Systems Biology in Molecular Psychiatry

Abstract

The last ten to fifteen years have seen a remarkable shift of research strategies from hypothesis-driven, reductionistic to data driven, hypothesis-free approaches. This tendency has become evident after completion of the sequencing of the human genome, when publications under the label systems biology have been skyrocketing. This shift marks a gradual revision of scientific understanding of biological systems. Whilst the former has been component-oriented, precluding elements that do not belong to the hypothesis, the latter try to extract information from the whole system in the first place. Only with this information at hand, data driven strategies develop hypotheses. Data driven strategies unearth the immense complexity of biological systems and, hence, necessitate computer-aided support. Mathematical tools derived from chaos theory appear to be applicable in biological systems, but require significant improvements. The combination of high throughput data collection with in silico modelling of molecular or higher order systems can markedly extend our understanding of onset and progression of diseases. Undoubtedly, systems thinking in brain research is the greatest challenge for the years to come.

References

• 1 Alkon DL. Memory storage and neural systems.  Sci Am. 1989;  261 ((1)) 42-50
• 2 Al-Shahrour F, Minguez P, Tárraga J, Medina I, Alloza E, Montaner D, Dopazo J. FatiGO+: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments.  Nucleic Acids Res. 2007;  35 ((Web Server issue)) W91-96 , . Epub 2007 May 3
• 3 Al-Shahrour F, Díaz-Uriarte R, Dopazo J. Discovering molecular functions significantly related to phenotypes by combining gene expression data and biological information.  Bioinformatics. 2005;  21 2988-2993
• 4 Antle MC, Foley DK, Foley NC, Silver R. Gates and oscillators: a network model of the brain clock.  J Biol Rhythms. 2003;  18 ((4)) 339-350
• 5 Assmus HE, Herwig R, Cho KH, Wolkenhauer O. Dynamics of biological systems: role of systems biology in medical research.  Expert Rev Mol Diagn. 2006;  6 ((6)) 891-902
• 6 Augustine GJ, Santamaria F, Tanaka K. Local calcium signaling in neurons.  Neuron. 2003;  40 ((2)) 331-346
• 7 Bachus SE, Kleinman JE. The neuropathology of schizophrenia.  J Clin Psychiatry. 1996;  57 ((Suppl 11)) 72-83
• 8 Bassett DS, Meyer-Lindenberg A, Achard S, Duke T, Bullmore E. Adaptive reconfiguration of fractal small-world human brain functional networks.  Proc Natl Acad Sci USA. 2006;  103 ((51)) 19518-19523
• 9 Bayer KU, Koninck P De, Leonard AS, Hell JW, Schulman H. Interaction with the NMDA receptor locks CaMKII in an active conformation.  Nature. 2001;  411 801-805
• 10 Benes FM, Kwok EW, Vincent SL, Todtenkopf MS. A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives.  Biol Psychiatry. 1998;  44 ((2)) 88-97
• 11 Benes FM, Khan Y, Vincent SL, Wickramasinghe R. Differences in the subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain.  Synapse. 1996;  22 ((4)) 338-349
• 12 Benes FM. The role of stress and dopamine-GABA interactions in the vulnerability for schizophrenia.  J Psychiatr Res. 1997;  31 ((2)) 257-275
• 13 Bertin N, Simonis N, Dupuy D, Cusick ME, Han JD, Fraser HB, Roth FP, Vidal M. Confirmation of organized modularity in the yeast interactome.  PLoS Biol. 2007;  5 ((6)) e153
• 14 Bezard E, Dovero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, Crossman AR, Bioulac B, Brotchie JM, Gross CE. Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.  J Neurosci. 2001;  21 ((17)) 6853-6861
• 15 Bieberich E. Recurrent fractal neural networks: a strategy for the exchange of local and global information processing in the brain.  Biosystems. 2002;  66 ((3)) 145-164
• 16 Blythe SN, Atherton JF, Bevan MD. Synaptic activation of dendritic AMPA and NMDA receptors generates transient high-frequency firing in substantia nigra dopamine neurons in vitro.  J Neurophysiol. 2007;  97 ((4)) 2837-2850
• 17 Budd GE. On the origin and evolution of major morphological characters.  Biol Rev Camb Philos Soc. 2006;  81 ((4)) 609-628
• 18 Card SK, Mackinlay JD, Shneiderman B. Information visualization: Using vision to think. Morgan Kaufmann 1999
• 19 Chiang T, Scholtens D, Sarkar D, Gentleman R, Huber W. Coverage and error models of protein-protein interaction data by directed graph analysis.  Genome Biol. 2007;  8 ((9)) R186
• 20 Deakin JF, Slater P, Simpson MD, Gilchrist AC, Skan WJ, Royston MC, Reynolds GP, Cross AJ. Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia.  J Neurochem. 1989;  52 ((6)) 1781-1786
• 21 DeRisi JL, Iyer VR, Brown PO. Exploring the metabolic and genetic control of gene expression on a genomic scale.  Science. 1997;  278 ((5338)) 680-686
• 22 Pietro NC Di, Seamans JK. Dopamine and serotonin interactions in the prefrontal cortex: insights on antipsychotic drugs and their mechanism of action.  Pharmacopsychiatry. 2007;  40 ((Suppl. 1)) S27-S33
• 23 Edelman GM. Naturalizing consciousness: a theoretical framework.  Proc Natl Acad Sci USA. 2003;  100 ((9)) 5520-5524
• 24 Fernandez E, Schiappa R, Girault JA, Le Novère N. DARPP-32 is a robust integrator of dopamine and glutamate signals.  PLoS Comput Biol. 2006;  2 ((12)) e176 , . Epub 2006 Nov 6
• 25 Forger DB, Peskin CS. A detailed predictive model of the mammalian circadian clock.  Proc Natl Acad Sci USA. 2003;  100 ((25)) 14806-14811
• 26 Gass P, Leonardi-Essmann F, Zueger M, Spanagel R, Gebicke-Haerter PJ. Transcriptional changes in insulin- and lipid metabolism-related genes in the hippocampus of olfactory bulbectomized mice.  J Neurosci Res. 2008;  , in press
• 27 Grace AA, Floresco SB, Goto Y, Lodge DJ. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors.  Trends Neurosci. 2007;  30 ((5)) 220-227
• 28 Grant SG, Marshall MC, Page KL, Cumiskey MA, Armstrong JD. Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases.  Hum Mol Genet. 2005;  14 ((Spec No.2)) R225-R234
• 29 Haber SN, Fudge JL. The interface between dopamine neurons and the amygdala: implications for schizophrenia.  Schizophr Bull. 1997;  23 ((3)) 471-482
• 30 Haenschel C, Uhlhaas PJ, Singer W. Sychronous oscillatory activity and working memory in schizophrenia.  Pharmacopsychiatry. 2007;  40 ((Suppl. 1)) S54-S61
• 31 Han JD, Bertin N, Hao T, Goldberg DS, Berriz GF, Zhang LV, Dupuy D, Walhout AJ, Cusick ME, Roth FP, Vidal M. Evidence for dynamically organized modularity in the yeast protein-protein interaction network.  Nature. 2004;  430 ((6995)) 88-93
• 32 Haussecker H. Mehrgitter-Bewegungssegmentierung in Bildfolgen mit Anwendung zur Detektion von Sedimentverlagerungen. M.S. thesis at the Institut für Umweltphysik. University of Heidelberg 1993
• 33 Huang S, Wikswo J. Dimensions of systems biology.  Rev Physiol Biochem Pharmacol. 2006;  157 81-104
• 34 Indic P, Schwartz WJ, Herzog ED, Foley NC, Antle MC. Modeling the behavior of coupled cellular circadian oscillators in the suprachiasmatic nucleus.  J Biol Rhythms. 2007;  22 ((3)) 211-219
• 35 Insight: Molecular Sensing . Molecular Sensing in Hearing and Balance.  Nature. 2001;  413 232-234
• 36 Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.  Neuropsychopharmacology. 1999;  20 ((3)) 201-225
• 37 Joshi-Tope G, Gillespie M, Vastrik I, D’Eustachio P, Schmidt E, Bono B de, Jassal B, Gopinath GR, Wu GR, Matthews L, Lewis S, Birney E, Stein L. Reactome: a knowledgebase of biological pathways.  Nucleic Acids Res. 2005;  , (33 Database) D428-D432
• 38 Jun JK, Jin DZ. Development of neural circuitry for precise temporal sequences through spontaneous activity, axon remodeling, and synaptic plasticity.  PLoS ONE. 2007;  2 ((1)) e723
• 39 Kanamaru T. Chaotic pattern transitions in pulse neural networks.  Neural Networks. 2007;  20 ((7)) 781-790
• 40 Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M. The KEGG resource for deciphering the genome.  Nucleic Acids Res. 2004;  (32 Database) D277-280
• 41 Karp PD, Ouzounis CA, Moore-Kochlacs C, Goldovsky L, Kaipa P, Ahren D, Tsoka S, Darzentas N, Kunin V, Lopez-Bigas N. Expansion of the BioCyc collection of pathway/genome databases to 160 genomes.  Nucleic Acids Res. 2005;  33 ((19)) 6083-6089
• 42 King CC. Fractal and chaotic dynamics in nervous systems.  Progress in Neurobiology. 1991;  36 279-308
• 43 Klonowski W. From conformons to human brains: an informal overview of nonlinear dynamics and its applications in biomedicine.  Nonlinear Biomed Phys. 2007;  1 ((1)) 5
• 44 Krull M, Pistor S, Voss N, Kel A, Reuter I, Kronenberg D, Michael H, Schwarzer K, Potapov A, Choi C, Kel-Margoulis O, Wingender E. TRANSPATH: an information resource for storing and visualizing signaling pathways and their pathological aberrations.  Nucleic Acids Res. 2006;  (34 Database) D546-D551
• 45 Kuznetsov AS, Kopell NJ, Wilson CJ. Transient high-frequency firing in a coupled-oscillator model of the mesencephalic dopaminergic neuron.  J Neurophysiol. 2006;  95 ((2)) 932-947
• 46 Laruelle M, Abi-Dargham A. Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies.  J Psychopharmacol. 1999;  13 ((4)) 358-371
• 47 Leonardi-Essmann F, Emig M, Kitamura Y, Spanagel R, Gebicke-Haerter PJ. Fractalkine-upregulated milk-fat globule EGF factor-8 (MFG-E8) protein in cultured rat microglia.  J Neuroimmunol. 2005;  160 92-101
• 48 Li CY, Mao X, Wei L. Genes and (common) pathways underlying drug addiction.  PLoS Comput Biol. 2008;  4 ((1)) e2
• 49 Li S, Armstrong CM, Bertin N, Ge H, Milstein S, Boxem M, Vidalain PO, Han JD, Chesneau A, Hao T, Goldberg DS, Li N, Martinez M, Rual JF, Lamesch P, Xu L, Tewari M, Wong SL, Zhang LV, Berriz GF, Jacotot L, Vaglio P, Reboul J, Hirozane-Kishikawa T, Li Q, Gabel HW, Elewa A, Baumgartner B, Rose DJ, Yu H, Bosak S, Sequerra R, Fraser A, Mango SE, Saxton WM, Strome S, Heuvel S Van Den, Piano F, Vandenhaute J, Sardet C, Gerstein M, Doucette-Stamm L, Gunsalus KC, Harper JW, Cusick ME, Roth FP, Hill DE, Vidal M. A map of the interactome network of the metazoan C. elegans.  Science. 2004;  303 ((5657)) 540-543
• 50 Lindskog M, Kim M, Wikström MA, Blackwell KT, Kotaleski JH. Transient calcium and dopamine increase PKA activity and DARPP-32 phosphorylation.  PLoS Comput Biol. 2006;  2 ((9)) e119
• 51 Ma H, Sorokin A, Mazein A, Selkov A, Selkov E, Demin O, Goryanin I. The Edinburgh human metabolic network reconstruction and its functional analysis.  Mol Syst Biol. 2007;  3 135
• 52 Mandelbrot BB. The fractal geometry of nature. Freeman WH., New York 1977
• 53 Mishkin M, Appenzeller T. The anatomy of memory.  Sci Am. 1987;  256 ((6)) 80-89
• 54 Nagayama S, Zeng S, Xiong W, Fletcher ML, Masurkar AV, Davis DJ, Pieribone VA, Chen WR. In vivo simultaneous tracing and Ca(2+) imaging of local neuronal circuits.  Neuron. 2007;  53 ((6)) 789-803
• 55 Neuhoff H, Neu A, Liss B, Roeper J. I(h) channels contribute to the different functional properties of identified dopaminergic subpopulations in the midbrain.  J Neurosci. 2002;  22 ((4)) 1290-1302
• 56 Noack S, Wahl A, Qeli E, Wiechert W. Visualizing regulatory interactions in metabolic networks.  BMC Biol. 2007;  5 ((1)) 46 , [Epub ahead of print]
• 57 Oestreicher C. A history of chaos theory.  Dialogues Clin Neurosci. 2007;  9 ((3)) 279-289
• 58 Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia.  J Psychiatr Res. 1999;  33 ((6)) 523-533
• 59 Qeli E. Information visualization techniques for metabolic engineering. Diss., Marburg 2007
• 60 Pearson JC, Finkel LH, Edelman G. Plasticity in the organization of adult cerebral cortical maps: a computer simulation based on neuronal group selection.  J Neurosci. 1987;  7 ((12)) 4209-4223
• 61 Pellionisz AJ. Models of brain function. (Cotterill RMJ, ed.), Cambridge University Press, U.K. 1989
• 62 Penn AA. Early brain wiring: activity-dependent processes.  Schizophr Bull. 2001;  27 ((3)) 337-347
• 63 Penrose R. The Road to Reality. A Complete Guide to the Laws of the Universe. Random House 2004
• 64 Penrose R. The Emperor's New Mind. Concerning Computers, Minds, and the Laws of Physics: Concerning Computers, Minds and the Laws of Physics. Oxford University Press 1989
• 65 Pocklington AJ, Cumiskey M, Armstrong JD, Grant SG. The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.  Mol Syst Biol. 2006;  2 0023 , . Epub 2006 Jan 17
• 66 Przulj N, Corneil DG, Jurisica I. Modeling interactome: scale-free or geometric?.  Bioinformatics. 2004;  20 ((18)) 3508-3515
• 67 Pu S, Vlasblom J, Emili A, Greenblatt J, Wodak SJ. Identifying functional modules in the physical interactome of Saccharomyces cerevisiae.  Proteomics. 2007;  7 ((6)) 944-960
• 68 Rachlin J, Cohen DD, Cantor C, Kasif S. Biological context networks: a mosaic view of the interactome.  Mol Syst Biol. 2006;  2 66
• 69 Rapaport F, Zinovyev A, Dutreix M, Barillot E, Vert J-P. Classification of microarray data using gene networks.  BMC Bioinformatics. 2007;  8 35
• 70 Reynolds GP. Increased concentrations and lateral asymmetry of amygdala dopamine in schizophrenia.  Nature. 1983;  305 ((5934)) 527-529
• 71 Rothemund PW, Papadakis N, Winfree E. Algorithmic self-assembly of DNA Sierpinski triangles.  PLoS Biol. 2004;  2 ((12)) e424
• 72 Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M. Towards a proteome-scale map of the human protein-protein interaction network.  Nature. 2005;  437 ((7062)) 1173-1178
• 73 Sander LM. Fractal Growth.  Sci Am. 1987;  256 94-100
• 74 Schierwagen A. Segmental cable modelling of electrotonic transfer properties of deep superior colliculus neurons in the cat.  J Hirnforsch. 1986;  27 ((6)) 679-690
• 75 Schierwagen AK. Growth, structure and dynamics of real neurons: model studies and experimental results.  Biomed Biochim Acta. 1990;  49 ((8–9)) 709-722
• 76 Scholtens D, Vidal M, Gentleman R. Local modeling of global interactome networks.  Bioinformatics. 2005;  21 ((17)) 3548-3557
• 77 Singer W. Development and plasticity of cortical processing architectures.  Science. 1995;  270 ((5237)) 758-764
• 78 Skarda CA, Freeman WJ. How brains make chaos in order to make sense of the world.  Behav Brain Sci. 1987;  10 ((2)) 161-195
• 79 Stam CJ, Reijneveld JC. Graph theoretical analysis of complex networks in the brain.  Nonlinear Biomed Phys. 2007;  1 ((1)) 3
• 80 Sullivan PF, Fan C, Perou CM. Evaluating the comparability of gene expression in blood and brain.  Am J Med Genet B Neuropsychiatr Genet. 2006;  141 ((3)) 261-268
• 81 Thelen E, Smith L. A dynamic systems approach to the development of cognition and action. MIT Press, Cambridge, MA and London 1994: 376
• 82 Tong AH, Lesage G, Bader GD, Ding H, Xu H, Xin X, Young J, Berriz GF, Brost RL, Chang M, Chen Y, Cheng X, Chua G, Friesen H, Goldberg DS, Haynes J, Humphries C, He G, Hussein S, Ke L, Krogan N, Li Z, Levinson JN, Lu H, Ménard P, Munyana C, Parsons AB, Ryan O, Tonikian R, Roberts T, Sdicu AM, Shapiro J, Sheikh B, Suter B, Wong SL, Zhang LV, Zhu H, Burd CG, Munro S, Sander C, Rine J, Greenblatt J, Peter M, Bretscher A, Bell G, Roth FP, Brown GW, Andrews B, Bussey H, Boone C. Global mapping of the yeast genetic interaction network.  Science. 2004;  303 ((5659)) 808-813
• 83 Tretter F, Albus M. “Computational Neuropsychiatry” of working memory disorders in schizophrenia: the network connectivity in prefrontal cortex- data and models.  Pharmacopsychiatry. 2007;  40 ((Suppl. 1)) S2-S16
• 84 Valencia A, Pazos F. Computational methods for the prediction of protein interactions.  Curr Opin Struct Biol. 2002;  12 ((3)) 368-373
• 85 Weis S, Llenos IC, Dulay JR, Elashoff M, Martínez-Murillo F, Miller CL. Quality control for microarray analysis of human brain samples: The impact of postmortem factors, RNA characteristics, and histopathology.  J Neurosci Methods. 2007;  165 ((2)) 198-209
• 86 Werner T. Regulatory networks: linking microarray data to systems biology.  Mech Ageing Dev. 2007;  128 ((1)) 168-172 , . Epub 2006 Nov 20
• 87 Willner P. The dopamine hypothesis of schizophrenia: current status, future prospects.  Int Clin Psychopharmacol. 1997;  12 ((6)) 297-308
• 88 Wilson CJ, Callaway JC. Coupled oscillator model of the dopaminer-gic neuron of the substantia nigra.  J Neurophysiol. 2000;  83 ((5)) 3084-3100
• 89 Winterer G. Prefrontal dopamine signalling in schizophrenia – the corticocentric model.  Pharmacopsychiatry. 2007;  40 ((Suppl. 1)) S45-S53
• 90 Witkin JM, Marek GJ, Johnson BG, Schoepp DD. Metabotropic glutamate receptors in the control of mood disorders.  CNS Neurol Disord Drug Targets. 2007;  6 ((2)) 87-100
• 91 Wren JD, Yao M, Langer M, Conway T. Simulated annealing of microarray data reduces noise and enables cross-experimental comparisons.  DNA Cell Biol. 2004;  23 ((10)) 695-700
• 92 Wuchty S, Oltvai ZN, Barabasi AL. Evolutionary conservation of motif constituents in the yeast protein interaction network.  Nat Genet. 2003;  35 ((2)) 176-179
• 93 Zhang ZJ, Reynolds GP. A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia.  Schizophr Res. 2002;  55 ((1–2)) 1-10
• 94 Zhu X, Gerstein M, Snyder M. Getting connected: analysis and principles of biological networks.  Genes Dev. 2007;  21 ((9)) 1010-1024

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