Advertisement

The pathophysiology of major depressive disorder through the lens of systems biology: Network analysis of the psycho-immune-neuroendocrine physiome

Published:September 02, 2022DOI:https://doi.org/10.1016/j.jneuroim.2022.577959

      Highlights

      • The psycho-immune-neuroendocrine network for major depressive disorder (MDD) is summarized.
      • An edge table with all physiological pathways in pairs of origin nodes and target nodes is presented.
      • A directed network graph of the psycho-immune-neuroendocrine network is provided.
      • Four key network nodes representing central structural and regulatory elements are identified.
      • The nodes summarized are strategic targets for therapeutic intervention or prevention of MDD.

      Abstract

      Background/Aims

      The psycho-immune-neuroendocrine (PINE) network is a predominantly physiological (metabolomic) model constructed from the literature, inter-linking multiple biological processes associated with major depressive disorder (MDD), thereby integrating putative mechanistic pathways for MDD into a single network.

      Material and methods

      Previously published metabolomic pathways for the PINE network based on literature searches conducted in 1991–2021 were used to construct an edge table summarizing all physiological pathways in pairs of origin nodes and target nodes. The Gephi software program was used to calculate network metrics from the edge table, including total degree and centrality measures, to ascertain key network nodes and construct a directed network graph.

      Results

      An edge table and directional network graph of physiological relationships in the PINE network is presented. The network has properties consistent with complex biological systems, with analysis yielding key network nodes comprising pro-inflammatory cytokines (TNF- α, IL6 and IL1), glucocorticoids and corticotropin releasing hormone (CRH). These may represent central structural and regulatory elements in the context of MDD.

      Conclusion

      The identified hubs have a high degree of connection and are known to play roles in the progression from health to MDD. These nodes represent strategic targets for therapeutic intervention or prevention. Future work is required to build a weighted and dynamic simulation of the network PINE.

      Keywords

      Abbreviation:

      5-HIAA (5-Hydroxyindoleacetic Acid), ACTH) (Adrenocorticotropic Hormone), AMPK (Adenosine Monophosphate-Activated Protein Kinase), AP − 1 (Activator protein−1), BBB (Blood brain barrier), BC (Betweenness centrality), BDNF (Brain-Derived Neurotrophic Factor), CART (Cocaine- And Amphetamine-Regulated Transcript), CBG (Corticosteroid Binding Globulin), CC (Closeness centrality), CNS (Central Nervous System), CRH (Corticotropin releasing hormone), HPA (Hypothalamus-Pituiatry-Adrenal), IDO (Indoleamine 2,3-Dioxygenase), IEB (Permeability of the Intestinal Epithelial Barrier), LPS (Lipopolysaccharide), MDD (Major depressive disorder), MDR (Multidrug Resistance P-Glycoprotein), MR (Mineralocorticoid Receptors), NCDs (Non-communicable diseases), NF-κB (Nuclear Factor Kappa-B), NMDA (N-Methyl-D-Aspartate), PINE (The psycho-immune-neuroendocrine), PVN (Paraventricularnucleus), ROS (Reactive Oxygen Species)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Neuroimmunology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Abizaid A.
        • Anisman H.
        Gut feelings about depression.
        J. Psychiatry Neurosci. 2014; 39: 364
        • Achacoso T.B.
        • Yamamoto W.S.
        AY’s Neuroanatomy of C. elegans for Computation.
        CRC Press, 1991
        • Aggarwal A.
        • Cutts T.F.
        • Abell T.L.
        • Cardoso S.
        • Familoni B.
        • Bremer J.
        • Karas J.
        Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities.
        Gastroenterology. 1994; 106: 945-950
        • Albert R.
        • Barabási A.-L.
        Statistical mechanics of complex networks.
        Rev. Mod. Phys. 2002; 74: 47
        • Albert R.
        • Jeong H.
        • Barabási A.-L.
        Error and attack tolerance of complex networks.
        Nature. 2000; 406: 378-382
        • Asakawa A.
        • Inui A.
        • Kaga T.
        • Yuzuriha H.
        • Nagata T.
        • Fujimiya M.
        • Kasuga M.
        A role of ghrelin in neuroendocrine and behavioral responses to stress in mice.
        Neuroendocrinology. 2001; 74: 143-147
        • Axelrod J.
        • Reisine T.D.
        Stress hormones- Their interaction and regulation.
        Science. 1984; 224: 452-459
        • Barabási A.-L.
        • Gulbahce N.
        • Loscalzo J.
        Network medicine: a network-based approach to human disease.
        Nat. Rev. Genet. 2011; 12: 56
        • Barman S.M.
        • Boitano S.
        • Brooks H.
        Ganong’s Review of Medical Physiology.
        25 ed. McGraw-Hill Publishing, 2015
        • Barnes P.
        Corticosteroid effects on cell signalling.
        Eur. Respir. J. 2006; 27: 413-426
        • Bashan A.
        • Bartsch R.P.
        • Kantelhardt J.W.
        • Havlin S.
        • Ivanov P.C.
        Network physiology reveals relations between network topology and physiological function.
        Nat. Commun. 2012; 3: 702
        • Bassett D.S.
        • Bullmore E.T.
        Small-world brain networks revisited.
        Neuroscientist. 2016; 1073858416667720
        • Bastian M.
        • Heymann S.
        • Jacomy M.
        Gephi: an open source software for exploring and manipulating networks.
        Icwsm. 2009; 8: 361-362
        • Baver S.B.
        • Hope K.
        • Guyot S.
        • Bjørbaek C.
        • Kaczorowski C.
        • O’Connell K.M.
        Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus.
        J. Neurosci. 2014; 34: 5486-5496
        • Bercik P.
        • Denou E.
        • Collins J.
        • Jackson W.
        • Lu J.
        • Jury J.
        • McCoy K.D.
        The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
        Gastroenterology. 2011; 141 (599-609. e593)
        • Besedovsky H.O.
        • Rey A.D.
        Immune-neuro-endocrine interactions: facts and hypotheses.
        Endocr. Rev. 1996; 17: 64-102
        • Björntorp P.
        Do stress reactions cause abdominal obesity and comorbidities?.
        Obes. Rev. 2001; 2: 73-86
        • Black P.H.
        The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X.
        Brain Behav. Immun. 2003; 17: 350-364
        • Boje K.M.K.
        Cerebrovascular permeability changes during experimental meningitis in the rat.
        J. Pharmacol. Exp. Ther. 1995; 274 (Retrieved from): 1199-1203
        • Braidy N.
        • Grant R.
        • Adams S.
        • Brew B.J.
        • Guillemin G.J.
        Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons.
        Neurotox. Res. 2009; 16: 77-86https://doi.org/10.1007/s12640-009-9051-z
        • Budd R.C.
        • Fortner K.A.
        T lymphocytes.
        in: Kelley and Firestein’s Textbook of Rheumatology. Tenth edition. Elsevier, 2017: 189-206
        • Campbell S.J.
        • Deacon R.M.
        • Jiang Y.
        • Ferrari C.
        • Pitossi F.J.
        • Anthony D.C.
        Overexpression of IL−1β by adenoviral-mediated gene transfer in the rat brain causes a prolonged hepatic chemokine response, axonal injury and the suppression of spontaneous behaviour.
        Neurobiol. Dis. 2007; 27: 151-163
        • Chavez A.M.
        • Menconi M.J.
        • Hodin R.A.
        • Fink M.P.
        Cytokine-induced intestinal epithelial hyperpermeability: role of nitric oxide.
        Crit. Care Med. 1999; 27: 2246-2251
        • Chen K.
        • Li F.
        • Li J.
        • Cai H.
        • Strom S.
        • Bisello A.
        • McCrory M.A.
        Induction of leptin resistance through direct interaction of C-reactive protein with leptin.
        Nat. Med. 2006; 12: 425
        • Clark E.
        • Hoare C.
        • Tanianis-Hughes J.
        • Carlson G.L.
        • Warhurst G.
        Interferon γ induces translocation of commensal Escherichia coli across gut epithelial cells via a lipid raft--mediated process.
        Gastroenterology. 2005; 128: 1258-1267
        • Connor B.
        • Dragunow M.
        The role of neuronal growth factors in neurodegenerative disorders of the human brain.
        Brain Res. Brain Res. Rev. 1998; 27: 1
        • Cotter D.
        • Mackay D.
        • Landau S.
        • Kerwin R.
        • Everall I.
        Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder.
        Arch. Gen. Psychiatry. 2001; 58: 545
        • Cusick M.E.
        • Yu H.
        • Smolyar A.
        • Venkatesan K.
        • Carvunis A.-R.
        • Simonis N.
        • Dreze M.
        Literature-curated protein interaction datasets.
        Nat. Methods. 2009; 6: 39-46
        • da Silva A.A.
        • do Carmo J.
        • Dubinion J.
        • Hall J.E.
        The role of the sympathetic nervous system in obesity-related hypertension.
        Curr. Hypertens. Rep. 2009; 11: 206-211
        • Dantzer R.
        Cytokine, sickness behavior, and depression.
        Immunol. Allergy Clin. N. Am. 2009; 29: 247
        • Dantzer R.
        • Bluthé R.
        • Laye S.
        • Bret-Dibat J.L.
        • Parnet P.
        • Kelley K.W.
        Cytokines and sickness behavior.
        Ann. N. Y. Acad. Sci. 1998; 840: 586-590
        • Dantzer R.
        • Aubert A.
        • Bluthe R.M.
        • Gheusi G.
        • Cremona S.
        • Laye S.
        • Kelley K.W.
        Mechanisms of the behavioural effects of cytokines.
        Adv. Exp. Med. Biol. 1999; 461: 83-105https://doi.org/10.1007/978-0-585-37970-8_6
        • Dantzer R.
        • O’Connor J.C.
        • Freund G.G.
        • Johnson R.W.
        • Kelley K.W.
        From inflammation to sickness and depression: when the immune system subjugates the brain.
        Nat. Rev. Neurosci. 2008; 9: 46-56
        • Date Y.
        • Murakami N.
        • Toshinai K.
        • Matsukura S.
        • Niijima A.
        • Matsuo H.
        • Nakazato M.
        The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats.
        Gastroenterology. 2002; 123: 1120-1128
        • Davis T.E.
        • Kis-Toth K.
        • Szanto A.
        • Tsokos G.C.
        Glucocorticoids suppress T cell function by up-regulating MicroRNA-98.
        Arthritis Rheum. 2013; 65: 1882-1890
        • de la Cour C.D.
        • Norlén P.
        • Håkanson R.
        Secretion of ghrelin from rat stomach ghrelin cells in response to local microinfusion of candidate messenger compounds: a microdialysis study.
        Regul. Pept. 2007; 143: 118-126
        • Del Sol A.
        • Balling R.
        • Hood L.
        • Galas D.
        Diseases as network perturbations.
        Curr. Opin. Biotechnol. 2010; 21: 566-571
        • Deli M.A.
        • Descamps L.
        • Dehouck M.P.
        • Cecchelli R.
        • Joó F.
        • Ábrahám C.S.
        • Torpier G.
        Exposure of tumor necrosis factor-α to luminal membrane of bovine brain capillary endothelial cells cocultured with astrocytes induces a delayed increase of permeability and cytoplasmic stress fiber formation of actin.
        J. Neurosci. Res. 1995; 41: 717-726https://doi.org/10.1002/jnr.490410602
        • DiDonato J.A.
        • Hayakawa M.
        • Rothwarf D.M.
        • Zandi E.
        • Karin M.
        A cytokine-responsive IκB kinase that activates the transcription factor NF-κB.
        Nature. 1997; 388: 548-554
        • Dintenfass L.
        Blood Viscosity.
        Kluwer Academic Pub, 1985
        • Dixit V.D.
        • Schaffer E.M.
        • Pyle R.S.
        • Collins G.D.
        • Sakthivel S.K.
        • Palaniappan R.
        • Taub D.D.
        Ghrelin inhibits leptin-and activation-induced proinflammatory cytokine expression by human monocytes and T cells.
        J. Clin. Invest. 2004; 114: 57-66
        • Drapeau E.
        • Mayo W.
        • Aurousseau C.
        • Le Moal M.
        • Piazza P.-V.
        • Abrous D.N.
        Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis.
        Proc. Natl. Acad. Sci. 2003; 100: 14385-14390
        • Elenkov I.J.
        • Chrousos G.P.
        Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease.
        Trends Endocrinol. Metab. 1999; 10: 359-368
        • Fard A.T.
        • Ragan M.A.
        Modeling the attractor landscape of disease progression: a network-based approach.
        Front. Genet. 2017; 8
        • Fink G.
        • Sumner B.E.
        Oestrogen and mental state.
        Nature. 1996; 383: 306
        • Fink G.
        • Sumner B.E.
        • Rosie R.
        • Grace O.
        • Quinn J.P.
        Estrogen control of central neurotransmission: effect on mood, mental state, and memory.
        Cell. Mol. Neurobiol. 1996; 16: 325-344
        • Flier J.S.
        • Harris M.
        • Hollenberg A.N.
        Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring.
        J. Clin. Investig. 2000; 105: 859
        • Ford D.N.
        A behavioral approach to feedback loop dominance analysis.
        Syst. Dyn. Rev. 1999; 15: 3
        • Frago L.M.
        • Baquedano E.
        • Argente J.
        • Chowen J.A.
        Neuroprotective actions of ghrelin and growth hormone secretagogues.
        Front. Mol. Neurosci. 2011; 4: 23
        • Freeman L.C.
        Centrality in social networks conceptual clarification.
        Soc. Networks. 1978; 1: 215-239
        • Freeman L.C.
        • Roeder D.
        • Mulholland R.R.
        Centrality in social networks: II. Experimental results.
        Soc. Networks. 1979; 2: 119-141
        • Gao C.
        • Wei D.
        • Hu Y.
        • Mahadevan S.
        • Deng Y.
        A modified evidential methodology of identifying influential nodes in weighted networks.
        Phys. A. 2013; 392: 5490-5500
        • Gaykema R.P.
        • Goehler L.E.
        Lipopolysaccharide challenge-induced suppression of Fos in hypothalamic orexin neurons: their potential role in sickness behavior.
        Brain Behav. Immun. 2009; 23: 926-930
        • Gaykema R.P.
        • Park S.-M.
        • McKibbin C.R.
        • Goehler L.E.
        Lipopolysaccharide suppresses activation of the tuberomammillary histaminergic system concomitant with behavior: a novel target of immune-sensory pathways.
        Neuroscience. 2008; 152: 273-287
        • Gehlenborg N.
        • O’Donoghue S.I.
        • Baliga N.S.
        • Goesmann A.
        • Hibbs M.A.
        • Kitano H.
        • Tenenbaum D.
        Visualization of omics data for systems biology.
        Nat. Methods. 2010; 7: S56-S68
        • Globus G.G.
        The postmodern brain.
        Vol. 1. John Benjamins Publishing, 1995
        • Golczynska A.
        • Lenders J.W.
        • Goldstein D.S.
        Glucocorticoid-induced sympathoinhibition in humans.
        Clin. Pharmacol. Therap. 1995; 58: 90-98
        • Griendling K.K.
        • Sorescu D.
        • Ushio-Fukai M.
        NAD(P)H oxidase: Role in cardiovascular biology and disease.
        Circ. Res. 2000; 86 (Retrieved from): 494-501
        • Grohmann U.
        • Fallarino F.
        • Puccetti P.
        Tolerance, DCs and tryptophan: much ado about IDO.
        Trends Immunol. 2003; 24: 242-248
        • Guimera R.
        • Amaral L.A.N.
        Functional cartography of complex metabolic networks.
        Nature. 2005; 433: 895-900
        • Haas H.
        • Panula P.
        The role of histamine and the tuberomamillary nucleus in the nervous system.
        Nat. Rev. Neurosci. 2003; 4: 121
        • Hakim A.M.
        Depression, strokes and dementia: New biological insights into an unfortunate pathway.
        Cardiovasc. Psychiatry Neurol. 2011; https://doi.org/10.1155/2011/649629
        • Halbreich U.
        Role of estrogen in postmenopausal depression.
        Neurology. 1997; 48: 16S-20S
        • Hall J.
        Guyton and Hall Textbook of Medical Physiology.
        WB Saunders, Philadelphia2015
        • Hanke M.
        • Foraita R.
        Clone temporal centrality measures for incomplete sequences of graph snapshots.
        BMC Bioinform. 2017; 18: 261
        • Harris G.C.
        • Wimmer M.
        • Aston-Jones G.
        A role for lateral hypothalamic orexin neurons in reward seeking.
        Nature. 2005; 437: 556
        • Headrick J.P.
        • Peart J.N.
        • Budiono B.P.
        • Shum D.H.
        • Neumann D.L.
        • Stapelberg N.J.
        The heartbreak of depression:‘Psycho-cardiac’coupling in myocardial infarction.
        J. Mol. Cell. Cardiol. 2017; 106: 14-28
        • Heiman M.L.
        • Ahima R.S.
        • Craft L.S.
        • Schoner B.
        • Stephens T.W.
        • Flier J.S.
        Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress.
        Endocrinology. 1997; 138: 3859-3863
        • Hogenesch J.B.
        • Ueda H.R.
        Understanding systems-level properties: timely stories from the study of clocks.
        Nat. Rev. Genet. 2011; 12: 407-416
        • Huang S.
        • Eichler G.
        • Bar-Yam Y.
        • Ingber D.E.
        Cell fates as high-dimensional attractor states of a complex gene regulatory network.
        Phys. Rev. Lett. 2005; 94128701
        • Inui A.
        Ghrelin: an orexigenic and somatotrophic signal from the stomach.
        Nat. Rev. Neurosci. 2001; 2: 551-560
        • Isidori A.M.
        • Caprio M.
        • Strollo F.
        • Moretti C.
        • Frajese G.
        • Isidori A.
        • Fabbri A.
        Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels 1.
        J. Clin. Endocrinol. Metabol. 1999; 84: 3673-3680
        • Jansson L.
        • Holmdahl R.
        Estrogen-mediated immunosuppression in autoimmune diseases.
        Inflamm. Res. 1998; 47: 290-301
        • Jeong H.
        • Tombor B.
        • Albert R.
        • Oltvai Z.N.
        • Barabási A.-L.
        The large-scale organization of metabolic networks.
        Nature. 2000; 407: 651-654
        • Julliard W.
        • Fechner J.H.
        • Mezrich J.D.
        The aryl hydrocarbon receptor meets immunology: friend or foe? A little of both.
        Front. Immunol. 2014; 5: 458
        • Juruena M.F.
        • Cleare A.J.
        • Papadopoulos A.S.
        • Poon L.
        • Lightman S.
        • Pariante C.M.
        Different responses to dexamethasone and prednisolone in the same depressed patients.
        Psychopharmacology. 2006; 189: 225-235
        • Kalra S.P.
        • Ueno N.
        • Kalra P.S.
        Stimulation of appetite by ghrelin is regulated by leptin restraint: peripheral and central sites of action.
        J. Nutr. 2005; 135: 1331-1335
        • Kashyap P.C.
        • Marcobal A.
        • Ursell L.K.
        • Larauche M.
        • Duboc H.
        • Earle K.A.
        • Million M.
        Complex interactions among diet, gastrointestinal transit, and gut microbiota in humanized mice.
        Gastroenterology. 2013; 144: 967-977
        • Keightley P.C.
        • Koloski N.A.
        • Talley N.J.
        Pathways in gut-brain communication: evidence for distinct gut-to-brain and brain-to-gut syndromes.
        Aust. N. Z. J. Psychiatry. 2015; 49: 207-214
        • Khanin R.
        • Wit E.
        How scale-free are biological networks.
        J. Comput. Biol. 2006; 13: 810-818
        • Kim M.
        • Leskovec J.
        The network completion problem: Inferring missing nodes and edges in networks.
        in: Paper presented at the Proceedings of the 2011 SIAM International Conference on Data Mining. 2011
        • Kirschner M.W.
        The meaning of systems biology.
        Cell. 2005; 121: 503-504
        • Kitano H.
        Systems biology: a brief overview.
        Science. 2002; 295: 1662-1664https://doi.org/10.1126/science.1069492 [doi] 295/5560/1662 [pii]
        • Kitano H.
        Biological robustness.
        Nat. Rev. Genet. 2004; 5: 826-837
        • Klok M.
        • Jakobsdottir S.
        • Drent M.
        The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review.
        Obes. Rev. 2007; 8: 21-34
        • Kossinets G.
        Effects of missing data in social networks.
        Soc. Networks. 2006; 28: 247-268
        • Ley R.E.
        • Turnbaugh P.J.
        • Klein S.
        • Gordon J.I.
        Microbial ecology: human gut microbes associated with obesity.
        Nature. 2006; 444: 1022-1023
        • Liu J.
        • Xiong Q.
        • Shi W.
        • Shi X.
        • Wang K.
        Evaluating the importance of nodes in complex networks.
        Phys. A. 2016; 452: 209-219
        • Lu X.-Y.
        The leptin hypothesis of depression: a potential link between mood disorders and obesity?.
        Curr. Opin. Pharmacol. 2007; 7: 648-652
        • Lutter M.
        • Sakata I.
        • Osborne-Lawrence S.
        • Rovinsky S.A.
        • Anderson J.G.
        • Jung S.
        • Nestler E.J.
        The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress.
        Nat. Neurosci. 2008; 11: 752-753
        • Lyte M.
        • Vulchanova L.
        • Brown D.R.
        Stress at the intestinal surface: catecholamines and mucosa–bacteria interactions.
        Cell Tissue Res. 2011; 343: 23-32
        • Maes M.
        Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression.
        Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2011; 35: 664-675
        • Maes M.
        • Supasitthumrong T.
        • Limotai C.
        • Michelin A.P.
        • Matsumoto A.K.
        • de Oliveira Semão L.
        • de Lima Pedrão
        • Moreira E.G.
        • Carvalho A.F.
        • Sirivichayakul S.
        • Barbosa D.S.
        • Kanchanatawan B.
        Increased oxidative stress toxicity and lowered antioxidant defenses in temporal lobe epilepsy and mesial temporal sclerosis: associations with psychiatric comorbidities.
        Mol. Neurobiol. 2020; 57: 3334-3348https://doi.org/10.1007/s12035-020-01949-8
        • Mándi Y.
        • Vécsei L.
        The kynurenine system and immunoregulation.
        J. Neural Transm. 2012; 119: 197-209
        • McEwen B.S.
        Stress, adaptation, and disease: allostasis and allostatic load.
        Ann. N. Y. Acad. Sci. 1998; 840: 33-44
        • McKay L.I.
        • Cidlowski J.A.
        Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways.
        Endocr. Rev. 1999; 20 (Retrieved from): 435-459
        • McNally R.J.
        Can network analysis transform psychopathology?.
        Behav. Res. Ther. 2016; 86: 95-104
        • McNally L.
        • Bhagwagar Z.
        • Hannestad J.
        Inflammation, glutamate, and glia in depression: a literature review.
        CNS Spectrums. 2008; 13: 501
        • Meier U.
        • Gressner A.M.
        Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin.
        Clin. Chem. 2004; 50: 1511-1525
        • Menche J.
        • Sharma A.
        • Kitsak M.
        • Ghiassian S.D.
        • Vidal M.
        • Loscalzo J.
        • Barabási A.-L.
        Uncovering disease-disease relationships through the incomplete interactome.
        Science. 2015; 347: 1257601
        • Miller A.H.
        • Maletic V.
        • Raison C.L.
        Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.
        Biol. Psychiatry. 2009; 65: 732-741
        • Morikawa O.
        • Sakai N.
        • Obara H.
        • Saito N.
        Effects of interferon-α, interferon-γ and cAMP on the transcriptional regulation of the serotonin transporter.
        Eur. J. Pharmacol. 1998; 349: 317-324https://doi.org/10.1016/S0014-2999(98)00187-3
        • Morris M.K.
        • Saez-Rodriguez J.
        • Sorger P.K.
        • Lauffenburger D.A.
        Logic-based models for the analysis of cell signaling networks.
        Biochemistry. 2010; 49: 3216-3224
        • Müller N.
        • Schwarz M.
        The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression.
        Mol. Psychiatry. 2007; 12: 988-1000
        • Naznin F.
        • Toshinai K.
        • Waise T.Z.
        • NamKoong C.
        • Moin A.S.M.
        • Sakoda H.
        • Nakazato M.
        Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation.
        J. Endocrinol. 2015; 226: 81-92
        • Nicholson J.K.
        • Holmes E.
        • Kinross J.
        • Burcelin R.
        • Gibson G.
        • Jia W.
        • Pettersson S.
        Host-gut microbiota metabolic interactions.
        Science. 2012; 336: 1262-1267
        • Noorbakhsh F.
        • Overall C.M.
        • Power C.
        Deciphering complex mechanisms in neurodegenerative diseases: the advent of systems biology.
        Trends Neurosci. 2009; 32 (doi:S0166-2236(08)00267-1 [pii] 10.1016/j.tins.2008.10.003 [doi]): 88-100
        • O'connor T.
        • O'halloran D.
        • Shanahan F.
        The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia.
        Qjm. 2000; 93: 323-333
        • Oke S.L.
        • Tracey K.J.
        The inflammatory reflex and the role of complementary and alternative medical therapies.
        Ann. N. Y. Acad. Sci. 2009; 1172: 172-180
        • Okuda S.
        • Nishiyama N.
        • Saito H.
        • Katsuki H.
        3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity.
        J. Neurochem. 1998; 70 (Retrieved from): 299-307
        • Oxenkrug G.F.
        Tryptophan-kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later.
        Isr. J. Psychiatry Relat. Sci. 2010; 47 (Retrieved from): 56-63
        • Patist C.M.
        • Stapelberg N.J.
        • Du Toit E.F.
        • Headrick J.P.
        The brain-adipocyte-gut network: linking obesity and depression subtypes.
        Cogn. Affect. Behav. Neurosci. 2018; : 1-24
        • Pavlov V.A.
        • Tracey K.J.
        The cholinergic anti-inflammatory pathway.
        Brain Behav. Immun. 2005; 19: 493-499
        • Pavlov V.A.
        • Wang H.
        • Czura C.J.
        • Friedman S.G.
        • Tracey K.J.
        The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation.
        Mol. Med. 2003; 9: 125
        • Pecoraro N.
        • Dallman M.F.
        • Warne J.P.
        • Ginsberg A.B.
        • Laugero K.D.
        • la Fleur S.E.
        • Akana S.F.
        From Malthus to motive: how the HPA axis engineers the phenotype, yoking needs to wants.
        Prog. Neurobiol. 2006; 79: 247-340
        • Petersenn S.
        Structure and regulation of the growth hormone secretagogue receptor.
        Minerva Endocrinol. 2002; 27: 243-256
        • Picchi A.
        • Gao X.
        • Belmadani S.
        • Potter B.J.
        • Focardi M.
        • Chilian W.M.
        • Zhang C.
        Tumor necrosis factor-α induces endothelial dysfunction in the prediabetic metabolic syndrome.
        Circ. Res. 2006; 99: 69-77https://doi.org/10.1161/01.RES.0000229685.37402.80
        • Pittenger C.
        • Sanacora G.
        • Krystal J.H.
        The NMDA receptor as a therapeutic target in major depressive disorder.
        CNS Neurol. Disorders-Drug Targets. 2007; 6: 101-115
        • Port R.F.
        • Van Gelder T.
        Mind as Motion: Explorations in the Dynamics of Cognition.
        MIT press, 1995
        • Pratt R.
        • Stapelberg N.J.C.
        Early warning biomarkers in major depressive disorder: a strategic approach to a testing question.
        Biomarkers. 2018; (Accepted for Publication)https://doi.org/10.1080/1354750X.2018.1463563
        • Prill R.J.
        • Iglesias P.A.
        • Levchenko A.
        Dynamic properties of network motifs contribute to biological network organization.
        PLoS Biol. 2005; 3e343
        • Quigley E.M.
        Microflora modulation of motility.
        J. Neurogastroenterol. Motil. 2011; 17: 140-147
        • Rahmouni K.
        Obesity, sympathetic overdrive, and hypertension the leptin connection.
        Hypertension. 2010; 55: 844-845
        • Raison C.L.
        • Capuron L.
        • Miller A.H.
        Cytokines sing the blues: inflammation and the pathogenesis of depression.
        Trends Immunol. 2006; 27: 24-31
        • Ravasz E.
        • Somera A.L.
        • Mongru D.A.
        • Oltvai Z.N.
        • Barabasi A.L.
        Hierarchical organization of modularity in metabolic networks.
        Science. 2002; 297: 1551-1555https://doi.org/10.1126/science.1073374 [doi] 297/5586/1551 [pii]
        • Rottenberg J.
        Cardiac vagal control in depression: a critical analysis.
        Biol. Psychol. 2007; 74: 200-211https://doi.org/10.1016/j.biopsycho.2005.08.010
        • Rouach V.
        • Bloch M.
        • Rosenberg N.
        • Gilad S.
        • Limor R.
        • Stern N.
        • Greenman Y.
        The acute ghrelin response to a psychological stress challenge does not predict the post-stress urge to eat.
        Psychoneuroendocrinology. 2007; 32: 693-702
        • Rozenfeld H.D.
        • Gallos L.K.
        • Song C.
        • Makse H.A.
        Fractal and transfractal scale-free networks.
        in: In Encyclopedia of Complexity and Systems Science. Springer, 2009: 3924-3943
        • Rubin R.T.
        Adrenal cortical activity changes in manic-depressive illness: influence on intermediary metabolism of tryptophan.
        Arch. Gen. Psychiatry. 1967; 17: 671-679https://doi.org/10.1001/archpsyc.1967.01730300031006
        • Rupprecht R.
        • Reul J.M.
        • van Steensel B.
        • Spengler D.
        • Söder M.
        • Berning B.
        • Damm K.
        Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands.
        Eur. J. Pharmacol. 1993; 247: 145-154
        • Sahay A.
        • Hen R.
        Hippocampal neurogenesis and depression.
        in: Paper Presented at the Novartis Foundation Symposium. 2008
        • Sapolsky R.M.
        • Romero L.M.
        • Munck A.U.
        How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.
        Endocr. Rev. 2000; 21: 55-89
        • Scheffer M.
        Critical Transitions in Nature and Society.
        Princeton University Press, 2009
        • Scheffer M.
        • Bascompte J.
        • Brock W.A.
        • Brovkin V.
        • Carpenter S.R.
        • Dakos V.
        • Sugihara G.
        Early-warning signals for critical transitions.
        Nature. 2009; 461: 53-59
        • Schmid D.A.
        • Held K.
        • Ising M.
        • Uhr M.
        • Weikel J.C.
        • Steiger A.
        Ghrelin stimulates appetite, imagination of food, GH, ACTH, and cortisol, but does not affect leptin in normal controls.
        Neuropsychopharmacology. 2005; 30: 1187-1192
        • Shao H.
        • Mesbahi M.
        • Li D.
        • Xi Y.
        Inferring centrality from network snapshots.
        Sci. Rep. 2017; 7
        • Shintani M.
        • Ogawa Y.
        • Ebihara K.
        • Aizawa-Abe M.
        • Miyanaga F.
        • Takaya K.
        • Kojima M.
        Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway.
        Diabetes. 2001; 50: 227-232
        • Silverman M.N.
        • Sternberg E.M.
        Neuroendocrine-immune interactions in rheumatoid arthritis: mechanisms of glucocorticoid resistance.
        Neuroimmunomodulation. 2008; 15: 19-28
        • Silverman M.N.
        • Sternberg E.M.
        Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction.
        Ann. N. Y. Acad. Sci. 2012; 1261: 55-63
        • Sivaprakasam S.
        • Prasad P.D.
        • Singh N.
        Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis.
        Pharmacol. Ther. 2016; 164: 144-151
        • Smith S.M.
        • Vaughan J.M.
        • Donaldson C.J.
        • Rivier J.
        • Li C.
        • Chen A.
        • Vale W.W.
        Cocaine-and amphetamine-regulated transcript activates the hypothalamic-pituitary-adrenal axis through a corticotropin-releasing factor receptor-dependent mechanism.
        Endocrinology. 2004; 145: 5202-5209
        • Stapelberg N.J.C.
        • Neumann D.L.
        • Shum D.
        • Headrick J.P.
        Health, pre-disease and critical transition to disease in the psycho-immune-neuroendocrine network: Are there distinct states in the progression from health to major depressive disorder?.
        Physiol. Behav. 2019; 198: 108-119
        • Stapelberg N.J.
        • Neumann D.L.
        • Shum D.H.
        • McConnell H.
        • Hamilton-Craig I.
        A topographical map of the causal network of mechanisms underlying the relationship between major depressive disorder and coronary heart disease.
        Aust. N. Z. J. Psychiatry. 2011; 45: 351-369
        • Stapelberg N.J.
        • Neumann D.L.
        • Shum D.H.
        • McConnell H.
        • Hamilton-Craig I.
        From physiome to pathome: a systems biology model of major depressive disorder and the psycho-immune-neuroendocrine network.
        Curr. Psychiatr. Rev. 2015; 11: 32-62
        • Stapelberg N.
        • Neumann D.
        • Shum D.
        • Headrick J.
        Health, pre-disease and critical transition to disease in the psycho-immune-neuroendocrine network: Are there distinct states in the progression from health to major depressive disorder?.
        Physiol. Behav. 2018; 198: 108-119
        • Stapelberg N.J.C.
        • Pratt R.
        • Neumann D.L.
        • Shum D.H.K.
        • Brandis S.
        • Muthukkumarasamy V.
        • Headrick J.P.
        From feedback loop transitions to biomarkers in the psycho-immune-neuroendocrine network: Detecting the critical transition from health to major depression.
        Neurosci. Biobehav. Rev. 2018; 90: 1-15
        • Starr C.
        • McMillan B.
        Human Biology.
        Brooks/Cole Publishing Company, 2012
        • Steffenach H.-A.
        • Sloviter R.S.
        • Moser E.I.
        • Moser M.-B.
        Impaired retention of spatial memory after transection of longitudinally oriented axons of hippocampal CA3 pyramidal cells.
        Proc. Natl. Acad. Sci. 2002; 99: 3194-3198
        • Sterling P.
        • Eyer J.
        Allostasis: a new paradigm to explain arousal pathology.
        in: Fisher S.E. Reason J.E. Handbook of Life Stress, Cognition and Health. John Wiley & Sons, 1988
        • Sterman J.D.
        Business Dynamics: Systems Thinking and Modeling for a Complex World.
        Irwin/McGraw-Hill, 2000
        • Stone T.
        • Perkins M.
        Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS.
        Eur. J. Pharmacol. 1981; 72: 411
        • Stower H.
        Complex disease: family history versus SNPs for disease predictions.
        Nat. Rev. Genet. 2012; 13: 827
        • Sugaya K.
        • Chouinard M.
        • Greene R.
        • Robbins M.
        • Personett D.
        • Kent C.
        • McKinney M.
        Molecular indices of neuronal and glial plasticity in the hippocampal formation in a rodent model of age-induced spatial learning impairment.
        J. Neurosci. 1996; 16: 3427-3443
        • Sutcliffe J.G.
        • de Lecea L.
        The hypocretins: setting the arousal threshold.
        Nat. Rev. Neurosci. 2002; 3: 339
        • Sweetlove L.J.
        • Fernie A.R.
        Regulation of metabolic networks: understanding metabolic complexity in the systems biology era.
        New Phytol. 2005; 168: 9-24
        • Taché Y.
        • Bonaz B.
        Corticotropin-releasing factor receptors and stress-related alterations of gut motor function.
        J. Clin. Investig. 2007; 117: 33
        • Tan J.
        • McKenzie C.
        • Potamitis M.
        • Thorburn A.N.
        • Mackay C.R.
        • Macia L.
        The role of short-chain fatty acids in health and disease.
        Adv. Immunol. 2014; 121e119
        • Thayer J.F.
        Vagal tone and the inflammatory reflex.
        Cleve. Clin. J. Med. 2009; 76: S23-S26
        • Thelen E.
        Self-Organization in Developmental Processes: Can Systems Approaches Work?.
        A Reader, Second Edition, Brain Development and Cognition1989: 336-374
        • Tracey K.J.
        The inflammatory reflex.
        Nature. 2002; 420: 853-859
        • Tremaroli V.
        • Bäckhed F.
        Functional interactions between the gut microbiota and host metabolism.
        Nature. 2012; 489: 242-249
        • Tsigos C.
        • Chrousos G.P.
        Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress.
        J. Psychosom. Res. 2002; 53: 865-871
        • Turnbaugh P.J.
        • Bäckhed F.
        • Fulton L.
        • Gordon J.I.
        Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome.
        Cell Host Microbe. 2008; 3: 213-223
        • Vogelstein B.
        • Lane D.
        • Levine A.J.
        Surfing the p53 network.
        Nature. 2000; 408: 307-310
        • Wagner A.
        • Fell D.A.
        The small world inside large metabolic networks.
        Proc. R. Soc. Lond. B Biol. Sci. 2001; 268: 1803-1810
        • Watts D.J.
        • Strogatz S.H.
        Collective dynamics of’small-world’networks.
        Nature. 1998; 393: 440
        • Winder W.
        • Hardie D.
        AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes.
        Am. J. Physiol. Endocrinol. Metabol. 1999; 277: E1-E10
        • Wolf D.M.
        • Arkin A.P.
        Motifs, modules and games in bacteria.
        Curr. Opin. Microbiol. 2003; 6: 125-134
        • Wu A.
        • Ying Z.
        • Gomez-Pinilla F.
        Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats.
        J. Neurotrauma. 2004; 21: 1457-1467
        • Yamanaka A.
        • Tsujino N.
        • Funahashi H.
        • Honda K.
        • Guan J.-L.
        • Wang Q.-P.
        • Sakurai T.
        Orexins activate histaminergic neurons via the orexin 2 receptor.
        Biochem. Biophys. Res. Commun. 2002; 290: 1237-1245
        • Zarouna S.
        • Wozniak G.
        • Papachristou A.I.
        Mood disorders: A potential link between ghrelin and leptin on human body?.
        World J. Exp. Med. 2015; 5: 103
        • Zhao T.-J.
        • Sakata I.
        • Li R.L.
        • Liang G.
        • Richardson J.A.
        • Brown M.S.
        • Zigman J.M.
        Ghrelin secretion stimulated by β1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice.
        Proc. Natl. Acad. Sci. 2010; 107: 15868-15873
        • Zhu C.B.
        • Blakely R.D.
        • Hewlett W.A.
        The proinflammatory cytokines interleukin−1beta and tumor necrosis factor-alpha activate serotonin transporters.
        Neuropsychopharmacology. 2006; 31: 2121-2131https://doi.org/10.1038/sj.npp.1301029
        • Zou J.Y.
        • Crews F.T.
        TNFα potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NFκB inhibition.
        Brain Res. 2005; 1034: 11-24