© The Institution of Engineering and Technology
Dopamine (DA) is an important neurotransmitter for multiple brain functions, and dysfunctions of the dopaminergic system are implicated in neurological and neuropsychiatric disorders. Although the dopaminergic system has been studied at multiple levels, an integrated and efficient computational model that bridges from molecular to neuronal circuit level is still lacking. In this study, the authors aim to develop a realistic yet efficient computational model of a dopaminergic pre-synaptic terminal. They first systematically perturb the variables/substrates of an established computational model of DA synthesis, release and uptake, and based on their relative dynamical timescales and steady-state changes, approximate and reduce the model into two versions: one for simulating hourly timescale, and another for millisecond timescale. They show that the original and reduced models exhibit rather similar steady and perturbed states, whereas the reduced models are more computationally efficient and illuminate the underlying key mechanisms. They then incorporate the reduced fast model into a spiking neuronal model that can realistically simulate the spiking behaviour of dopaminergic neurons. In addition, they successfully include autoreceptor-mediated inhibitory current explicitly in the neuronal model. This integrated computational model provides the first step toward an efficient computational platform for realistic multiscale simulation of dopaminergic systems in in silico neuropharmacology.
References
-
-
1)
-
22. Scranton, R., Cincotta, A.: ‘Bromocriptine-unique formulation of a dopamine agonist for the treatment of type 2 diabetes’, Expert Opin. Pharmacother., 2010, 11, pp. 269–279 (doi: 10.1517/14656560903501544).
-
2)
-
23. Aiken, C.B.: ‘Pramipexole in psychiatry: a systematic review of the literature’, J. Clin. Psychiatry, 2007, 68, pp. 1230–1236 (doi: 10.4088/JCP.v68n0810).
-
3)
-
44. Dreyer, J.K., Herrik, K.F., Berg, R.W., et al: ‘Influence of phasic and tonic dopamine release on receptor activation’, J. Neurosci., 2010, 30, pp. 14273–14283 (doi: 10.1523/JNEUROSCI.1894-10.2010).
-
4)
-
48. Jalewa, J., Joshi, A., McGinnity, T.M., et al: ‘Neural circuit interactions between the dorsal raphe nucleus and the lateral hypothalamus: an experimental and computational study’, PLoS One, 2014, 9, (2), p. e88003, (doi: 10.1371/journal.pone.0088003).
-
5)
-
49. Wong-Lin, K., Joshi, A., Prasad, G., et al: ‘Network properties of a computational model of the dorsal raphe nucleus’, Neural Netw., 2012, 32, pp. 15–25 (doi: 10.1016/j.neunet.2012.02.009).
-
6)
-
36. Veech, R.L., Eggleston, L.V., Krebs, H.A.: ‘The redox state of free nicotinamide-adenine dinucleotide phosphate in the cytoplasm of rat liver’, Biochem. J., 1969, 115, pp. 609–619 (doi: 10.1042/bj1150609a).
-
7)
-
32. Lo, B., Field, M.J.: ‘Conflict of interest in medical research education and practice’ (National Academy Press, Washington DC, 2009).
-
8)
-
1. Missale, C., Nash, S.R., Robinson, , et al: ‘Dopamine receptors: from structure to function’, Physiol. Rev., 1998, 78, pp. 189–225.
-
9)
-
20. Brooks, D.J.: ‘Dopamine agonists: their role in the treatment of Parkinson's disease’, J. Neurol. Neurosurg. Psychiatry, 2000, 68, pp. 685–689 (doi: 10.1136/jnnp.68.6.685).
-
10)
-
42. Benoit-Marand, M., Borrelli, E., Gonon, F.: ‘Inhibition of dopamine release via presynaptic D2 receptors: time course and functional characteristics in vivo’, J. Neurosci., 2001, 21, (23), pp. 9134–9141.
-
11)
-
21. Pivonello, R., Ferone, D., de Herder, W.W., et al: ‘Dopamine receptor expression and function in corticotroph pituitary tumors’, J. Clin. Endocrinol. Metab., 2004, 89, pp. 2452–2462 (doi: 10.1210/jc.2003-030837).
-
12)
-
9. Tost, H., Alam, T., Meyer-Lindenberg, A.: ‘Dopamine and psychosis: theory, pathomechanisms and intermediate phenotypes’, Neurosci. Biobeh. Rev., 2010, 34, pp. 689–700 (doi: 10.1016/j.neubiorev.2009.06.005).
-
13)
-
50. Joshi, A., Wong-Lin, K., McGinnity, T.M., et al: ‘A mathematical model to explore the interdependence between the serotonin and orexin/hypocretin systems’. Proc. IEEE Engineering in Medicine and Biology Society Conf., 2011, pp. 7270–7273.
-
14)
-
11. Volkow, N.D., Fowler, J.S., Wang, G.J., et al: ‘Imaging dopamine's role in drug abuse and addiction’, Neuropharmacology, 2009, 56, , pp. 3–8 (doi: 10.1016/j.neuropharm.2008.05.022).
-
15)
-
6. Damier, P., Hirsch, E.C., Agid, Y., et al: ‘The substantia nigra of the human brain II. Patterns of loss of dopamine-containing neurons in Parkinson's disease’, Brain, 1999, 122, pp. 1437–1448 (doi: 10.1093/brain/122.8.1437).
-
16)
-
15. el Mestikawy, S., Glowinski, J., Hamon, M.: ‘Presynaptic dopamine autoreceptors control tyrosine hydroxylase activation in depolarized striatal dopaminergic terminals’, J. Neurochem., 1986, 46, (1), pp. 12–22 (doi: 10.1111/j.1471-4159.1986.tb12919.x).
-
17)
-
2. Glimcher, P.W.: ‘Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis’, Proc. Natl. Acad. Sci., 2011, 108, pp. 15647–15654 (doi: 10.1073/pnas.1014269108).
-
18)
-
37. Grace, A.A., Bunney, B.S.: ‘The control of firing pattern in nigral dopamine neurons: burst firing’, J. Neurosci., 1983, 4, pp. 2877–2890.
-
19)
-
8. El Mansari, M., Guiard, B.P., Chernoloz, O., et al: ‘Relevance of norepinephrine–dopamine interactions in the treatment of major depressive disorder’, CNS Neurosci. Therapeutics, 2010, 16, (3), pp. e1–17, (doi: 10.1111/j.1755-5949.2010.00146.x).
-
20)
-
39. Izhikevich, E.M.: ‘Simple model of spiking neurons’, IEEE Trans. Neural Netw., 2003, 14, pp. 1569–1572 (doi: 10.1109/TNN.2003.820440).
-
21)
-
33. Ou-Yang, S.S., Lu, J.Y., Kong, X.Q., et al: ‘Computational drug discovery’, Acta Pharmacol. Sin., 2012, 33, pp. 1131–1140 (doi: 10.1038/aps.2012.109).
-
22)
-
10. Bonci, A., Bernardi, G., Grillner, P., et al: ‘The dopamine-containing neuron: maestro or simple musician in the orchestra of addiction’, Trends Pharmacol. Sci., 2003, 24, pp. 172–177 (doi: 10.1016/S0165-6147(03)00068-3).
-
23)
-
35. Flower, G., Wong-Lin, K.: ‘Reduced computational models of serotonin synthesis, release and reuptake’, IEEE Trans. Biomed. Eng., 2014, 61, pp. 1054–1061 (doi: 10.1109/TBME.2013.2293538).
-
24)
-
28. Eckhoff, P., Wong-Lin, K.F., Holmes, P.: ‘Optimality and robustness of a biophysical decision-making model under norepinephrine modulation’, J. Neurosci., 2009, 29, pp. 4301–4311 (doi: 10.1523/JNEUROSCI.5024-08.2009).
-
25)
-
40. Kita, J.M., Kile, B.M., Parker, L.E., et al: ‘In vivo measurement of somatodendritic release of dopamine in the ventral tegmental area’, Synapse, 2009, 63, pp. 951–960 (doi: 10.1002/syn.20676).
-
26)
-
4. Baldessarini, R.J., Tarazi, F.I.: ‘Drugs and the treatment of psychiatric disorders’, in Hardman, J.G., Limbird, L.E. (EDs.): ‘The pharmacologic basis of therapeutics’ (McGraw-Hill, New York, 2001), pp. 485–520.
-
27)
-
26. Best, J.A., Nijhout, H.F., Reed, M.C.: ‘Homeostatic mechanisms in dopamine synthesis and release: a mathematical model’, Theor. Biol. Med. Model., 2009, 6, p. 21, (doi: 10.1186/1742-4682-6-21).
-
28)
-
24. Beaulieu, J.-M., Gainetdinov, R.R.: ‘The physiology, signaling, and pharmacology of dopamine receptors’, Pharmacol. Rev., 2011, 63, pp. 182–217 (doi: 10.1124/pr.110.002642).
-
29)
-
16. Marinelli, M., Cooper, D.C., Baker, L.K., et al: ‘Impulse activity of midbrain dopamine neurons modulates drug-seeking behavior’, Psychopharmacology (Berl), 2003, 168, (1–2), pp. 84–98 (doi: 10.1007/s00213-003-1491-1).
-
30)
-
41. Belle, A.M., Owesson-White, C., Herr, N.R., et al: ‘Controlled ionophoresis coupled with fast-scan cyclic voltammetry/electrophysiology in awake, freely moving animals’, ACS Chem. Neurosci., 2013, 4, pp. 761–771 (doi: 10.1021/cn400031v).
-
31)
-
29. Eckhoff, P., Wong-Lin, K., Holmes, P.: ‘Dimension reduction and dynamics of a spiking neural network model for decision making under neuromodulation’, SIAM J. Appl. Dyn. Syst., 2011, 10, pp. 148–188 (doi: 10.1137/090770096).
-
32)
-
51. Bjorklund, A., Dunnett, S.B.: ‘Dopamine neuron systems in the brain: an update’, Trends Neurosci., 2007, 30, (5), pp. 194–202 (doi: 10.1016/j.tins.2007.03.006).
-
33)
-
13. Lacey, M.G., Mercuri, N.B., North, R.A.: ‘Dopamine acts on D2 receptors to increase potassium conductance in neurons of the rat substantia nigra zona compacta’, J. Physiol., 1987, 392, pp. 397–416 (doi: 10.1113/jphysiol.1987.sp016787).
-
34)
-
45. Einhorn, L.C., Johansen, P.A., White, F.J.: ‘Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area’, J. Neurosci., 1988, 8, (1), pp. 100–112.
-
35)
-
30. Wang, D.H., Wong-Lin, K.: ‘Comodulation of dopamine and serotonin on prefrontal cortical rhythms: a theoretical study’, Front. Integr. Neurosci, 2013, 7, p. 54, (doi: 10.3389/fnint.2013.00054).
-
36)
-
5. Goetz, C.G.: ‘Dopaminergic agonists in the treatment of Parkinson's disease’, Neurology, 1990, 40, pp. 50–54 (doi: 10.1212/WNL.40.2.273).
-
37)
-
17. Yamada, S., Yokoo, H., Nishi, S.: ‘Changes in sensitivity of dopamine autoreceptors in rat striatum after subchronic treatment with methamphetamine’, Eur. J. Pharmacol., 1991, 205, (1), pp. 43–47 (doi: 10.1016/0014-2999(91)90768-L).
-
38)
-
25. Qi, Z., Miller, G.W., Voit, E.O.: ‘Computational systems analysis of dopamine metabolism’, PLoS One, 2008, 3, (6), p. e2444, (doi: 10.1371/journal.pone.0002444).
-
39)
-
27. Reed, M., Nijhout, H.F., Best, J.: ‘Mathematical insights into the effects of levodopa’, Front. Integr. Neurosci., 2012, 6, p. 21, (doi: 10.3389/fnint.2012.00021).
-
40)
-
7. Laruelle, M., Abi-Dargham, A., Gil, R., et al: ‘Increased dopamine transmission in schizophrenia: relationship to illness phases’, Biol. Psychiatry, 1999, 46, pp. 56–72 (doi: 10.1016/S0006-3223(99)00067-0).
-
41)
-
14. Beckstead, M.J., Grandy, D.K., Wickman, K., et al: ‘Vesicular dopamine release elicits an inhibitory postsynaptic current in midbrain dopamine neurons’, Neuron, 2004, 42, (6), pp. 939–946 (doi: 10.1016/j.neuron.2004.05.019).
-
42)
-
31. Reed, M.C., Nijhout, H.F., Best, J.: ‘Computational studies of the role of serotonin in the basal ganglia’, Front. Integr. Neurosci., 2013, 7, p. 24, (doi: 10.3389/fnint.2013.00041).
-
43)
-
12. Neve, K.A., Seamans, J.K., Trantham-Davidson, H.: ‘Dopamine receptor signaling’, J. Receptors Signal Transduct. Res., 2004, 24, pp. 165–205 (doi: 10.1081/RRS-200029981).
-
44)
-
47. Schultz, W.: ‘Neuronal reward and decision signals: from theories to data’, Physiol. Rev., 2015, 95, pp. 853–951 (doi: 10.1152/physrev.00023.2014).
-
45)
-
34. Kokotovic, P.V., Allenmong, J.J., Winelman, J.R., et al: ‘Singular perturbation and iterative separation of time scales’, Automatica, 1980, 16, pp. 23–33 (doi: 10.1016/0005-1098(80)90083-7).
-
46)
-
3. Steinberg, E.E., Keiflin, R., Boivin, J.R., et al: ‘A causal link between prediction errors, dopamine neurons and learning’, Nat. Neurosci., 2013, 16, pp. 966–973 (doi: 10.1038/nn.3413).
-
47)
-
19. Bello, E.P., Mateo, Y., Gelman, D.M., et al: ‘Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2’, Nat. Neurosci., 2011, 14, (8), pp. 1033–1038 (doi: 10.1038/nn.2862).
-
48)
-
43. Dreyer, J.K., Hounsgaard, J.: ‘Mathematical model of dopamine autoreceptors and uptake inhibitors and their influence on tonic and phasic dopamine signaling’, J. Neurophysiol., 2013, 109, pp. 171–182 (doi: 10.1152/jn.00502.2012).
-
49)
-
18. Sharpe, A.L., Varela, E., Bettinger, L., et al: ‘Methamphetamine self-administration in mice decreases GIRK channel-mediated currents in midbrain dopamine neurons’, Int. J. Neuropsychopharmacol., 2014, .
-
50)
-
38. Hyland, B.I., Reynolds, J.N., Hay, J., et al: ‘Firing modes of midbrain dopamine cells in the freely moving rat’, Neuroscience, 2002, 114, pp. 475–492 (doi: 10.1016/S0306-4522(02)00267-1).
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