl sulfate

SN:

Substantia nigra

Sp1:

Specificity protein 1

TH:

Tyrosine hydroxylase

VTA:

Ventral tegmental area

References

  • Af Bjerken S, Stenmark Persson R, Barkander A, Karalija N, Pelegrina-Hidalgo N, Gerhardt GA, Virel A, Stromberg I (2019) Noradrenaline is crucial for the substantia nigra dopaminergic cell maintenance. Neurochem Int 131:104551

    CAS  PubMed  Google Scholar 

  • Anlezark GM, Crow TJ, Greenway AP (1973) Impaired learning and decreased cortical norepinephrine after bilateral locus coeruleus lesions. Science 181:682–684

    CAS  PubMed  Google Scholar 

  • Antelman SM, Caggiula AR (1977) Norepinephrine-dopamine interactions and behavior. Science 195:646–653

    CAS  PubMed  Google Scholar 

  • Aston-Jones G, Rajkowski J, Cohen J (2000) Locus coeruleus and regulation of behavioral flexibility and attention. Prog Brain Res 126:165–182

    CAS  PubMed  Google Scholar 

  • Benarroch EE (2018) Locus coeruleus. Cell Tissue Res 373:221–232

    PubMed  Google Scholar 

  • Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42:33–84

    PubMed  Google Scholar 

  • Bing G, Zhang Y, Watanabe Y, McEwen BS, Stone EA (1994) Locus coeruleus lesions potentiate neurotoxic effects of MPTP in dopaminergic neurons of the substantia nigra. Brain Res 668:261–265

    CAS  PubMed  Google Scholar 

  • Blanchard V, Raisman-Vozari R, Savasta M, Hirsch E, Javoy-Agid F, Feuerstein C, Agid Y (1993) Cellular quantification of tyrosine hydroxylase in the rat brain by immunoautoradiography. J Neurochem 61:617–626

    CAS  PubMed  Google Scholar 

  • Brown RW, Gonzalez CL, Whishaw IQ, Kolb B (2001) Nicotine improvement of Morris water task performance after fimbria-fornix lesion is blocked by mecamylamine. Behav Brain Res 119:185–192

    CAS  PubMed  Google Scholar 

  • Buchman AS, Nag S, Shulman JM, Lim AS, VanderHorst VG, Leurgans SE, Schneider JA, Bennett DA (2012) Locus coeruleus neuron density and parkinsonism in older adults without Parkinson’s disease. Mov Disord 27:1625–1631

    PubMed  PubMed Central  Google Scholar 

  • Card JP, Lois J, Sved AF (2010) Distribution and phenotype of Phox2a-containing neurons in the adult Sprague-Dawley rat. J Comp Neurol 518:2202–2220

    PubMed  Google Scholar 

  • Chan-Palay V, Asan E (1989) Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression. J Comp Neurol 287:357–372

    CAS  PubMed  Google Scholar 

  • Choi HK, Won LA, Kontur PJ, Hammond DN, Fox AP, Wainer BH, Hoffmann PC, Heller A (1991) Immortalization of embryonic mesencephalic dopaminergic neurons by somatic cell fusion. Brain Res 552:67–76

    CAS  PubMed  Google Scholar 

  • Church WH (2005) Column chromatography analysis of brain tissue: an advanced laboratory exercise for neuroscience majors. J Undergrad Neurosci Educ 3:A36–A41

    PubMed  PubMed Central  Google Scholar 

  • Cole BJ, Robbins TW (1992) Forebrain norepinephrine: role in controlled information processing in the rat. Neuropsychopharmacology 7:129–142

    CAS  PubMed  Google Scholar 

  • DeKosky S, Palmer A (1994) Neurochemistry of aging. Oxford University Press, New York

    Google Scholar 

  • Delaville C, Deurwaerdere PD, Benazzouz A (2011) Noradrenaline and Parkinson’s disease. Front Syst Neurosci 5:31

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deng M, Tufan T, Raza MU, Jones TC, Zhu MY (2016) MicroRNAs 29b and 181a down-regulate the expression of the norepinephrine transporter and glucocorticoid receptors in PC12 cells. J Neurochem 139:197–207

    CAS  PubMed  PubMed Central  Google Scholar 

  • Devauges V, Sara SJ (1990) Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav Brain Res 39:19–28

    CAS  PubMed  Google Scholar 

  • Driscoll I, Howard SR, Stone JC, Monfils MH, Tomanek B, Brooks WM, Sutherland RJ (2006) The aging hippocampus: a multi-level analysis in the rat. Neuroscience 139:1173–1185

    CAS  PubMed  Google Scholar 

  • Eisch AJ, Barrot M, Schad CA, Self DW, Nestler EJ (2000) Opiates inhibit neurogenesis in the adult rat hippocampus. Proc Natl Acad Sci U S A 97:7579–7584

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fan Y, Huang J, Kieran N, Zhu MY (2009) Effects of transcription factors Phox2 on expression of norepinephrine transporter and dopamine beta-hydroxylase in SK-N-BE(2)C cells. J Neurochem 110:1502–1513

    CAS  PubMed  Google Scholar 

  • Fan Y, Huang J, Duffourc M, Kao RL, Ordway GA, Huang R, Zhu MY (2011) Transcription factor Phox2 upregulates expression of norepinephrine transporter and dopamine beta-hydroxylase in adult rat brains. Neuroscience 192:37–53

    CAS  PubMed  Google Scholar 

  • Fornai F, Torracca MT, Bassi L, D’Errigo DA, Scalori V, Corsini GU (1996) Norepinephrine loss selectively enhances chronic nigrostriatal dopamine depletion in mice and rats. Brain Res 735:349–353

    CAS  PubMed  Google Scholar 

  • German DC, Walker BS, Manaye K, Smith WK, Woodward DJ, North AJ (1988) The human locus coeruleus: computer reconstruction of cellular distribution. J Neurosci 8:1776–1788

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gibbons RJ (2005) Histone modifying and chromatin remodelling enzymes in cancer and dysplastic syndromes. Hum Mol Genet 14(Spec No 1):R85-92

  • Grenhoff J, Svensson TH (1993) Prazosin modulates the firing pattern of dopamine neurons in rat ventral tegmental area. Eur J Pharmacol 233:79–84

    CAS  PubMed  Google Scholar 

  • Grenhoff J, Nisell M, Ferre S, Aston-Jones G, Svensson TH (1993) Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat. J Neural Transm Gen Sect 93:11–25

    CAS  PubMed  Google Scholar 

  • Grunstein M (1997) Histone acetylation in chromatin structure and transcription. Nature 389:349–352

    CAS  PubMed  Google Scholar 

  • Guiard BP, El Mansari M, Merali Z, Blier P (2008) Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions. Int J Neuropsychopharmacol 11:625–639

    CAS  PubMed  Google Scholar 

  • Hammerschmidt T, Kummer MP, Terwel D, Martinez A, Gorji A, Pape HC, Rommelfanger KS, Schroeder JP, Stoll M, Schultze J, Weinshenker D, Heneka MT (2013) Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice. Biol Psychiatry 73:454–463

    CAS  PubMed  Google Scholar 

  • Haring JH, Davis JN (1985) Differential distribution of locus coeruleus projections to the hippocampal formation: anatomical and biochemical evidence. Brain Res 325:366–369

    CAS  PubMed  Google Scholar 

  • Hassani OK, Rymar VV, Nguyen KQ, Huo L, Cloutier JF, Miller FD, Sadikot AF (2020) The noradrenergic system is necessary for survival of vulnerable midbrain dopaminergic neurons: implications for development and Parkinson’s disease. Neurobiol Aging 85:22–37

    CAS  PubMed  Google Scholar 

  • Huang J, Tufan T, Deng M, Wright G, Zhu MY (2015) Corticotropin releasing factor up-regulates the expression and function of norepinephrine transporter in SK-N-BE (2) M17 cells. J Neurochem 135:38–49

    CAS  PubMed  Google Scholar 

  • Isaias IU, Marotta G, Pezzoli G, Sabri O, Schwarz J, Crenna P, Classen J, Cavallari P (2011) Enhanced catecholamine transporter binding in the locus coeruleus of patients with early Parkinson disease. BMC Neurol 11:88

    PubMed  PubMed Central  Google Scholar 

  • Jacobs HI, Wiese S, van de Ven V, Gronenschild EH, Verhey FR, Matthews PM (2015) Relevance of parahippocampal-locus coeruleus connectivity to memory in early dementia. Neurobiol Aging 36:618–626

    PubMed  Google Scholar 

  • Kalinin S, Polak PE, Lin SX, Sakharkar AJ, Pandey SC, Feinstein DL (2012) The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer’s disease. Neurobiol Aging 33:1651–1663

    CAS  PubMed  Google Scholar 

  • Kang BJ, Chang DA, Mackay DD, West GH, Moreira TS, Takakura AC, Gwilt JM, Guyenet PG et al (2007) Central nervous system distribution of the transcription factor Phox2b in the adult rat. J Comp Neurol 503:627–641

    CAS  PubMed  Google Scholar 

  • Kaufman S, Friedman S (1965) Dopamine-beta-hydroxylase. Pharmacol Rev 17:71–100

    CAS  PubMed  Google Scholar 

  • Keller JN (2006) Age-related neuropathology, cognitive decline, and Alzheimer’s disease. Ageing Res Rev 5:1–13

    CAS  PubMed  Google Scholar 

  • Kilbourn MR, Sherman P, Abbott LC (1998) Reduced MPTP neurotoxicity in striatum of the mutant mouse tottering. Synapse 30:205–210

    CAS  PubMed  Google Scholar 

  • Kim HS, Park JS, Hong SJ, Woo MS, Kim SY, Kim KS (2003) Regulation of the tyrosine hydroxylase gene promoter by histone deacetylase inhibitors. Biochem Biophys Res Commun 312:950–957

    CAS  PubMed  Google Scholar 

  • Lapiz MD, Mateo Y, Durkin S, Parker T, Marsden CA (2001) Effects of central noradrenaline depletion by the selective neurotoxin DSP-4 on the behaviour of the isolated rat in the elevated plus maze and water maze. Psychopharmacology 155:251–259

    CAS  PubMed  Google Scholar 

  • Lee EH, Lee CP, Wang HI, Lin WR (1993) Hippocampal CRF, NE, and NMDA system interactions in memory processing in the rat. Synapse 14:144–153

    CAS  PubMed  Google Scholar 

  • Lenartowski R, Goc A (2011) Epigenetic, transcriptional and posttranscriptional regulation of the tyrosine hydroxylase gene. Int J Dev Neurosci 29:873–883

    CAS  PubMed  Google Scholar 

  • Leslie FM, Loughlin SE, Sternberg DB, McGaugh JL, Young LE, Zornetzer SF (1985) Noradrenergic changes and memory loss in aged mice. Brain Res 359:292–299

    CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔCT) method. Methods 25:402–408

    CAS  PubMed  Google Scholar 

  • Lucas ME, Muller F, Rudiger R, Henion PD, Rohrer H (2006) The bHLH transcription factor hand2 is essential for noradrenergic differentiation of sympathetic neurons. Development 133:4015–4024

    CAS  PubMed  Google Scholar 

  • Ma L, Wang DD, Zhang TY, Yu H, Wang Y, Huang SH, Lee FS, Chen ZY (2011) Region-specific involvement of BDNF secretion and synthesis in conditioned taste aversion memory formation. J Neurosci 31:2079–2090

    CAS  PubMed  PubMed Central  Google Scholar 

  • Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110

    CAS  PubMed  PubMed Central  Google Scholar 

  • Manaye KF, McIntire DD, Mann DM, German DC (1995) Locus coeruleus cell loss in the aging human brain: a non-random process. J Comp Neurol 358:79–87

    CAS  PubMed  Google Scholar 

  • Marien M, Lategan A, Colpaert F (1994) Noradrenergic control of striatal dopamine. In: Briley M, Marien M (eds) Noradrenergic mechanisms in Parkinson’s disease, vol. CRC Press, Boca Raton, pp 127–138

    Google Scholar 

  • Mavridis M, Degryse AD, Lategan AJ, Marien MR, Colpaert FC (1991) Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: a possible role for the locus coeruleus in the progression of Parkinson’s disease. Neuroscience 41:507–523

    CAS  PubMed  Google Scholar 

  • Morin X, Cremer H, Hirsch MR, Kapur RP, Goridis C, Brunet JF (1997) Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a. Neuron 18:411–423

    CAS  PubMed  Google Scholar 

  • Morrison JH, Molliver ME, Grzanna R (1979) Noradrenergic innervation of cerebral cortex: widespread effects of local cortical lesions. Science 205:313–316

    CAS  PubMed  Google Scholar 

  • Narlikar GJ, Fan HY, Kingston RE (2002) Cooperation between complexes that regulate chromatin structure and transcription. Cell 108:475–487

    CAS  PubMed  Google Scholar 

  • Parodi S, Di Zanni E, Di Lascio S, Bocca P, Prigione I, Fornasari D, Pennuto M, Bachetti T et al (2012) The E3 ubiquitin ligase TRIM11 mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expanded PHOX2B. J Mol Med (Berl) 90:1025–1035

    CAS  Google Scholar 

  • Pattyn A, Goridis C, Brunet JF (2000) Specification of the central noradrenergic phenotype by the homeobox gene Phox2b. Mol Cell Neurosci 15:235–243

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Elsevier, Oxford

    Google Scholar 

  • Puumala T, Greijus S, Narinen K, Haapalinna A, Riekkinen P Sr, Sirvio J (1998) Stimulation of alpha-1 adrenergic receptors facilitates spatial learning in rats. Eur Neuropsychopharmacol 8:17–26

    CAS  PubMed  Google Scholar 

  • Raisman-Vozari R, Hirsch E, Javoy-Agid F, Vassort C, Savasta M, Feuerstein C, Thibault J, Agid Y (1991) Quantitative autoradiography of tyrosine hydroxylase immunoreactivity in the rat brain. J Neurochem 57:1212–1222

    CAS  PubMed  Google Scholar 

  • Rapp PR, Heindel WC (1994) Memory systems in normal and pathological aging. Curr Opin Neurol 7:294–298

    CAS  PubMed  Google Scholar 

  • Reiff T, Tsarovina K, Majdazari A, Schmidt M, del Pino I, Rohrer H (2010) Neuroblastoma phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons. J Neurosci 30:905–915

    CAS  PubMed  PubMed Central  Google Scholar 

  • Robertson IH (2013) A noradrenergic theory of cognitive reserve: implications for Alzheimer’s disease. Neurobiol Aging 34:298–308

    CAS  PubMed  Google Scholar 

  • Rodriguez M, Rodriguez-Sabate C, Morales I, Sanchez A, Sabate M (2015) Parkinson’s disease as a result of aging. Aging Cell 14:293–308

    CAS  PubMed  PubMed Central  Google Scholar 

  • Roeder RG (2005) Transcriptional regulation and the role of diverse coactivators in animal cells. FEBS Lett 579:909–915

    CAS  PubMed  Google Scholar 

  • Rollo CD (2009) Dopamine and aging: intersecting facets. Neurochem Res 34:601–629

    CAS  PubMed  Google Scholar 

  • Rommelfanger KS, Weinshenker D, Miller GW (2004) Reduced MPTP toxicity in noradrenaline transporter knockout mice. J Neurochem 91:1116–1124

    CAS  PubMed  Google Scholar 

  • Rudow G, O'Brien R, Savonenko AV, Resnick SM, Zonderman AB, Pletnikova O, Marsh L, Dawson TM et al (2008) Morphometry of the human substantia nigra in ageing and Parkinson’s disease. Acta Neuropathol 115:461–470

    PubMed  PubMed Central  Google Scholar 

  • Safe S, Abdelrahim M (2005) Sp transcription factor family and its role in cancer. Eur J Cancer 41:2438–2448

    CAS  PubMed  Google Scholar 

  • Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10:211–223

    CAS  PubMed  Google Scholar 

  • Schmidt M, Lin S, Pape M, Ernsberger U, Stanke M, Kobayashi K, Howard MJ, Rohrer H (2009) The bHLH transcription factor Hand2 is essential for the maintenance of noradrenergic properties in differentiated sympathetic neurons. Dev Biol 329:191–200

    CAS  PubMed  PubMed Central  Google Scholar 

  • Srinivasan J, Schmidt WJ (2003) Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats. Eur J Neurosci 17:2586–2592

    CAS  PubMed  Google Scholar 

  • Stanke M, Junghans D, Geissen M, Goridis C, Ernsberger U, Rohrer H (1999) The Phox2 homeodomain proteins are sufficient to promote the development of sympathetic neurons. Development 126:4087–4094

    CAS  PubMed  Google Scholar 

  • Sturrock RR, Rao KA (1985) A quantitative histological study of neuronal loss from the locus coeruleus of ageing mice. Neuropathol Appl Neurobiol 11:55–60

    CAS  PubMed  Google Scholar 

  • Swanson DJ, Zellmer E, Lewis EJ (1997) The homeodomain protein Arix interacts synergistically with cyclic AMP to regulate expression of neurotransmitter biosynthetic genes. J Biol Chem 272:27382–27392

    CAS  PubMed  Google Scholar 

  • Swanson DJ, Zellmer E, Lewis EJ (1998) AP1 proteins mediate the cAMP response of the dopamine beta-hydroxylase gene. J Biol Chem 273:24065–24074

    CAS  PubMed  Google Scholar 

  • Swerdlow RH (2011) Brain aging, Alzheimer's disease, and mitochondria. Biochim Biophys Acta 1812:1630–1639

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tatton WG, Greenwood CE, Verrier MC, Holland DP, Kwan MM, Biddle FE (1991) Different rates of age-related loss for four murine monoaminergic neuronal populations. Neurobiol Aging 12:543–556

    CAS  PubMed  Google Scholar 

  • Tiveron MC, Hirsch MR, Brunet JF (1996) The expression pattern of the transcription factor Phox2 delineates synaptic pathways of the autonomic nervous system. J Neurosci 16:7649–7660

    CAS  PubMed  PubMed Central  Google Scholar 

  • Troadec JD, Marien M, Darios F, Hartmann A, Ruberg M, Colpaert F, Michel PP (2001) Noradrenaline provides long-term protection to dopaminergic neurons by reducing oxidative stress. J Neurochem 79:200–210

    CAS  PubMed  Google Scholar 

  • Tsarovina K, Reiff T, Stubbusch J, Kurek D, Grosveld FG, Parlato R, Schutz G, Rohrer H (2010) The Gata3 transcription factor is required for the survival of embryonic and adult sympathetic neurons. J Neurosci 30:10833–10843

    CAS  PubMed  PubMed Central  Google Scholar 

  • Udenfriend S (1966) Tyrosine hydroxylase. Pharmacol Rev 18:43–51

    CAS  PubMed  Google Scholar 

  • Valarche I, Tissier-Seta JP, Hirsch MR, Martinez S, Goridis C, Brunet JF (1993) The mouse homeodomain protein Phox2 regulates Ncam promoter activity in concert with Cux/CDP and is a putative determinant of neurotransmitter phenotype. Development 119:881–896

    CAS  PubMed  Google Scholar 

  • van Groen T, Kadish I, Wyss JM (2002) Old rats remember old tricks; memories of the water maze persist for 12 months. Behav Brain Res 136:247–255

    PubMed  Google Scholar 

  • Verdone L, Caserta M, Di Mauro E (2005) Role of histone acetylation in the control of gene expression. Biochem Cell Biol 83:344–353

    CAS  PubMed  Google Scholar 

  • Verret L, Trouche S, Zerwas M, Rampon C (2007) Hippocampal neurogenesis during normal and pathological aging. Psychoneuroendocrinology 32(Suppl 1):S26–S30

    CAS  PubMed  Google Scholar 

  • Wang Y, Zhang QJ, Liu J, Ali U, Gui ZH, Hui YP, Chen L, Wu ZH, Li Q (2010) Noradrenergic lesion of the locus coeruleus increases apomorphine-induced circling behavior and the firing activity of substantia nigra pars reticulata neurons in a rat model of Parkinson’s disease. Brain Res 1310:189–199

    CAS  PubMed  Google Scholar 

  • Warner TA, Drugan RC (2012) Morris water maze performance deficit produced by intermittent swim stress is partially mediated by norepinephrine. Pharmacol Biochem Behav 101:24–34

    CAS  PubMed  Google Scholar 

  • Wilson RS, Nag S, Boyle PA, Hizel LP, Yu L, Buchman AS, Schneider JA, Bennett DA (2013) Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology 80:1202–1208

    PubMed  PubMed Central  Google Scholar 

  • Yang C, Kim HS, Seo H, Kim KS (1998) Identification and characterization of potential cis-regulatory elements governing transcriptional activation of the rat tyrosine hydroxylase gene. J Neurochem 71:1358–1368

    CAS  PubMed  Google Scholar 

  • Zellmer E, Zhang Z, Greco D, Rhodes J, Cassel S, Lewis EJ (1995) A homeodomain protein selectively expressed in noradrenergic tissue regulates transcription of neurotransmitter biosynthetic genes. J Neurosci 15:8109–8120

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zha Q, Wang Y, Fan Y, Zhu MY (2011) Dexamethasone-induced up-regulation of the human norepinephrine transporter involves the glucocorticoid receptor and increased binding of C/EBP-beta to the proximal promoter of norepinephrine transporter. J Neurochem 119:654–663

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu MY, Wang WP, Huang J, Feng YZ, Regunathan S, Bissette G (2008) Repeated immobilization stress alters rat hippocampal and prefrontal cortical morphology in parallel with endogenous agmatine and arginine decarboxylase levels. Neurochem Int 53:346–354

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu MY, Raza MU, Zhan Y, Fan Y (2019) Norepinephrine upregulates the expression of tyrosine hydroxylase and protects dopaminegic neurons against 6-hydrodopamine toxicity. Neurochem Int 131:104549

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work is supported by NIH grant AG055107.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA

    Yan Fan, Fei Zeng, Russell W. Brown & Meng-Yang Zhu

  2. Department of Biochemistry, Nantong University College of Medicine, Nantong, China

    Yan Fan

  3. Department of Neurology, Remin Hospital of the Wuhan University, Wuhan, China

    Fei Zeng

  4. Department of Biological Sciences, College of Arts and Sciences, East Tennessee State University, Johnson City, TN, USA

    Jennifer B. Price & Thomas C. Jones

Authors
  1. Yan Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fei Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Russell W. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jennifer B. Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas C. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Meng-Yang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meng-Yang Zhu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fan, Y., Zeng, F., Brown, R.W. et al. Transcription Factors Phox2a/2b Upregulate Expression of Noradrenergic and Dopaminergic Phenotypes in Aged Rat Brains. Neurotox Res 38, 793–807 (2020). https://doi.org/10.1007/s12640-020-00250-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-020-00250-9

Keywords

Search

Navigation