Skip to main content

Advertisement

SpringerLink
Log in

Dysfunctional Nucleus Tractus Solitarius: Its Crucial Role in Promoting Neuropathogentic Cascade of Alzheimer’s Dementia—A Novel Hypothesis

  • Overview
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The pathophysiological mechanism(s) underlying Alzheimer’s disease (AD) still remain unclear, and no disease-modifying or prophylactic therapies are currently available. Unraveling the fundamental neuropathogenesis of AD is an important challenge. Several studies on AD have suggested lesions in a number of CNS areas including the basal forebrain, hippocampus, entorhinal cortex, amygdale/insula, and the locus coeruleus. However, plausible unifying studies on the upstream factors that involve these heterogeneous regions and herald the onset of AD pathogenesis are not available. The current article presents a novel nucleus tractus solitarius (NTS) vector hypothesis that underpins several disparate biological mechanisms and neural circuits, and identifies relevant hallmarks of major presumptive causative factor(s) linked to the NTS, in older/aging individuals. Aging, obesity, infection, sleep apnea, smoking, neuropsychological states, and hypothermia—all activate inflammatory cytokines and oxidative stress. The synergistic impact of systemic proinflammatory mediators activates microglia and promotes neuroinflammation. Acutely, the innate immune response is protective defending against pathogens/toxins; however, when chronic, it causes neuroinflammation and neuronal dysfunction, particularly in brainstem and neocortex. The NTS in the brainstem is an essential multiple signaling hub, and an extremely important central integration site of baroreceptor, chemoreceptor, and a multitude of sensory afferents from gustatory, gastrointestinal, cardiac, pulmonary, and upper airway systems. Owing to persistent neuroinflammation, the dysfunctional NTS exerts deleterious impact on nucleus ambiguus, dorsal motor nucleus of vagus, hypoglossal, parabrachial, locus coeruleus and many key nuclei in the brainstem, and the hippocampus, entorhinal cortex, prefrontal cortex, amygdala, insula, and basal forebrain in the neocortex. The neuronal and synaptic dysfunction emanating from the inflamed NTS may affect its interconnected pathways impacting almost the entire CNS—which is already primed by neuroinflammation, thus promoting cognitive and neuropsychiatric symptoms. The upstream factors discussed here may underpin the neuropathopgenesis of AD. AD pathology is multifactorial; the current perspective underscores the value of attenuating disparate upstream factors—in conjunction with anticholinesterase, anti-inflammatory, immunosuppressive, and anti-oxidant pharmacotherapy. Amelioration of the NTS pathology may be of central importance in countering the neuropathological cascade of AD. The NTS, therefore, may be a potential target of novel therapeutic strategies.

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

Similar content being viewed by others

Abbreviations

α1-ACT:

α1-Antichymotrypsin

Aβ:

Amyloid beta

Ach:

Acetylcholine

BFB:

Basal forebrain

BP:

Blood pressure

AD:

Alzheimer’s disease

AHI:

Apnea hypopnea index

AP:

Area postrema

APR:

Acute phase response

BFB:

Basal forebrain

BMI:

Basal metabolic index

BBB:

Blood brain barrier

CBF:

Cerebral blood flow

CCL2:

Chemokine ligand 2

CD15:

Immunological carbohydrate adhesion molecule

CIC:

Circulating inflammatory cytokines,

c-fos:

Proto-oncogene

CIM:

Circulating inflammatory mediators

CNS:

Central nervous system

COX-2:

Cyclooxygenase-2

CRP:

C-reactive protein

DMNV:

Dorsal motor nucleus of the vagus nerve

DVC:

Dorsal vagal complex

ERC:

Entorhinal cortex

GMV:

Gray matter volume

HIF-1:

Hypoxia-inducible factor 1

ICAM 1:

Intercellular adhesion molecule 1

IFNγ:

Interferon gamma

IL:

Interleukin

LPS:

Lipopolysaccharide

MCI:

Mild cognitive impairment

MIP-2:

Macrophage inflammatory protein

NA:

Nucleus ambiguus

NF-κB:

Nuclear factor of kappa light polypeptide gene enhancer in B-cells

NTS:

Nucleus tractus solitarius

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NK:

Natural killer cell

OB:

Olfactory bulb

OFC:

Orbitofrontal cortex

ON:

Olfactory nerve

OSA:

Obstructive sleep apnea

PC:

Piriform cortex

PFC:

Prefrontal cortex

p-tau:

Hyperphosphorylated tau

ROS:

Reactive oxygen species

TGF-β:

Transforming growth factor beta

THP-1:

Human acute monocytic leukemia cell line

TNF:

Tumor necrosis factor

VCAM-1:

Vascular cell adhesion molecule-1

VNS:

Vagus nerve stimulation

References

  1. Giannakopoulos P, Hof PR, Michel JP, Guimon J, Bouras C (1997) Cerebral cortex pathology in aging and Alzheimer’s disease: a quantitative survey of large hospital-based geriatric and psychiatric cohorts. Brain Res Brain Res Rev 25:217–245

    PubMed  CAS  Google Scholar 

  2. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP BP, Leeuwenburgh C (2009) Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev 8:18–30

    PubMed  CAS  Google Scholar 

  3. Deng XH, Bertini G, Xu YZ, Yan Z, Bentivoglio M (2006) Cytokine-induced activation of glial cells in the mouse brain is enhanced at an advanced age. Neuroscience 141:645–661

    PubMed  CAS  Google Scholar 

  4. Choi DY, Zhang J, Bing G (2010) Aging enhances the neuroinflammatory response and alpha-synuclein nitration in rats. Neurobiol Aging 31:1649–1653

    PubMed  CAS  Google Scholar 

  5. Mattson MP (2002) Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer’s disease. J Neurovirol 8:539–550

    PubMed  CAS  Google Scholar 

  6. Butterfield DA (2002) Amyloid beta-peptide (1–42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res 36:1307–1313

    PubMed  CAS  Google Scholar 

  7. Praticò D (2008) Evidence of oxidative stress in Alzheimer’s disease brain and antioxidant therapy: lights and shadows. Ann N Y Acad Sci 1147:70–78

    PubMed  Google Scholar 

  8. Clark TA, Lee HP, Rolston RK, Zhu X, Marlatt MW, Castellani RJ, Nunomura A, Casadesus G, Smith MA, Lee HG, Perry G (2010) Oxidative stress and its implications for future treatments and management of Alzheimer disease. Int J Biomed Sci 6:225–227

    PubMed  Google Scholar 

  9. Head E, Liu J, Hagen TM, Muggenburg BA, Milgram NW, Ames BN, Cotman CW (2002) Oxidative damage increases with age in a canine model of human brain aging. J Neurochem 82:375–381

    PubMed  CAS  Google Scholar 

  10. Montiel T, Quiroz-Baez R, Massieu L, Arias C (2006) Role of oxidative stress on beta-amyloid neurotoxicity elicited during impairment of energy metabolism in the hippocampus: protection by antioxidants. Exp Neurol 200:496–508

    PubMed  CAS  Google Scholar 

  11. Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH (2003) Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74:788–789

    PubMed  CAS  Google Scholar 

  12. Richwine AF, Sparkman NL, Dilger RN, Buchanan JB, Johnson RW (2009) Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain Behav Immun 23:794–802

    PubMed  CAS  Google Scholar 

  13. Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW (2008) Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 22:301–311

    PubMed  CAS  Google Scholar 

  14. Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68:930–941

    PubMed  CAS  Google Scholar 

  15. Ye SM, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9:183–192

    PubMed  CAS  Google Scholar 

  16. Tan ZS, Seshadri S (2010) Inflammation in the Alzheimer’s disease cascade: culprit or innocent bystander? Alzheimers Res Ther 2:6

    PubMed  Google Scholar 

  17. Wofford JL, Loehr LR, Schwartz E (1996) Acute cognitive impairment in elderly ED patients: etiologies and outcomes. Am J Emerg Med 14:649–653

    PubMed  CAS  Google Scholar 

  18. Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 19:1329–1331

    PubMed  CAS  Google Scholar 

  19. Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D (2010) Inflammation in Alzheimer’s disease: relevance to pathogenesis and therapy. Alzheimers Res Ther 2:1

    PubMed  Google Scholar 

  20. Barrientos RM, Higgins EA, Biedenkapp JC et al (2006) Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol Aging 27:723–732

    PubMed  Google Scholar 

  21. Tanaka S, Ide M, Shibutani T et al (2006) Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats. J Neurosci Res 83:557–566

    PubMed  CAS  Google Scholar 

  22. Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161–167

    PubMed  CAS  Google Scholar 

  23. Torelli F, Moscufo N, Garreffa G, Placidi F, Romigi A, Zannino S, Bozzali M, Fasano F, Giulietti G, Djonlagic I, Malhotra A, Marciani MG, Guttmann CR (2011) Cognitive profile and brain morphological changes in obstructive sleep apnea. Neuroimage 54:787–793

    PubMed  Google Scholar 

  24. Canessa N, Castronovo V, Cappa SF, Aloia MS, Marelli S, Falini A, Alemanno F, Ferini-Strambi L (2011) Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am J Respir Crit Care Med 183:1419–1426

    PubMed  Google Scholar 

  25. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015

    PubMed  CAS  Google Scholar 

  26. Loewy AD (1990) Central autonomic pathways. In: Loewy AD, Spyer KM (eds) Central regulation of autonomic functions. Oxford University Press, Oxford, pp 88–103

    Google Scholar 

  27. Loewy AD (1998) Viruses as transneuronal tracers for defining neural circuits. Neurosci Biobehav Rev 22:679–684

    PubMed  CAS  Google Scholar 

  28. Beckman ME, Whitehead MC (1991) Intramedullary connections of the rostral nucleus of the solitary tract in the hamster. Brain Res 557:265–279

    PubMed  CAS  Google Scholar 

  29. Borke RC, Nau ME, Ringler RL Jr (1983) Brain stem afferents of hypoglossal neurons in the rat. Brain Res 269:47–55

    PubMed  CAS  Google Scholar 

  30. Onai T, Saji M, Miura M (1987) Functional subdivisions of the nucleus tractus solitarii of the rat as determined by circulatory and respiratory responses to electrical stimulation of the nucleus. J Auton Nerv Syst 21:195–202

    PubMed  CAS  Google Scholar 

  31. Streefland C, Jansen K (1999) Intramedullary projections of the rostral nucleus of the solitary tract in the rat: gustatory influences on autonomic output. Chem Senses 24:655–664

    PubMed  CAS  Google Scholar 

  32. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421

    PubMed  CAS  Google Scholar 

  33. Eikelenboom P, Veerhuis R, Scheper W, Rozemuller AJ, van Gool WA, Hoozemans JJ (2006) The significance of neuroinflammation in understanding Alzheimer’s disease. J Neural Transm 113:1685–1695

    PubMed  CAS  Google Scholar 

  34. Böhrer H, Qiu F, Zimmermann T, Zhang Y, Jllmer T, Männel D, Böttiger BW, Stern DM, Waldherr R, Saeger HD, Ziegler R, Bierhaus A, Martin E, Nawroth PP (1997) Role of NFkappaB in the mortality of sepsis. J Clin Invest 100:972–985

    PubMed  Google Scholar 

  35. Makarov SS (2000) NF-kappaB as a therapeutic target in chronic inflammation: recent advances. Mol Med Today 6:441–448

    PubMed  CAS  Google Scholar 

  36. Henry CJ, Huang Y, Wynne AM, Godbout JP (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun 23:309–317

    PubMed  CAS  Google Scholar 

  37. Zou Y, Jung KJ, Kim JW, Yu BP, Chung HY (2004) Alteration of soluble adhesion molecules during aging and their modulation by calorie restriction. FASEB J 18:320–322

    PubMed  CAS  Google Scholar 

  38. Kohman RA, Crowell B, Kusnecov AW (2010) Differential sensitivity to endotoxin exposure in young and middle-age mice. Brain Behav Immun 24:486–492

    PubMed  CAS  Google Scholar 

  39. Sawada H, Hishida R, Hirata Y, Ono KK, Suzuki H, Muramatsu S, Nakano I, Nagatsu T, Sawada M (2007) Activated microglia affect the nigro-striatal dopamine neurons differently in neonatal and aged mice treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. J Neurosci Res 85:1752–1761

    PubMed  CAS  Google Scholar 

  40. Gaykema RP, Balachandran MK, Godbout JP, Johnson RW, Goehler LE (2007) Enhanced neuronal activation in central autonomic network nuclei in aged mice following acute peripheral immune challenge. Auton Neurosci 131:137–142

    PubMed  Google Scholar 

  41. Casserly I, Topol E (2004) Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet 363:1139–1146

    PubMed  CAS  Google Scholar 

  42. Ishida Y, Shirokawa T, Miyaishi O, Komatsu Y, Isobe K (2000) Age-dependent changes in projections from locus coeruleus to hippocampus dentate gyrus and frontal cortex. Eur J Neurosci 12:1263–1270

    PubMed  CAS  Google Scholar 

  43. O’Neil JN, Mouton PR, Tizabi Y, Ottinger MA, Lei DL, Ingram DK, Manaye KF (2007) Catecholaminergic neuronal loss in locus coeruleus of aged female dtg APP/PS1 mice. J Chem Neuroanat 34:102–107

    PubMed  Google Scholar 

  44. Kennedy DJ, Kuchibhotla S, Westfall KM, Silverstein RL, Morton RE, Febbraio MA (2011) CD36-dependent pathway enhances macrophage and adipose tissue inflammation and impairs insulin signalling. Cardiovasc Res 89:604–613

    PubMed  CAS  Google Scholar 

  45. Annone F, Lapadula G (2010) Obesity and inflammation-targets for OA therapy. Curr Drug Targets 11:586–598

    Google Scholar 

  46. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17:179–188

    PubMed  CAS  Google Scholar 

  47. Look C, Morano I, Ehrhart-Bornstein M, Bornstein SR, Lamounier-Zepter V (2011) Adipocyte-derived factors suppress heart contraction. Int J Obes 35:84–90

    CAS  Google Scholar 

  48. Zanni MV, Stanley TL, Makimura H, Chen CY, Grinspoon SK (2010) Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation. Clin Endocrinol (Oxf) 73:48–54

    CAS  Google Scholar 

  49. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A (2005) Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 62:1556–1560

    PubMed  Google Scholar 

  50. Rosengren A, Skoog I, Gustafson D, Wilhelmsen L (2005) Body mass index, other cardiovascular risk factors, and hospitalization for dementia. Arch Intern Med 165:321–326

    PubMed  Google Scholar 

  51. Whitmer RA, Gunderson EP, Barrett-Connor E (2005) Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. Br Med J 330:1360

    Google Scholar 

  52. Gustafson D, Lissner L, Bengtsson C, Björkelund C, Skoog I (2004) A 24-year follow-up of body mass index and cerebral atrophy. Neurology 63:1876–1881

    PubMed  CAS  Google Scholar 

  53. Walther K, Birdsill AC, Glisky EL, Ryan L (2010) Structural brain differences and cognitive functioning related to body mass index in older females. Hum Brain Mapp 31:1052–1064

    PubMed  Google Scholar 

  54. Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, Hua X, Leow AD, Toga AW, Thompson PM (2010) Brain structure and obesity. Hum Brain Mapp 31:353–364

    PubMed  Google Scholar 

  55. Wolf PA, Beiser A, Elias MF, Au R, Vasan RS, Seshadri S (2007) Relation of obesity to cognitive function: importance of central obesity and synergistic influence of concomitant hypertension. The Framingham Heart Study. Curr Alzheimer Res 4:111–116

    PubMed  CAS  Google Scholar 

  56. Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F, van Duijn CN, Van Broeckhoven C, Grobbee DE (1997) Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet 349:151–154

    PubMed  CAS  Google Scholar 

  57. Chandra V, Pandav R (1998) Gene-environment interaction in Alzheimer’s disease: a potential role for cholesterol. Neuroepidemiology 17:225–232

    PubMed  CAS  Google Scholar 

  58. Romas SN, Tang MX, Berglund L, Mayeux R (1999) APOE genotype, plasma lipids, lipoproteins, and AD in community elderly. Neurology 53:517–521

    PubMed  CAS  Google Scholar 

  59. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K et al (2002) Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med 137:149–155

    PubMed  CAS  Google Scholar 

  60. Kivipelto M, Helkala EL, Hanninen T, Laakso MP, Hallikainen M, Alhainen K et al (2001) Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology 56:1683–1689

    PubMed  CAS  Google Scholar 

  61. Peila R, Rodriguez BL, Launer LJ (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu–Asia Aging Study. Diabetes 51:1256–1262

    PubMed  CAS  Google Scholar 

  62. Winther B, Gwaltney JM Jr, Mygind N, Hendley JO (1988) Viral-induced rhinitis. Am J Rhinol 12:17–20

    Google Scholar 

  63. Gwaltney JM (2002) Clinical significance and pathogenesis of viral respiratory infections. Am J Med 112(Suppl 6A):13S–18S

    PubMed  Google Scholar 

  64. Bruewer M, Luegering A, Kucharzik T, Parkos CA, Madara JL, Hopkins AM, Nusrat A (2003) Proinflammatory cytokines disrupt epithelial barrier function by apoptosis independent mechanisms. J Immunol 171:6164–6172

    PubMed  CAS  Google Scholar 

  65. Vieira SM, Lemos HP, Grespan R, Napimoga MH, Dal-Secco D, Freitas A, Cunha TM, Verri WA Jr, Souza-Junior DA, Jamur MC, Fernandes KS, Oliver C, Silva JS, Teixeira MM, Cunha FQ (2009) A crucial role for TNF-alpha in mediating neutrophil influx induced by endogenously generated or exogenous chemokines, KC/CXCL1 and LIX/CXCL5. Br J Pharmacol 158:779–789

    PubMed  CAS  Google Scholar 

  66. Wang S, Quang Le T, Chida J, Cisse Y, Yano M, Kido H (2010) Mechanisms of matrix metalloproteinase-9 upregulation and tissue destruction in various organs in influenza A virus infection. J Med Invest 57:26–34

    PubMed  Google Scholar 

  67. de La Serre CB, Ellis CL, Lee J, Hartman AL, Rutledge JC, Raybould HE (2010) Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol 299:G440–G448

    PubMed  Google Scholar 

  68. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R (2010) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57:1470–1481

    Google Scholar 

  69. Lupp C, Robertson ML, Wickham ME et al (2007) Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2:119–129

    PubMed  CAS  Google Scholar 

  70. Kountouras J, Boziki M, Gavalas E, Zavos C, Deretzi G, Grigoriadis N, Tsolaki M, Chatzopoulos D, Katsinelos P, Tzilves D, Zabouri A, Michailidou I (2009) Increased cerebrospinal fluid Helicobacter pylori antibody in Alzheimer’s disease. Int J Neurosci 119:765–777

    PubMed  CAS  Google Scholar 

  71. Chapman TR, Barrientos RM, Ahrendsen JT, Hoover JM, Maier SF, Patterson SL (2011) Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus. Neurobiol Aging [Epub ahead of print]

  72. Wannamethee SG, Lowe GD, Shaper AG, Rumley A, Lennon L, Whincup PH (2005) Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease. Eur Heart J 26:1765–1773

    PubMed  CAS  Google Scholar 

  73. Helmersson J, Larsson A, Vessby B, Basu S (2005) Active smoking and a history of smoking are associated with enhanced prostaglandin F(2alpha), interleukin-6 and F2-isoprostane formation in elderly men. Atherosclerosis 181:201–207

    PubMed  CAS  Google Scholar 

  74. Durazzo TC, Meyerhoff DJ, Nixon SJ (2011) A comprehensive assessment of neurocognition in middle-aged chronic cigarette smokers. Drug Alcohol Depend [Epub ahead of print]

  75. Bailey MT, Kinsey SG, Padgett DA, Sheridan JF, Leblebicioglu B (2009) Social stress enhances IL-1beta and TNF-alpha production by Porphyromonas gingivalis lipopolysaccharide-stimulated CD11b+ cells. Physiol Behav 98:351–358

    PubMed  CAS  Google Scholar 

  76. Gibb J, Hayley S, Gandhi R, Poulter MO, Anisman H (2008) Synergistic and additive actions of a psychosocial stressor and endotoxin challenge: circulating and brain cytokines, plasma corticosterone and behavioral changes in mice. Brain Behav Immun 22:573–589

    PubMed  CAS  Google Scholar 

  77. Curry JM, Hanke ML, Piper MG, Bailey MT, Bringardner BD, Sheridan JF, Marsh CB (2010) Social disruption induces lung inflammation. Brain Behav Immun 24:394–402

    PubMed  CAS  Google Scholar 

  78. Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF (2007) Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun 21:47–59

    PubMed  CAS  Google Scholar 

  79. O’Connor MF, Irwin MR, Wellisch DK (2009) When grief heats up: pro-inflammatory cytokines predict regional brain activation. Neuroimage 47:891–896

    PubMed  Google Scholar 

  80. Jankord R, Zhang R, Flak JN, Solomon MB, Albertz J, Herman JP (2010) Stress activation of IL-6 neurons in the hypothalamus. Am J Physiol Regul Integr Comp Physiol 299:R343–R351

    PubMed  CAS  Google Scholar 

  81. Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD AF, Schatzberg AF, Myers RM, Akil H, Watson SJ (2011) Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry 16:634–646

    PubMed  CAS  Google Scholar 

  82. Chen E, Miller GE, Kobor MS, Cole SW (2011) Maternal warmth buffers the effects of low early-life socioeconomic status on pro-inflammatory signaling in adulthood. Mol Psychiatry 16:729–737

    PubMed  CAS  Google Scholar 

  83. Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, Reddy R, Aschner M, Lewis DA, Mirnics K (2011) Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry 16:751–762

    PubMed  CAS  Google Scholar 

  84. Peters JL, Weisskopf MG, Spiro A 3rd, Schwartz J, Sparrow D, Nie H et al (2010) Interaction of stress, lead burden, and age on cognition in older men: the VA Normative Aging Study. Environ Health Perspect 118:505–510

    PubMed  CAS  Google Scholar 

  85. Fairchild KD, Singh IS, Patel S, Drysdale BE, Viscardi RM, Hester L, Lazusky HM, Hasday JD (2004) Hypothermia prolongs activation of NF-kappaB and augments generation of inflammatory cytokines. Am J Physiol Cell Physiol 287:C422–C431

    PubMed  CAS  Google Scholar 

  86. Matsui T, Ishikawa T, Takeuchi H, Okabayashi K, Maekawa T (2006) Mild hypothermia promotes pro-inflammatory cytokine production in monocytes. J Neurosurg Anesthesiol 18:189–193

    PubMed  Google Scholar 

  87. Matsui T, Kakeda T (2008) IL-10 production is reduced by hypothermia but augmented by hyperthermia in rat microglia. J Neurotrauma 25:709–715

    PubMed  Google Scholar 

  88. Saito H, Sherwood ER, Varma TK, Evers BM (2003) Effects of aging on mortality, hypothermia, and cytokine induction in mice with endotoxemia or sepsis. Mech Ageing Dev 124:1047–1058

    PubMed  CAS  Google Scholar 

  89. Daulatzai M (2010) Conversion of elderly to Alzheimer’s dementia: role of confluence of hypothermia and senescent stigmata—the plausible pathway. J Alzheimers Dis 21:1039–1063

    PubMed  CAS  Google Scholar 

  90. Guasti L, Marino F, Cosentino M, Maroni L, Maresca AM, Colombo F, Maio RC, Castiglioni L, Saporiti F, Loraschi A, Gaudio G, Bernasconi A, Laurita E, Grandi AM, Venco A (2011) Cytokine production from peripheral blood mononuclear cells and polymorphonuclear leukocytes in patients studied for suspected obstructive sleep apnea. Sleep Breath 15:3–11

    PubMed  Google Scholar 

  91. Woodson BT, Garancis JC, Toohill RJ (1991) Histopathologic changes in snoring and obstructive sleep apnea syndrome. Laryngoscope 101:1318–1322

    PubMed  CAS  Google Scholar 

  92. Bassiouny A, Nasr S, Mashaly M, Ayad E, Qotb M, Atef A (2009) Electron microscopy study of peripheral nerves in the uvulae of snorers and obstructive sleep apnoea patients. J Laryngol Otol 123:203–207

    PubMed  CAS  Google Scholar 

  93. Stål PS, Lindman R, Johansson B (2009) Capillary supply of the soft palate muscles is reduced in long-term habitual snorers. Respiration 77:303–310

    PubMed  Google Scholar 

  94. Loubaki L, Jacques E, Semlali A, Biardel S, Chakir J, Sériès F (2008) Tumor necrosis factor-alpha expression in uvular tissues differs between snorers and apneic patients. Chest 134:911–918

    PubMed  CAS  Google Scholar 

  95. Almendros I, Acerbi I, Puig F, Montserrat JM, Navajas D, Farré R (2007) Upper-airway inflammation triggered by vibration in a rat model of snoring. Sleep 30:225–227

    PubMed  Google Scholar 

  96. Puig F, Rico F, Almendros I, Montserrat JM, Navajas D, Farre R (2005) Vibration enhances interleukin-8 release in a cell model of snoring-induced airway inflammation. Sleep 28:1312–1316

    PubMed  Google Scholar 

  97. Bloom JW, Kaltenborn WT, Quan SF (1988) Risk factors in a general population for snoring. Importance of cigarette smoking and obesity. Chest 93:678–683

    PubMed  CAS  Google Scholar 

  98. Nagayoshi M, Yamagishi K, Tanigawa T, Sakurai S, Kitamura A, Kiyama M, Imano H, Ohira T, Sato S, Sankai T, Iso H (2011) Risk factors for snoring among Japanese men and women: a community-based cross-sectional study. Sleep Breath 15:63–69

    PubMed  Google Scholar 

  99. Van de Berg JF, Neven AK, Tulen JH, Hofman A, Witteman JC, Miedema HM, Tiemeier H (2008) Actigraphic sleep duration and fragmentation are related to obesity in the elderly: the Rotterdam Study. Int J Obes (Lond) 32:1083–1090

    Google Scholar 

  100. Lavie L (2003) Obstructive sleep apnea syndrome—an oxidative stress disorder. Sleep Med Rev 7:35–51

    PubMed  Google Scholar 

  101. Yamauchi M, Nakano H, Maekawa J, Okamoto Y, Ohnishi Y, Suzuki T, Kimura H (2005) Oxidative stress in obstructive sleep apnea. Chest 127:1674–1679

    PubMed  CAS  Google Scholar 

  102. Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, Somers VK (2002) Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 105:2462–2464

    PubMed  CAS  Google Scholar 

  103. Dyugovskaya L, Lavie P, Lavie L (2002) Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 165:859–860

    Google Scholar 

  104. Ohga E, Nagase T, Tomita T, Teramoto S, Matsuse T, Katayama H, Ouchi Y (1999) Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome. J Appl Physiol 87:10–14

    PubMed  CAS  Google Scholar 

  105. Dyugovskaya L, Lavie P, Lavie L (2005) Lymphocyte activation as a possible measure of atherosclerotic risk in patients with sleep apnea. Ann N Y Acad Sci 1051:340–350

    PubMed  CAS  Google Scholar 

  106. Lavie L, Vishnevsky A, Lavie P (2004) Evidence for lipid peroxidation in obstructive sleep apnea. Sleep 27:123–128

    PubMed  Google Scholar 

  107. Chen L, Einbinder E, Zhang Q, Hasday J, Balke CW, Scharf SM (2005) Oxidative stress and left ventricular function with chronic intermittent hypoxia in rats. Am J Respir Crit Care Med 172:915–920

    PubMed  Google Scholar 

  108. Xu W, Chi L, Row BW, Xu R, Ke Y, Xu B, Luo C, Kheirandish L, Gozal D, Liu R (2004) Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea. Neuroscience 126:313–323

    PubMed  CAS  Google Scholar 

  109. Carnevale D, Lembo G (2011) ‘Alzheimer-like’ pathology in a murine model of arterial hypertension. Biochem Soc Trans 39:939–944

    PubMed  CAS  Google Scholar 

  110. de la Torre JC (2002) Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33:1152–1162

    Google Scholar 

  111. Johnson KA, Albert MS (2000) Perfusion abnormalities in prodromal AD. Neurobiol Aging 21:289–292

    PubMed  CAS  Google Scholar 

  112. Kiratli PO, Demir AU, Volkan-Salanci B, Demir B, Sahin A (2010) Cerebral blood flow and cognitive function in obstructive sleep apnea syndrome. Hell J Nucl Med 13:138–143

    PubMed  Google Scholar 

  113. Peled N, Abinader EG, Pillar G, Sharif D, Lavie P (1999) Nocturnal ischemic events in patients with obstructive sleep apnea syndrome and ischemic heart disease: effects of continuous positive air pressure treatment. J Am Coll Cardiol 34:1744–1749

    PubMed  CAS  Google Scholar 

  114. Corfield DR, Meadows GE (2006) Control of cerebral blood flow during sleep and the effects of hypoxia. Adv Exp Med Biol 588:65–73

    PubMed  Google Scholar 

  115. Ayalon L, Peterson S (2007) Functional central nervous system imaging in the investigation of obstructive sleep apnea. Curr Opinion Pulmon Med 13:479–483

    Google Scholar 

  116. Macey KE, Macey PM, Woo MA, Henderson LA, Frysinger RC, Harper RK, Alger JR, Yan-Go F, Harper RM (2006) Inspiratory loading elicits aberrant fMRI signal changes in obstructive sleep apnea. Resp Physiol Neurobiol 151:44–60

    Google Scholar 

  117. Ismail Z, Herrmann N, Francis PL et al (2009) A SPECT study of sleep disturbance and Alzheimer’s disease. Dementia Geriat Cogn Disord 27:254–259

    CAS  Google Scholar 

  118. Kakeda S, Korogi Y (2010) The efficacy of a voxel-based morphometry on the analysis of imaging in schizophrenia, temporal lobe epilepsy, and Alzheimer’s disease/mild cognitive impairment: a review. Neuroradiology 52:711–721

    PubMed  Google Scholar 

  119. Hayakawa T, Terashima M, Kayukawa Y, Ohta T, Okada T (1996) Changes in cerebral oxygenation and hemodynamics during obstructive sleep apneas. Chest 109:916–921

    PubMed  CAS  Google Scholar 

  120. Engleman HM, Kingshott RN, Martin SE et al (2000) Cognitive function in the sleep apnea/hypopnea syndrome (SAHS). Sleep 23(Suppl 4):S102–S108

    PubMed  Google Scholar 

  121. Cohen-Zion M, Stepnowsky C, Marler ShochatT, Kripke DF, Ancoli-Israel S (2001) Changes in cognitive function associated with sleep disordered breathing in older people. J Am Geriatr Soc 49:1622–1627

    PubMed  CAS  Google Scholar 

  122. Shamsuzzaman AS, Gersh BJ, Somers VK (2003) Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 290:1906–1914

    PubMed  CAS  Google Scholar 

  123. Altay T, Gonzales ER, Park TS, Gidday JM (2004) Cerebrovascular inflammation after brief episodic hypoxia: modulation by neuronal and endothelial nitric oxide synthase. J Appl Physiol 96:1223–1230

    PubMed  CAS  Google Scholar 

  124. Cohen-Zion M, Stepnowsky C, Johnson S, Marler M, Dimsdale JE, Ancoli-Israel S (2004) Cognitive changes and sleep disordered breathing in elderly: differences in race. J Psychosom Res 56:549–553

    PubMed  Google Scholar 

  125. Butt M, Dwivedi G, Khair O, Lip GY (2010) Obstructive sleep apnea and cardiovascular disease. Int J Cardiol 139:7–16

    PubMed  Google Scholar 

  126. Mou L, Gates A, Mosser VA, Tobin A, Jackson DA (2006) Transient hypoxia induces sequestration of M1 and M2 muscarinic acetylcholine receptors. J Neurochem 96:510–519

    PubMed  CAS  Google Scholar 

  127. Zimmerman ME, Aloia MS (2006) A review of neuroimaging in obstructive sleep apnea. J Clin Sleep Med 2:461–471

    PubMed  Google Scholar 

  128. Quan SF, Wright R (2006) Obstructive sleep apnea-hypopnea and neurocognitive functioning in the Sleep Heart Health Study. Sleep Med 7:498–507

    PubMed  Google Scholar 

  129. Gu XQ, Haddad GG (2001) Decreased neuronal excitability in hippocampal neurons of mice exposed to cyclic hypoxia. J Appl Physiol 91:1245–1250

    PubMed  CAS  Google Scholar 

  130. Alchanatis M, Zias N, Deligiorgis N et al (2008) Comparison of cognitive performance among different age groups in patients with obstructive sleep apnea. Sleep Breath 12:17–24

    PubMed  Google Scholar 

  131. Gale SD, Hopkins RO (2004) Effects of hypoxia on the brain: neuroimaging and neuropsychological findings following carbon monoxide poisoning and obstructive sleep apnea. J Int Neuropsychol Soc 10:60–71

    PubMed  Google Scholar 

  132. Spira AP, Blackwell T, Stone KL, Redline S, Cauley JA, Ancoli-Israel S, Yaffe K (2008) Sleep-disordered breathing and cognition in older women. J Am Geriatr Soc 56:45–50

    PubMed  Google Scholar 

  133. Carlson BW, Neelon VJ, Carlson JR, Hartman M, Bliwise DL (2011) Cerebral oxygenation in wake and during sleep and its relationship to cognitive function in community-dwelling older adults without sleep disordered breathing. J Gerontol A Biol Sci Med Sci 66:150–156

    PubMed  Google Scholar 

  134. Walker MP (2009) The role of sleep in cognition and emotion. Ann N Y Acad Sci 1156:168–197

    PubMed  Google Scholar 

  135. Bartlett DJ, Rae C, Thompson CH, Byth K, Joffe DA, Enright T, Grunstein RR (2004) Hippocampal area metabolites relate to severity and cognitive function in obstructive sleep apnea. Sleep Med 5:593–596

    PubMed  Google Scholar 

  136. Bliwise DL (1996) Is sleep apnea a cause of reversible dementia in old age? J Am Geriatr Soc 44:1407–1409

    PubMed  CAS  Google Scholar 

  137. Allahdadi KJ, Duling LC, Walker BR, Kanagy NL (2008) Eucapnic intermittent hypoxia augments endothelin-1 vasoconstriction in rats: role of PKCdelta. Am J Physiol Heart Circ Physiol 294:H920–H927

    PubMed  CAS  Google Scholar 

  138. Farré R, Montserrat JM, Navajas D (2008) Morbidity due to obstructive sleep apnea: insights from animal models. Curr Opin Pulm Med 14:530–536

    PubMed  Google Scholar 

  139. Bullitt E, Zeng D, Mortamet B et al (2010) The effects of healthy aging on intracerebral blood vessels visualized by magnetic resonance angiography. Neurobiol Aging 31:290–300

    PubMed  Google Scholar 

  140. Beebe DW, Groesz L, Wells C, Nichols A, McGee K (2003) The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep 26:298–307

    PubMed  Google Scholar 

  141. Thomas RJ, Rosen BR, Stern CE, Weiss JW, Kwong KK (2005) Functional imaging of working memory in obstructive sleep-disordered breathing. J Appl Physiol 98:2226–2234

    PubMed  Google Scholar 

  142. Ayalon L, Ancoli-Israel S, Aka AA, McKenna BS, Drummond SP (2009) Relationship between obstructive sleep apnea severity and brain activation during a sustained attention task. Sleep 32:373–381

    PubMed  Google Scholar 

  143. Kato M, Roberts-Thomson P, Phillips BG et al (2000) Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102:2607–2610

    PubMed  CAS  Google Scholar 

  144. Jelic S, Padeletti M, Kawut SM et al (2008) Inflammation, oxidative stress and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation 117:2270–2278

    PubMed  CAS  Google Scholar 

  145. Patt BT, Jarjoura D, Haddad DN, Sen CK, Roy S, Flavahan NA, Khayat RN (2010) Endothelial dysfunction in the microcirculation of patients with obstructive sleep apnea. Am J Respir Crit Care Med 182:1540–1545

    PubMed  Google Scholar 

  146. Li RC, Row BW, Gozal E, Kheirandish L, Fan Q, Brittian KR, Guo SZ, Sachleben LR Jr, Gozal D (2003) Cyclooxygenase 2 and intermittent hypoxia-induced spatial deficits in the rat. Am J Respir Crit Care Med 168:469–475

    PubMed  Google Scholar 

  147. Takase B, Akima T, Uehata A, Ohsuzu F, Kurita A (2004) Effect of chronic stress and sleep deprivation on both flow-mediated dilation in the brachial artery and the intracellular magnesium level in humans. Clin Cardiol 27:223–227

    PubMed  Google Scholar 

  148. Shearer WT, Reuben JM, Mullington JM, Price NJ, Lee BN, Smith EO, Szuba MP, Van Dongen HP, Dinges DF (2001) Soluble TNF-α receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight. J Allergy Clin Immunol 107:165–170

    PubMed  CAS  Google Scholar 

  149. Vgontzas AN, Zoumakis E, Bixler EO, Lin HM, Follett H, Kales A, Chrousos GP (2004) Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 89:2119–2126

    PubMed  CAS  Google Scholar 

  150. von Känel R, Dimsdale JE, Ancoli-Israel S, Mills PJ, Patterson TL, McKibbin CL, Archuleta C, Grant I (2006) Poor sleep is associated with higher plasma proinflammatory cytokine interleukin-6 and procoagulant marker fibrin D-dimer in older caregivers of people with Alzheimer’s disease. J Am Geriatr Soc 54:431–437

    Google Scholar 

  151. Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, Pritchard KA Jr (1998) Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 95:9220–9225

    PubMed  CAS  Google Scholar 

  152. Xia Y, Tsai AL, Berka V, Zweier JL (1998) Superoxide generation from endothelial nitric-oxide synthase. A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem 273:25804–25808

    PubMed  CAS  Google Scholar 

  153. Dhar-Mascareno M, Cárcamo JM, Golde DW (2005) Hypoxia-reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells are inhibited by vitamin C. Free Radic Biol Med 38:1311–1322

    PubMed  CAS  Google Scholar 

  154. Jean A (1991) The nucleus tractus solitarius: neuroanatomic, neurochemical and functional aspects. Arch Int Physiol Biochim Biophys 99:A3–A52

    PubMed  CAS  Google Scholar 

  155. Andresen MC, Kunze DL (1994) Nucleus tractus solitarius-gateway to neural circulatory control. Annu Rev Physiol 56:93–116

    PubMed  CAS  Google Scholar 

  156. Seller H, Illert M (1969) The localization of the first synapse in the carotid sinus baroreceptor reflex pathway and its alteration of the afferent input. Pflugers Arch 306:1–19

    PubMed  CAS  Google Scholar 

  157. Andresen MC, Mendelowitz D (1996) Sensory afferent neurotransmission in caudal nucleus tractus solitarius—common denominators. Chem Senses 21:387–395

    PubMed  CAS  Google Scholar 

  158. Aylwin ML, Horowitz JM, Bonham AC (1998) Non-NMDA and NMDA receptors in the synaptic pathway between area postrema and nucleus tractus solitarius. Am J Physiol 275:H1236–H1246

    PubMed  CAS  Google Scholar 

  159. Bajetto A, Bonavia R, Barbero S, Schettini G (2002) Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J Neurochem 82:1311–1329

    PubMed  CAS  Google Scholar 

  160. Emch GS, Hermann GE, Rogers RC (2001) TNF-alpha-induced c-Fos generation in the nucleus of the solitary tract is blocked by NBQX and MK-801. Am J Physiol Regul Integr Comp Physiol 281:R1394–R1400

    PubMed  CAS  Google Scholar 

  161. Kawanokuchi J, Mizuno T, Takeuchi H, Kato H, Wang J, Mitsuma N, Suzumura A (2006) Production of interferon-gamma by microglia. Mult Scler 12:558–564

    PubMed  CAS  Google Scholar 

  162. Hermann GE, Emch GS, Tovar CA, Rogers RC (2001) c-Fos generation in the dorsal vagal complex after systemic endotoxin is not dependent on the vagus nerve. Am J Physiol Regul Integr Comp Physiol 280:R289–R299

    PubMed  CAS  Google Scholar 

  163. Dantzer R (2004) Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol 500:399–411

    PubMed  CAS  Google Scholar 

  164. Rozovsky I, Finch CE, Morgan TE (1998) Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation. Neurobiol Aging 19:97–103

    PubMed  CAS  Google Scholar 

  165. Sternberg EM (2006) Neural regulation of innate immunity: a coordinated nonspecific response to pathogens. Nat Rev Immunol 6:318–328

    PubMed  CAS  Google Scholar 

  166. Tracey KJ (2007) Physiology and immunology of the cholinergic anti-inflammatory pathway. J Clin Invest 117:289–296

    PubMed  CAS  Google Scholar 

  167. Van der Zanden EP, Boeckxstaens GE, De Jonge WJ (2009) The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterol Motil 21:6–17

    Google Scholar 

  168. Maier SF, Goehler LE, Fleshner M, Watkins LR (1998) The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci 840:289–300

    PubMed  CAS  Google Scholar 

  169. Groves DA, Brown VJ (2005) Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neurosci Biobehav Rev 29:493–500

    PubMed  Google Scholar 

  170. Castle M, Comoli E, Loewy AD (2005) Autonomic brainstem nuclei are linked to the hippocampus. Neuroscience 134:657–669

    PubMed  CAS  Google Scholar 

  171. Rosas-Ballina M, Tracey KJ (2009) The neurology of the immune system: neural reflexes regulate immunity. Neuron 15(64):28–32

    Google Scholar 

  172. Rosas-Ballina M, Tracey KJ (2009) Cholinergic control of inflammation. J Intern Med 265:663–679

    PubMed  CAS  Google Scholar 

  173. Ter Horst GJ, Postema F (1997) Forebrain parasympathetic control of heart activity: retrograde transneuronal viral labeling in rats. Am J Physiol 273:H2926–H2930

    PubMed  CAS  Google Scholar 

  174. Weber CS, Thayer JF, Rudat M, Wirtz PH, Zimmermann-Viehoff F, Thomas A, Perschel FH, Arck PC, Deter HC (2010) Low vagal tone is associated with impaired post stress recovery of cardiovascular, endocrine, and immune markers. Eur J Appl Physiol 109:201–211

    PubMed  Google Scholar 

  175. Espinosa-Oliva AM, de Pablos RM, Villarán RF, Argüelles S, Venero JL, Machado A, Cano J (2011) Stress is critical for LPS-induced activation of microglia and damage in the rat hippocampus. Neurobiol Aging 32:85–102

    PubMed  CAS  Google Scholar 

  176. Tagliari B, Tagliari AP, Schmitz F, da Cunha AA, Dalmaz C, Wyse AT (2011) Chronic variable stress alters inflammatory and cholinergic parameters in hippocampus of rats. Neurochem Res 36:487–493

    PubMed  CAS  Google Scholar 

  177. Ricardo JA, Koh TE (1978) Anatomical evidence of direct projection from the nucleus of the solitary tract to the hypothalamus, amygdala, and forebrain structures in the rat. Brain Res 153:l–26

    Google Scholar 

  178. Schwaber JS, Kapp BS, Higgins GA, Rapp PR (1982) Amygdaloid and basal forebrain direct connections with the nucleus of the solitary tract and the dorsal motor nucleus. J Neurosci 2:1424–1438

    PubMed  CAS  Google Scholar 

  179. Clayton EC, Williams CL (2000) Adrenergic activation of the nucleus tractus solitarius potentiates amygdala norepinephrine release and enhances retention performance in emotionally arousing and spatial memory tasks. Behav Brain Res 112:151–158

    PubMed  CAS  Google Scholar 

  180. Barnes DE, Yaffe K, Satariano WA, Tager IB (2003) A longitudinal study of cardiorespiratory fitness and cognitive function in healthy older adults. J Am Geriatr Soc 51:459–465

    PubMed  Google Scholar 

  181. Adlard PA, Perreau VM, Pop V, Cotman CW (2005) Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J Neurosci 25:4217–4221

    PubMed  CAS  Google Scholar 

  182. Heyn P, Abreu BC, Ottenbacher KJ (2004) The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 85:1694–1704

    PubMed  Google Scholar 

  183. Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WT (1990) Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc Natl Acad Sci USA 87:5568–5572

    PubMed  CAS  Google Scholar 

  184. Cotman CW, Berchtold NC (2002) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25:295–301

    PubMed  CAS  Google Scholar 

  185. Neeper SA, Gómez-Pinilla F, Choi J, Cotman C (1995) Exercise and brain neurotrophins. Nature 373:109

    PubMed  CAS  Google Scholar 

  186. van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680–8685

    PubMed  Google Scholar 

  187. Drager LF, Diegues-Silva L, Diniz PM, Bortolotto LA, Pedrosa RP, Couto RB, Marcondes B, Giorgi DM, Lorenzi-Filho G, Krieger EM (2010) Obstructive sleep apnea, masked hypertension, and arterial stiffness in men. Am J Hypertens 23:249–254

    PubMed  Google Scholar 

  188. Miralbell J, Soriano JJ, Spulber G, López-Cancio E, Arenillas JF, Bargalló N, Galán A et al (2011) Structural brain changes and cognition in relation to markers of vascular dysfunction. Neurobiol Aging [Epub ahead of print]

  189. Sparks DL, Scheff SW, Liu H, Landers TM, Coyne CM, Hunsaker JC 3rd (1995) Increased incidence of neurofibrillary tangles (NFT) in non-demented individuals with hypertension. J Neurol Sci 131:162–169

    PubMed  CAS  Google Scholar 

  190. Makris TK, Thomopoulos C, Papadopoulos DP, Bratsas A, Papazachou O, Massias S, Michalopoulou E, Tsioufis C, Stefanadis C (2009) Association of passive smoking with masked hypertension in clinically normotensive nonsmokers. Am J Hypertens 22:853–859

    PubMed  Google Scholar 

  191. Qiu C, Winblad B, Fratiglioni L (2005) The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol 4:487–499

    PubMed  Google Scholar 

  192. Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol 100:328–335

    PubMed  CAS  Google Scholar 

  193. Mohaupt MG, Schmidli J, Luft FC (2007) Management of uncontrollable hypertension with a carotid sinus stimulation device. Hypertension 50:825–828

    PubMed  CAS  Google Scholar 

  194. Sloand JA, Illig KA, Bisognano JD (2007) Improved control of resistant hypertension with device-mediated electrical carotid sinus baroreflex stimulation. J Clin Hypertens 9:716–719

    Google Scholar 

  195. Loewy AD, McKellar S (1980) The neuroanatomical basis of central cardiovascular control. Fed Proc 39:2495–2503

    PubMed  CAS  Google Scholar 

  196. Ferrario CM, Barnes KL, Bohonek S (1981) Neurogenic hypertension produced by lesions of the nucleus tractus solitarii alone or with sinoaortic denervation in the dog. Hypertension 3:112–118

    Google Scholar 

  197. Machado BH, Mauad H, Chianca Júnior DA, Haibara AS, Colombari E (1997) Autonomic processing of the cardiovascular reflexes in the nucleus tractus solitarii. Braz J Med Biol Res 30:533–543

    PubMed  CAS  Google Scholar 

  198. Minson JB, Llewellyn-Smith IJ, Arnolda LF, Pilowsky PM, Chalmers JP (1997) C-fos expression in central neurons mediating the arterial baroreceptor reflex. Clin Exp Hypertens 19:631–643

    PubMed  CAS  Google Scholar 

  199. Paton JF, Deuchars J, Ahmad Z, Wong LF, Murphy D, Kasparov S (2001) Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat. J Physiol 531:445–458

    PubMed  CAS  Google Scholar 

  200. Waki H, Kasparov S, Wong LF, Murphy D, Shimizu T, Paton JF (2003) Chronic inhibition of endothelial nitric oxide synthase activity in nucleus tractus solitarii enhances baroreceptor reflex in conscious rats. J Physiol 546:233–242

    PubMed  CAS  Google Scholar 

  201. Itoh H, Buñag RD (1992) Catecholaminergic nucleus tractus solitarius lesions in anesthetized rats alter baroreflexes differently with age. Mech Ageing Dev 64:69–84

    PubMed  CAS  Google Scholar 

  202. Itoh H, Buñag RD (1993) Age-related reduction of reflex bradycardia in conscious rats by catecholaminergic nucleus tractus solitarius lesions. Mech Ageing Dev 67:47–63

    PubMed  CAS  Google Scholar 

  203. Ebert TJ, Morgan BJ, Barney JA, Denahan T, Smith JJ (1992) Effects of aging on baroreflex regulation of sympathetic activity in humans. Am J Physiol 263:H798–H803

    PubMed  CAS  Google Scholar 

  204. Hamaad A, Sosin M, Blann AD, Patel J, Lip GY, MacFadyen RJ (2005) Markers of inflammation in acute coronary syndromes: association with increased heart rate and reductions in heart rate variability. Clin Cardiol 28:570–576

    PubMed  Google Scholar 

  205. Francis GS (1989) The relationship of the sympathetic nervous system and the renin–angiotensin system in congestive heart failure. Am Heart J 118:642

    PubMed  CAS  Google Scholar 

  206. Zhang W, Huang BS, Leenen FH (1999) Brain renin–angiotensin system and sympathetic hyperactivity in rats after myocardial infarction. Am J Physiol 276:H1608–H1615

    PubMed  CAS  Google Scholar 

  207. Teisman AC, Westerink BH, van Veldhuisen DJ, Scholtens E, de Zeeuw D, van Gilst WH (1999) Direct interaction between the sympathetic and renin–angiotensin system in myocardial tissue: a microdialysis study in anaesthetised rats. J Auton Nerv Syst 78:117–121

    Google Scholar 

  208. Kalsner S, Quillan M (1988) Presynaptic interactions between acetylcholine and adrenergic antagonists on norepinephrine release. J Pharmacol Exp Ther 244:879–891

    PubMed  CAS  Google Scholar 

  209. Giessler C, Dhein S, Ponicke K, Brodde OE (1999) Muscarinic receptors in the failing human heart. Eur J Pharmacol 375:197–202

    PubMed  CAS  Google Scholar 

  210. Renaudon B, Bois P, Bescond J, Lenfant J (1997) Acetylcholine modulates I(f) and IK(ACh) via different pathways in rabbit sino-atrial node cells. J Mol Cell Cardiol 29:969–975

    PubMed  CAS  Google Scholar 

  211. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462

    PubMed  CAS  Google Scholar 

  212. Augustyniak RA, Thomas GD, Victor RG, Zhang W (2005) Nitric oxide pathway as new drug targets for refractory hypertension. Curr Pharm Des 11:3307–3315

    PubMed  CAS  Google Scholar 

  213. Gupta R, Imai M, Jiang A, Wang M, Sabba H (2006) Chronic therapy with selective electric vagus nerve stimulation normalizes plasma concentration of tissue necrosis factor? Interleukin-6 and B-type natriuretic peptide in dogs with heart failure. J Am Coll Cardiol 47:77A

    Google Scholar 

  214. Gupta R, Mishra S, Rastogi S, Imai M, Zaca V, Sabba H (2006) Chronic therapy with electric vagus nerve stimulation normalizes mRNA and protein expression of nitric oxide synthase in myocardium of dogs with heart failure. Eur Heart J 27:477A

    Google Scholar 

  215. Dean JB, Putnam RW (2010) The caudal solitary complex is a site of central CO(2) chemoreception and integration of multiple systems that regulate expired CO(2). Respir Physiol Neurobiol 173:274–287

    PubMed  Google Scholar 

  216. Yilmaz MS, Goktalay G, Millington WR, Myer BS, Cutrera RA, Feleder C (2008) Lipopolysaccharide-induced hypotension is mediated by a neural pathway involving the vagus nerve, the nucleus tractus solitarius and alpha-adrenergic receptors in the preoptic anterior hypothalamic area. J Neuroimmunol 203:39–49

    PubMed  CAS  Google Scholar 

  217. Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, Henry TR, Collins SD, Vaughn BV et al (1998) Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 51:48–55

    PubMed  CAS  Google Scholar 

  218. Krahl SE, Clark KB, Smith DC, Browning RA (1998) Locus coeroleus lesions suppress the seizure attenuating effects of vagus nerve stimulation. Epilepsia 39:709–714

    PubMed  CAS  Google Scholar 

  219. Naritoku DK, Terry WJ, Helfert RH (1995) Regional induction of Fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res 22:53–62

    PubMed  CAS  Google Scholar 

  220. Kessler W, Traeger T, Westerholt A, Neher F, Mikulcak M, Müller A, Maier S, Heidecke CD (2006) The vagal nerve as a link between the nervous and immune system in the instance of polymicrobial sepsis. Langenbecks Arch Surg 391:83–87

    PubMed  Google Scholar 

  221. Ulloa L (2005) The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov 4:673–684

    PubMed  CAS  Google Scholar 

  222. Boon P, Moors I, De Herdt V, Vonck K (2006) Vagus nerve stimulation and cognition. Seizure 15:259–263

    PubMed  Google Scholar 

  223. Helmstaedter C, Hoppe C, Elger CE (2001) Memory alterations during acute high-intensity vagus nerve stimulation. Epilepsy Res 47:37–42

    PubMed  CAS  Google Scholar 

  224. Ghacibeh GA, Shenker JI, Shenal B, Uthman BM, Heilman KM (2006) The influence of vagus nerve stimulation on memory. Cogn Behav Neurol 19:119–122

    PubMed  Google Scholar 

  225. Ghacibeh GA, Shenker JI, Shenal B, Uthman BM, Heilman KM (2006) Effect of vagus nerve stimulation on creativity and cognitive flexibility. Epilepsy Behav 8:720–725

    PubMed  Google Scholar 

  226. Hartig W, Bauer A, Brauer K, Grosche J, Hortobagyi T, Penke B, Schliebs R, Harkany T (2002) Functional recovery of cholinergic basal forebrain neurons under disease conditions: old problems, new solutions? Rev Neurosci 13:95–165

    PubMed  Google Scholar 

  227. Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221:555–563

    PubMed  CAS  Google Scholar 

  228. Nyakas C, Granic I, Halmy LG, Banerjee P, Luiten PG (2011) The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine. Behav Brain Res 221:594–603

    PubMed  CAS  Google Scholar 

  229. Mesulam M (2004) The cholinergic lesion of Alzheimer’s Disease: pivotal factor or side show? Learning & Memory 11:43–49

    Google Scholar 

  230. Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28:327–335

    PubMed  CAS  Google Scholar 

  231. Counts SE, Mufson EJ (2010) Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity. J Neurochem 113:649–660

    PubMed  CAS  Google Scholar 

  232. Insua D, Suárez ML, Santamarina G, Sarasa M, Pesini P (2010) Dogs with canine counterpart of Alzheimer’s disease lose noradrenergic neurons. Neurobiol Aging 31:625–635

    PubMed  CAS  Google Scholar 

  233. Foote SL, Bloom FE, Aston-Jones G (1983) Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev 63:844–914

    PubMed  CAS  Google Scholar 

  234. Heneka MT, Galea E, Gavriluyk V, Dumitrescu-Ozimek L, Daeschner J, O’Banion MK, Weinberg G, Klockgether T, Feinstein DL (2002) Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer’s disease. J Neurosci 22:2434–2442

    PubMed  CAS  Google Scholar 

  235. Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, Sastre M et al (2006) Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 26:1343–1354

    PubMed  CAS  Google Scholar 

  236. Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D (2010) Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107:6058–6063

    PubMed  CAS  Google Scholar 

  237. Kalinin S, Gavrilyuk V, Polak PE, Vasser R, Zhao J, Heneka MT, Feinstein DL (2007) Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer’s disease. Neurobiol Aging 28:1206–1214

    PubMed  CAS  Google Scholar 

  238. Madrigal JL, Kalinin S, Richardson JC, Feinstein DL (2007) Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta. J Neurochem 103:2092–2101

    PubMed  CAS  Google Scholar 

  239. Traver S, Salthun-Lassalle B, Marien M, Hirsch EC, Colpaert F, Michel PP (2005) The neurotransmitter noradrenaline rescues septal cholinergic neurons in culture from degeneration caused by low-level oxidative stress. Mol Pharmacol 67:1882–1891

    PubMed  CAS  Google Scholar 

  240. Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337–341

    PubMed  Google Scholar 

  241. Gonzalo-Ruiz A, González I, Sanz-Anquela JM (2003) Effects of beta-amyloid protein on serotoninergic, noradrenergic, and cholinergic markers in neurons of the pontomesencephalic tegmentum in the rat. J Chem Neuroanat 26:153–169

    PubMed  CAS  Google Scholar 

  242. Ohm TG, Busch C, Bohl J (1997) Unbiased estimation of neuronal numbers in the human nucleus coeruleus during aging. Neurobiol Aging 18:393–399

    PubMed  CAS  Google Scholar 

  243. Goldman G, Coleman PD (1981) Neuron numbers in locus coeruleus do not change with age in Fisher 344 rat. Neurobiol Aging 2:33–36

    PubMed  CAS  Google Scholar 

  244. Fujiwara N, Higashi H, Shimoji K, Yoshimura M (1987) Effects of hypoxia on rat hippocampal neurones in vitro. J Physiol 384:131–151

    PubMed  CAS  Google Scholar 

  245. Shimoji K, Higashi H, Fujiwara N, Fukuda S, Yoshimura M (1989) Hypoxia in brain slices. Biomed Biochim Acta 48:S149–S154

    PubMed  CAS  Google Scholar 

  246. Nieber K, Sevcik J, Illes P (1995) Hypoxic changes in rat locus coeruleus neurons in vitro. J Physiol 486:33–46

    PubMed  CAS  Google Scholar 

  247. Yang JJ, Chou YC, Lin MT, Chiu TH (1997) Hypoxia-induced differential electrophysiological changes in rat locus coeruleus neurons. Life Sci 61:1763–1773

    PubMed  CAS  Google Scholar 

  248. Ma S, Mifflin SW, Cunningham JT, Morilak DA (2008) Chronic intermittent hypoxia sensitizes acute hypothalamic-pituitary-adrenal stress reactivity and Fos induction in the rat locus coeruleus in response to subsequent immobilization stress. Neuroscience 154:1639–1647

    PubMed  CAS  Google Scholar 

  249. Zhu Y, Fenik P, Zhan G, Mazza E, Kelz M, Aston-Jones G, Veasey SC (2007) Selective loss of catecholaminergic wake active neurons in a murine sleep apnea model. J Neurosci 27:10060–10071

    PubMed  CAS  Google Scholar 

  250. Manta S, Dong J, Debonnel G, Blier P (2009) Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation. J Psychiatry Neurosci 34:272–280

    PubMed  Google Scholar 

  251. Insausti R, Amaral DG, Cowan WM (1987) The entorhinal cortex of the monkey: II. Cortical afferents. J Comp Neurol 264:356–395

    PubMed  CAS  Google Scholar 

  252. Liu P, Bilkey DK (1997) Parallel involvement of perirhinal and lateral entorhinal cortex in the polysynaptic activation of hippocampus by olfactory inputs. Hippocampus 7:296–306

    PubMed  CAS  Google Scholar 

  253. Mouly A-M, Litaudon P, Chabaud P, Ravel N, Gervais R (1998) Spatiotemporal distribution of a late synchronized activity in olfactory pathways following stimulation of the olfactory bulb in rats. Eur J Neurosci 10:1128–1135

    PubMed  CAS  Google Scholar 

  254. Chapman CA, Racine RJ (1997) Piriform cortex efferents to the entorhinal cortex in vivo: kindling-induced potentiation and the enhancement of long-term potentiation by low-frequency piriform cortex or medial septal stimulation. Hippocampus 7:257–270

    PubMed  CAS  Google Scholar 

  255. Th VanGroen, Lopes da Silva FH, Wadman WJ (1987) Synaptic organization of olfactory inputs and local circuits in the entorhinal cortex, a current source density analysis in the cat. Exp Brain Res 67:615–622

    Google Scholar 

  256. Witter MP, Amaral DG (1991) Entorhinal cortex of the monkey: V. Projections to the dentate gyrus, hippocampus, and subicular complex. J Comp Neurol 307:437–459

    PubMed  CAS  Google Scholar 

  257. Zola-Morgan S, Squire LR, Amaral DG, Suzuki WA (1989) Lesions of perirhinal and parahippocampal cortex that spare the amygdala and hippocampal formation produce severe memory impairment. J Neurosci 9:4355–4370

    PubMed  CAS  Google Scholar 

  258. Du AT, Schuff N, Amend D, Laakso MP, Hsu YY et al (2001) Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 71:441–447

    PubMed  CAS  Google Scholar 

  259. Gómez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16:4491–4500

    PubMed  Google Scholar 

  260. Pennanen C, Kivipelto M, Tuomainen S, Hartikainen P, Hanninen T, Laakso MP, Hallikainen M et al (2004) Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiol Aging 25:303–310

    PubMed  Google Scholar 

  261. Christen-Zaech S, Kraftsik R, Pillevuit O, Kiraly M, Martins R, Khalili K, Miklossy J (2003) Early olfactory involvement in Alzheimer’s disease. Can J Neurol Sci 30:20–25

    PubMed  CAS  Google Scholar 

  262. Wilson RS, Arnold SE, Schneider JA, Tang Y, Bennett DA (2007) The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry 78:30–35

    PubMed  CAS  Google Scholar 

  263. Velayudhan L, Lovestone S (2009) Smell identification test as a treatment response marker in patients with Alzheimer disease receiving donepezil. J Clin Psychopharmacol 29:387–390

    PubMed  CAS  Google Scholar 

  264. Ruggiero DA, Anwar S, Kim J, Glickstein SB (1998) Visceral afferent pathways to the thalamus and olfactory tubercle: behavioral implications. Brain Res 799:159–171

    PubMed  CAS  Google Scholar 

  265. Guevara-Guzman R, Garcia-Diaz DE, Solano-Flores LP, Wayner MJ, Armstrong DL (1991) Role of the paraventricular nucleus in the projection from the nucleus of the solitary tract to the olfactory bulb. Brain Res Bull 27:447–450

    PubMed  CAS  Google Scholar 

  266. García-Díaz DE, Aguilar-Baturoni HU, Guevara-Aguilar R, Wayner MJ (1984) Vagus nerve stimulation modifies the electrical activity of the olfactory bulb. Brain Res Bull 12:529–537

    PubMed  Google Scholar 

  267. de Toledo-Morrell L, Goncharova I, Dickerson B, Wilson RS, Bennett DA (2000) From healthy aging to early Alzheimer’s disease: in vivo detection of entorhinal cortex atrophy. Ann N Y Acad Sci 911:240–253

    PubMed  Google Scholar 

  268. Kerfoot EC, Chattillion EA, Williams CL (2008) Functional interactions between the nucleus tractus solitarius (NTS) and nucleus accumbens shell in modulating memory for arousing experiences. Neurobiol Learn Mem 89:47–60

    PubMed  Google Scholar 

  269. Danielsen EH, Magnuson DJ, Gray TS (1989) The central amygdaloid nucleus innervation of the dorsal vagal complex in rat: a Phaseolus vulgaris leucoagglutinin lectin anterograde tracing study. Brain Res Bull 22:705–715

    PubMed  CAS  Google Scholar 

  270. Saha S, Batten TF, Henderson Z (2000) A GABAergic projection from the central nucleus of the amygdala to the nucleus of the solitary tract: a combined anterograde tracing and electron microscopic immunohistochemical study. Neuroscience 99:613–626

    PubMed  CAS  Google Scholar 

  271. Saha S, Henderson Z, Batten TF (2002) Somatostatin immunoreactivity in axon terminals in rat nucleus tractus solitarii arising from central nucleus of amygdala: coexistence with GABA and postsynaptic expression of sst2A receptor. J Chem Neuroanat 24:1–13

    PubMed  CAS  Google Scholar 

  272. Zhang X, Cui J, Tan Z, Jiang C, Fogel R (2003) The central nucleus of the amygdala modulates gut-related neurons in the dorsal vagal complex in rats. J Physiol 553:1005–1018

    PubMed  CAS  Google Scholar 

  273. Rinaman L (2010) Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure. Brain Res 1350:18–34

    PubMed  CAS  Google Scholar 

  274. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291

    PubMed  CAS  Google Scholar 

  275. Tansey MG, McCoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 208:1–25

    PubMed  CAS  Google Scholar 

  276. Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A (2007) Neuroinflammation in Alzheimer’s disease and Parkinson’s disease: are microglia pathogenic in either disorder? Int Rev Neurobiol 82:235–246

    PubMed  CAS  Google Scholar 

  277. Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 37:289–305

    PubMed  CAS  Google Scholar 

  278. Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, Stijnen T, Hofman A, Witteman JC (2004) Inflammatory proteins in plasma and the risk of dementia: the Rotterdam Study. Arch Neurol 61:668–672

    PubMed  Google Scholar 

  279. Celle S, Peyron R, Faillenot I, Pichot V, Alabdullah M, Gaspoz JM, Laurent B, Barthélémy JC, Roche F (2009) Undiagnosed sleep-related breathing disorders are associated with focal brainstem atrophy in the elderly. Hum Brain Mapp 30:2090–2097

    PubMed  Google Scholar 

  280. Daulatzai M (2010) Early stages of pathogenesis in memory impairment during normal senescence and Alzheimer’s disease. J Alzheimers Dis 20:355–367

    PubMed  CAS  Google Scholar 

  281. Daulatzai M (2011) Role of sensory stimulation in amelioration of obstructive sleep apnea. Sleep Disorders 2011:596879

    Google Scholar 

  282. Waki H, Bhuiyan ME, Gouraud SS, Takagishi M, Hatada A, Kohsaka A, Paton JF, Maeda M (2011) Acute reductions in blood flow restricted to the dorsomedial medulla induce a pressor response in rats. J Hypertens 29:1536–1545

    PubMed  CAS  Google Scholar 

  283. Stanimirovic D, Shapiro A, Wong J, Hutchison J, Durkin JP (1997) The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion. J Neuroimmunol 76:193–205

    PubMed  CAS  Google Scholar 

  284. Mojsilovic-Petrovic J, Callaghan D, Cui H, Dean C, Stanimirovic DB, Zhang W (2007) Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes. J Neuroinflammation 4:12

    PubMed  Google Scholar 

  285. Zhang W, Mojsilovic-Petrovic J, Callaghan D, Jones A, Cui H, Howlett C, Stanimirovic D (2006) Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of Interleukin-1β (IL-1β) in astrocyte cultures. J Neuroimmunol 174:63–73

    PubMed  CAS  Google Scholar 

  286. Csiszar A, Wang M, Lakatta EG, Ungvari Z (2008) Inflammation and endothelial dysfunction during aging: role of NF-kappaB. J Appl Physiol 105:1333–1341

    PubMed  CAS  Google Scholar 

  287. Ohi Y, Ishii Y, Sasahara M, Haji A (2010) Involvement of platelet-derived growth factor-BB and its receptor-beta in hypoxia-induced depression of excitatory synaptic transmission in the nucleus tractus solitarius of mice. J Pharmacol Sci 112:477–481

    PubMed  CAS  Google Scholar 

  288. Macey PM, Macey KE, Henderson LA, Alger JR, Frysinger RC, Woo MA, Yan-Go F, Harper RM (2003) Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea. Respir Physiol Neurobiol 138:275–290

    PubMed  CAS  Google Scholar 

  289. Nair D, Dayyat EA, Zhang SX, Wang Y, Gozal D (2011) Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea. PLoS One 6:e19847

    PubMed  CAS  Google Scholar 

  290. Kim SJ, Lee JH, Lee DY, Jhoo JH, Woo JI (2011) Neurocognitive dysfunction associated with sleep quality and sleep apnea in patients with mild cognitive impairment. Am J Geriatr Psychiatry 19:374–381

    PubMed  Google Scholar 

  291. Zhu Y, Fenik P, Zhan G, Sanfillipo-Cohn B, Naidoo N, Veasey SC (2008) Eif-2a protects brainstem motoneurons in a murine model of sleep apnea. J Neurosci 28:2168–2178

    PubMed  CAS  Google Scholar 

  292. Kaur C, Viswanathan S, Ling EA (2011) Hypoxia-induced cellular and vascular changes in the nucleus tractus solitarius and ventrolateral medulla. J Neuropathol Exp Neurol 70:201–217

    PubMed  CAS  Google Scholar 

  293. Steiropoulos P, Papanas N, Nena E, Antoniadou M, Serasli E, Papoti S, Hatzizisi O, Kyriazis G, Tzouvelekis A, Maltezos E, Tsara V, Bouros D (2010) Inflammatory markers in middle-aged obese subjects: does obstructive sleep apnea syndrome play a role? Mediat Inflamm 2010:675320

    Google Scholar 

  294. Porzionato A, Macchi V, Guidolin D, Sarasin G, Parenti A, De Caro R (2008) Anatomic distribution of apoptosis in medulla oblongata of infants and adults. J Anat 212:106–113

    PubMed  CAS  Google Scholar 

  295. Stecco C, Porzionato A, Macchi V, Sarasin G, Calcagno A, Parenti A, De Caro R (2005) Detection of apoptosis in human brainstem by TUNEL assay. Ital J Anat Embryol 110:255–260

    PubMed  Google Scholar 

  296. Batti L, O’Connor JJ (2010) Tumor necrosis factor-alpha impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices. J Neuroimmunol 218:21–27

    PubMed  CAS  Google Scholar 

  297. Zhang JH, Fung SJ, Xi M, Sampogna S, Chase MH (2010) Apnea produces neuronal degeneration in the pons and medulla of guinea pigs. Neurobiol Dis 40:251–264

    PubMed  CAS  Google Scholar 

  298. Jamieson GA, Maitland NJ, Itzhaki RF (1992) Herpes simplex virus type 1 DNA sequences are present in aged normal and Alzheimer’s disease brain but absent in lymphocytes. Arch Gerontol Geriatr 15:197–201

    PubMed  Google Scholar 

  299. Wozniak MA, Itzhaki RF (2010) Antiviral agents in Alzheimer’s disease: hope for the future? Ther Adv Neurol Disord 3:141–152

    PubMed  CAS  Google Scholar 

  300. Fay RA, Norgren R (1997) Identification of rat brainstem multisynaptic connections to the oral motor nuclei using pseudorabies virus. III. Lingual muscle motor systems. Brain Res Rev 25:291–311

    PubMed  CAS  Google Scholar 

  301. Williams AE, Blakemore WF (1990) Monocyte-mediated entry of pathogens into the central nervous system. Neuropathol Appl Neurobiol 16:377–392

    PubMed  CAS  Google Scholar 

  302. Leyva-Grado VH, Churchill L, Wu M, Williams TJ, Taishi P, Majde JA, Krueger JM (2009) Influenza virus- and cytokine-immunoreactive cells in the murine olfactory and central autonomic nervous systems before and after illness onset. J Neuroimmunol 211:73–83

    PubMed  CAS  Google Scholar 

  303. Shinya K, Shimada A, Ito T, Otsuki K, Morita T, Tanaka H, Takada A, Kida H, Umemura T (2000) Avian influenza virus intranasally inoculated infects the central nervous system of mice through the general visceral afferent nerve. Arch Virol 145:187–195

    PubMed  CAS  Google Scholar 

  304. Matsuda K, Park CH, Sunden Y, Kimura T, Ochiai K, Kida H, Umemura T (2004) The vagus nerve is one route of transneural invasion for intranasally inoculated influenza a virus in mice. Vet Pathol 41:101–107

    PubMed  CAS  Google Scholar 

  305. McBride PA, Schulz-Schaeffer WJ, Donaldson M, Bruce M, Diringer H, Kretzschmar HA, Beekes M (2001) Early spread of scrapie from the gastrointestinal tract to the central nervous system involves autonomic fibers of the splanchnic and vagus nerves. J Virol 75:9320–9327

    PubMed  CAS  Google Scholar 

  306. Hansen MK, Taishi P, Chen Z, Krueger JM (1998) Vagotomy blocks the induction of interleukin-1beta (IL-1beta) mRNA in the brain of rats in response to systemic IL-1beta. J Neurosci 18:2247–2253

    PubMed  CAS  Google Scholar 

  307. Churchill L, Taishi P, Wang M, Brandt J, Cearley C, Rehman A, Krueger JM (2006) Brain distribution of cytokine mRNA induced by systemic administration of interleukin-1beta or tumor necrosis factor alpha. Brain Res 1120:64–73

    PubMed  CAS  Google Scholar 

  308. Doba N, Reis DJ (1973) Acute fulminating neurogenic hypertension produced by brainstem lesions in the rat. Circ Res 32:584–593

    PubMed  CAS  Google Scholar 

  309. Talman WT, Perrone MH, Reis DJ (1981) Acute hypertension after the local injection of kainic acid into the nucleus tractus solitarii of rats. Circ Res 48:292–298

    PubMed  CAS  Google Scholar 

  310. Waki H, Gouraud SS, Maeda M, Paton JF (2008) Specific inflammatory condition in nucleus tractus solitarii of the SHR: novel insight for neurogenic hypertension? Auton Neurosci 142:25–31

    PubMed  CAS  Google Scholar 

  311. Waki H, Gouraud SS, Maeda M, Paton JF (2008) Gene expression profiles of major cytokines in the nucleus tractus solitarii of the spontaneously hypertensive rat. Auton Neurosci 142:40–44

    PubMed  CAS  Google Scholar 

  312. Waki H, Gouraud SS, Maeda M, Paton JF (2010) Evidence of specific inflammatory condition in nucleus tractus solitarii of spontaneously hypertensive rats. Exp Physiol 95:595–600

    PubMed  CAS  Google Scholar 

  313. Waki H, Gouraud SS, Maeda M, Raizada MK, Paton JF (2011) Contributions of vascular inflammation in the brainstem for neurogenic hypertension. Respir Physiol Neurobiol 178:422–428

    PubMed  CAS  Google Scholar 

  314. Paton JF, Waki H (2009) Is neurogenic hypertension related to vascular inflammation of the brainstem? Neurosci Biobehav Rev 33:89–94

    PubMed  CAS  Google Scholar 

  315. Johnston H, Boutin H, Allan SM (2011) Assessing the contribution of inflammation in models of Alzheimer’s disease. Biochem Soc Trans 39:886–890

    PubMed  CAS  Google Scholar 

  316. Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC (2006) [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67:446–452

    PubMed  CAS  Google Scholar 

  317. Soscia SJ, Kirby JE, Washicosky KJ et al (2010) The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS One 5:e9505

    PubMed  Google Scholar 

  318. Kobayashi N, Masuda J, Kudoh J, Shimizu N, Yoshida T (2008) Binding sites on tau proteins as components for antimicrobial peptides. Biocontrol Sci 13:49–56

    PubMed  CAS  Google Scholar 

  319. Lee DC, Rizer J, Selenica ML, Reid P, Kraft C, Johnson A, Blair L, Gordon MN, Dickey CA, Morgan D (2010) LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J Neuroinflamm 7:56

    Google Scholar 

  320. Dickey C, Kraft C, Jinwal U, Koren J, Johnson A, Anderson L, Lebson L, Lee D, Dickson D, de Silva R, Binder LI, Morgan D, Lewis J (2009) Aging analysis reveals slowed tau turnover and enhanced stress response in a mouse model of tauopathy. Am J Pathol 174:228–238

    PubMed  CAS  Google Scholar 

  321. Quinn J, Montine T, Morrow J, Woodward WR, Kulhanek D, Eckenstein F (2003) Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer’s disease. J Neuroimmunol 137:32–41

    PubMed  CAS  Google Scholar 

  322. Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM (2005) Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci 25:8843–8853

    PubMed  CAS  Google Scholar 

  323. Li Y, Liu L, Barger SW, Griffin WS (2003) Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 23:1605–1611

    PubMed  CAS  Google Scholar 

  324. Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, LaFerla FM, Callahan LM, Federoff HJ, Bowers WJ (2008) Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol 173:1768–1782

    PubMed  CAS  Google Scholar 

  325. Rosi S, Ramirez-Amaya V, Vazdarjanova A, Worley PF, Barnes CA, Wenk GL (2005) Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression. J Neurosci 25:723–731

    PubMed  CAS  Google Scholar 

  326. El Solh AA, Akinnusi ME, Baddoura FH, Mankowski CR (2007) Endothelial cell apoptosis in obstructive sleep apnea. A link to endothelial dysfunction. Am J Respir Crit Care Med 175:1186–1191

    PubMed  Google Scholar 

Download references

Conflict of interest

I have no conflict of interest.

Author information

Authors and Affiliations

  1. Sleep Disorders Group, EEE Department, MSE, University of Melbourne, ICT Building, 3rd Floor, Room no. 344, 111 Barry Street, Parkville, VIC, 3010, Australia

    Mak Adam Daulatzai

Authors
  1. Mak Adam Daulatzai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mak Adam Daulatzai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Daulatzai, M.A. Dysfunctional Nucleus Tractus Solitarius: Its Crucial Role in Promoting Neuropathogentic Cascade of Alzheimer’s Dementia—A Novel Hypothesis. Neurochem Res 37, 846–868 (2012). https://doi.org/10.1007/s11064-011-0680-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0680-2

Keywords

Search

Navigation