Psychopharmacology

, Volume 219, Issue 2, pp 363–375 | Cite as

Effects of α-2A adrenergic receptor agonist on time and risk preference in primates

  • Soyoun Kim
  • Irina Bobeica
  • Nao J. Gamo
  • Amy F. T. Arnsten
  • Daeyeol Lee
Original Investigation

Abstract

Rationale

Subjective values of actions are influenced by the uncertainty and immediacy of expected rewards. Multiple brain areas, including the prefrontal cortex and basal ganglia, are implicated in selecting actions according to their subjective values. Alterations in these neural circuits, therefore, might contribute to symptoms of impulsive choice behaviors in disorders such as substance abuse and attention-deficit hyperactivity disorder (ADHD). In particular, the α-2A noradrenergic system is known to have a key influence on prefrontal cortical circuits, and medications that stimulate this receptor are currently in use for the treatment of ADHD.

Objective

We tested whether the preference of rhesus monkeys for delayed and uncertain reward is influenced by the α-2A adrenergic receptor agonist, guanfacine.

Methods

In each trial, the animal chose between a small, certain and immediate reward and another larger, more delayed reward. In half of the trials, the larger reward was certain, whereas in the remaining trials, the larger reward was uncertain.

Results

Guanfacine increased the tendency for the animal to choose the larger and more delayed reward only when it was certain. By applying an econometric model to the animal's choice behavior, we found that guanfacine selectively reduced the animal's time preference, increasing their choice of delayed, larger rewards, without significantly affecting their risk preference.

Conclusions

In combination with previous findings that guanfacine improves the efficiency of working memory and other prefrontal functions, these results suggest that impulsive choice behaviors may also be ameliorated by strengthening prefrontal functions.

Keywords

Temporal discounting Intertemporal choice Reward Decision making Neuroeconomics Prefrontal cortex Gambling Impulsivity Guanfacine ADHD 

References

  1. Anderhub V, Güth W, Gneezy U, Sonsino D (2003) On the interaction of risk and time preferences: an experimental study. German Econ Rev 2:239–253. doi:10.1111/1468-0475.00036 CrossRefGoogle Scholar
  2. Arnsten AFT (2009) Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 10:410–422. doi:10.1038/nrn2648 PubMedCrossRefGoogle Scholar
  3. Arnsten AFT (2010) The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder. Expert Rev Neurother 10:1595–1605. doi:10.1586/ern.10.133 PubMedCrossRefGoogle Scholar
  4. Arnsten AF, Goldman-Rakic PS (1985) α2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230:1273–1276PubMedCrossRefGoogle Scholar
  5. Arnsten AF, Cai JX, Goldman-Rakic PS (1988) The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 8:4287–4298PubMedGoogle Scholar
  6. Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450. doi:10.1146/annurev.neuro.28.061604.135709 PubMedCrossRefGoogle Scholar
  7. Barraclough DJ, Conroy ML, Lee D (2004) Prefrontal cortex and decision making in a mixed-strategy game. Nat Neurosci 7:404–410. doi:10.1038/nn1209 PubMedCrossRefGoogle Scholar
  8. Bateson M, Kacelnik A (1997) Starlings' preferences for predictable and unpredictable delays to food. Anim Behav 53:1129–1142PubMedCrossRefGoogle Scholar
  9. Benzion U, Rapoport A, Yagil J (1989) Discount rates inferred from decisions: an experimental study. Manag Sci 35:270–284CrossRefGoogle Scholar
  10. Bernoulli D (1954) Exposition of a new theory on the measurement of risk. Econometrica 22:23–36CrossRefGoogle Scholar
  11. Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AFT, Kelley AE, Schmeichel B, Hamilton C, Spencer RC (2006) Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 60:1111–1120. doi:10.1016/j.biopsych.2006.04.022 PubMedCrossRefGoogle Scholar
  12. Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010) Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68:815–834. doi:10.1016/j.neuron.2010.11.022 PubMedCrossRefGoogle Scholar
  13. Brozoski TJ, Brown RM, Rosvold HE, Goldman PS (1979) Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929–932PubMedCrossRefGoogle Scholar
  14. Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27:699–711PubMedCrossRefGoogle Scholar
  15. Cai X, Kim S, Lee D (2011) Heterogeneous coding of temporally discounted values in the dorsal and ventral striatum during intertemporal choice. Neuron 69:170–182. doi:10.1038/nn2007 PubMedCrossRefGoogle Scholar
  16. Caraco T (1980) On foraging time allocation in a stochastic environment. Ecology 61:119–128CrossRefGoogle Scholar
  17. Caraco T, Martindale S, Whittam TS (1980) An empirical demonstration of risk-sensitive foraging preferences. Anim Behav 28:820–830CrossRefGoogle Scholar
  18. Cardinal RN (2006) Neural systems implicated in delayed and probabilistic reinforcement. Neural Netw 19:1277–1301. doi:10.1016/j.neunet.2006.03.004 PubMedCrossRefGoogle Scholar
  19. Cardinal RN, Pennicott DR, Sugathapala CL, Robbins TW, Everitt BJ (2001) Impulsive choice induced by rats by lesions of the nucleus accumbens core. Science 292:2499–2501. doi:10.1126/science.1060818 PubMedCrossRefGoogle Scholar
  20. de Wit H, Enggasser JL, Richards JB (2002) Acute administration of d-amphetamine decreases impulsivity in healthy volunteers. Neuropsychopharmacology 27:813–825. doi:10.1016/S0893-133X(02)00343-3 PubMedCrossRefGoogle Scholar
  21. Doya K (2008) Modulators of decision making. Nat Neurosci 4:410–416. doi:10.1038/nn2077 CrossRefGoogle Scholar
  22. Durmer JS, Dinges DF (2005) Neurocognitive consequences of sleep deprivation. Semin Neurobiol 25:117–129. doi:10.1055/s-2005-867080 CrossRefGoogle Scholar
  23. Franowicz JS, Arnsten AFT (1998) The α-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 136:8–14. doi:10.1007/s002130050533 PubMedCrossRefGoogle Scholar
  24. Franowicz JS, Kessler LE, Borja CMD, Kobilka BK, Limbrid LE, Arnsten AFT (2002) Mutation of the α2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J Neurosci 22:8771–8777PubMedGoogle Scholar
  25. Frederick S, Loewenstein G, O'Donoghue T (2002) Time discounting and time preference: a critical review. J Econ Lit 40:351–401. doi:10.1257/002205102320161311 CrossRefGoogle Scholar
  26. Gamo NJ, Wang M, Arnsten AF (2010) Methylphenidate and atomoxetine enhance prefrontal function through α2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry 49:1011–1023. doi:10.1016/j.jaac.2010.06.015 PubMedCrossRefGoogle Scholar
  27. Glimcher PW, Camerer CF, Fehr E, Poldrack RA (2009) Neuroeconomics: decision making and the brain. Elsevier, LondonGoogle Scholar
  28. Goldman-Rakic PS (1995) Cellular basis of working memory. Neuron 14:477–485. doi:10.1016/0896-6273(95)90304-6 PubMedCrossRefGoogle Scholar
  29. Green L, Myerson J (2004) A discounting framework for choice with delayed and probabilistic rewards. Psychol Bull 130:769–792. doi:10.1037/0033-2909.130.5.769 PubMedCrossRefGoogle Scholar
  30. Heerey EA, Robinson BM, McMahon RP, Gold JM (2007) Delay discounting in schizophrenia. Cogn Neuropsychiatry 12:213–221. doi:10.1080/13546800601005900 PubMedCrossRefGoogle Scholar
  31. Hwang J, Kim S, Lee D (2009) Temporal discounting and inter-temporal choice in rhesus monkeys. Front Behav Neurosci 3:9. doi:10.3389/neuro.08.009.2009 PubMedGoogle Scholar
  32. Kable JW, Glimcher PW (2007) The neural correlates of subjective value during intertemporal choice. Nat Neurosci 10:1625–1633. doi:10.1038/nn2007 PubMedCrossRefGoogle Scholar
  33. Kable JW, Glimcher PW (2009) The neurobiology of decision: consensus and controversy. Neuron 63:733–745. doi:10.1016/j.neuron.2009.09.003 PubMedCrossRefGoogle Scholar
  34. Kacelnik A, Bateson M (1997) Risk-sensitivity: crossroads for theories of decision-making. Trends Cogn Sci 1:304–309PubMedCrossRefGoogle Scholar
  35. Kahneman D, Tversky A (1979) Prospect theory: an analysis of decision under risk. Econometrica 47:263–291CrossRefGoogle Scholar
  36. Kalenscher T, Pennartz CMA (2008) Is a bird in the hand worth two in the future? The neuroeconomics of intertemporal decision-making. Prog Neurobiol 84:284–315. doi:10.1016/j.pneurobio.2007.11.004 PubMedCrossRefGoogle Scholar
  37. Keren G, Roelofsma P (1995) Immediacy and certainty in intertemporal choice. Organ Behav Hum Decis Process 63:287–297CrossRefGoogle Scholar
  38. Kheramin S, Body S, Ho MY, Velázquez-Martinez DN, Bradshaw CM, Szabadi E, Deakin JFW, Anderson IM (2003) Role of the orbital prefrontal cortex in choice between delayed and uncertain reinforcers: a quantitative analysis. Behavioral Processes 64:239–250. doi:10.1016/S0376-6357(03)00142-6 CrossRefGoogle Scholar
  39. Kheramin S, Body S, Ho MY, Velázquez-Martinez DN, Bradshaw CM, Szabadi E, Deakin JFW, Anderson IM (2004) Effects of orbital prefrontal cortex dopamine depletion on inter-temporal choice: a quantitative analysis. Psychopharmacology 175:206–214. doi:10.1007/s00213-004-1813-y PubMedCrossRefGoogle Scholar
  40. Kim S, Hwang J, Lee D (2008) Prefrontal coding of temporally discounted values during intertemporal choice. Neuron 59:161–172. doi:10.1016/j.neuron.2008.05.010 PubMedCrossRefGoogle Scholar
  41. Kim S, Hwang J, Seo H, Lee D (2009) Valuation of uncertain and delayed rewards in primate prefrontal cortex. Neural Netw 22:294–304. doi:10.1016/j.neunet.2009.03.010 PubMedCrossRefGoogle Scholar
  42. Kirby KN, Petry NM (2004) Heroin and cocaine abusers have higher discount rates for delayed rewards than alcoholics or non-drug-using controls. Addiction 99:461–471. doi:10.1111/j.1360-0443.2003.00669.x PubMedCrossRefGoogle Scholar
  43. Lau B, Glimcher PW (2008) Value representations in the primate striatum during matching behavior. Neuron 58:451–463. doi:10.1016/j.neuron.2008.02.021 PubMedCrossRefGoogle Scholar
  44. Lee D, Rushworth MFS, Walton ME, Watanabe M, Sakagami M (2007) Functional specialization of the primate frontal cortex. J Neurosci 27:8170–8173. doi:10.1523/JNEUROSCI.1561-07.2007 PubMedCrossRefGoogle Scholar
  45. Li BM, Mei ZT (1994) Delayed response deficit induced by local injection of the alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav Neural Biol 62:134–139PubMedCrossRefGoogle Scholar
  46. Loewenstein G, Read D, Baumeister R (2003) Time and decision. Russell Sage Foundation, New YorkGoogle Scholar
  47. Luhmann CC, Chun MM, Yi DJ, Lee D, Wang XJ (2008) Neural dissociation of delay and uncertainty in intertemporal choice. J Neurosci 28:14459–14466. doi:10.1523/JNEUROSCI.5058-08.2008 PubMedCrossRefGoogle Scholar
  48. Madden GJ, Petry NM, Badger GJ, Bickel WK (1997) Impulsive and self-control choices in opioid-dependent patients and non-drug-using control patients: drug and monetary rewards. Exp Clin Psychopharmacol 5:256–262PubMedCrossRefGoogle Scholar
  49. Matsumoto M, Hikosaka O (2009) Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 459:837–841. doi:10.1038/nature08028 PubMedCrossRefGoogle Scholar
  50. McClure SM, Laibson DI, Loewenstein G, Cohen JD (2004) Separate neural systems value immediate and delayed monetary rewards. Science 306:503–507. doi:10.1126/science.1100907 PubMedCrossRefGoogle Scholar
  51. McKee SA, Sinha R, Weinberger AH, Sofuoglu M, Harrison ELR, Lavery M, Wanzer J (2011) Stress decreases the ability to resist smoking and potentiates smoking intensity and reward. J Psychopharmacol 25:490–502. doi:10.1177/0269881110376694 PubMedCrossRefGoogle Scholar
  52. Mitchell SH (1999) Measures of impulsivity in cigarette smokers and non-smokers. Psychopharmacology 146:455–464PubMedCrossRefGoogle Scholar
  53. Mobini S, Body S, Ho MY, Bradshaw CM, Szabadi E, Deakin JFW, Anderson IM (2002) Effects of lesions of the orbitofrontal cortex on sensitivity to delayed and probabilistic reinforcement. Psychopharmacology 160:290–298. doi:10.1007/s00213-001-0983-0 PubMedCrossRefGoogle Scholar
  54. Morrow BA, George TP, Roth RH (2004) Noradrenergic α-2 agonists have anxiolytic-like actions on stress-related behavior and mesoprefrontal dopamine biochemistry. Brain Res 1027:173–178. doi:10.1016/j.brainres.2004.08.057 PubMedCrossRefGoogle Scholar
  55. Nevai AL, Waite TA, Passino KM (2007) State-dependent choice and ecological rationality. J Theor Biol 247:471–479. doi:10.1016/j.jtbi.2007.03.029 PubMedCrossRefGoogle Scholar
  56. Padoa-Schioppa C (2011) Neurobiology of economic choice: a good-based model. Ann Rev Neurosci 34:333–359. doi:10.1146/annurev-neuro-061010-113648 PubMedCrossRefGoogle Scholar
  57. Paulus MP (2007) Decision-making dysfunctions in psychiatry—altered homeostatic processing? Science 318:602–606. doi:10.1126/science.1142997 PubMedCrossRefGoogle Scholar
  58. Pietras CJ, Cherek DR, Lane SD, Tcheremissine OV, Steinberg JL (2003a) Effects of methylphenidate on impulsive choice in adult humans. Psychopharmacology 170:390–398. doi:10.1007/s00213-003-1547-2 PubMedCrossRefGoogle Scholar
  59. Pietras CJ, Locey ML, Hackenberg TD (2003b) Human risky choice under temporal constraints: tests of an energy-budget model. J Exp Anal Behav 80:59–75. doi:10.1901/jeab.2003.80-59 PubMedCrossRefGoogle Scholar
  60. Pine A, Seymour B, Roiser JP, Bossaerts P, Friston KJ, Curran HV, Dolan RJ (2009) Encoding of marginal utility across time in the human brain. J Neurosci 29:9575–9581. doi:10.1523/JNEUROSCI.1126-09.2009 PubMedCrossRefGoogle Scholar
  61. Ramos BP, Stark D, Verduzco L, van Dyck CH, Arnsten AFT (2006) α2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. Learn Mem 13:770–776. doi:10.1101/lm.298006 PubMedCrossRefGoogle Scholar
  62. Rangel A, Camerer C, Montague PR (2008) A framework for studying the neurobiology of value-based decision making. Nat Rev Neurosci 9:545–556. doi:10.1038/nrn2357 PubMedCrossRefGoogle Scholar
  63. Reynolds B (2006) Review of delay-discounting research with humans: relations to drug use and gambling. Behav Pharmacol 17:651–667. doi:10.1097/FBP.0b013e3280115f99 PubMedCrossRefGoogle Scholar
  64. Robbins TW, Arnsten AF (2009) The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu Rev Neurosci 32:267–287. doi:10.1146/annurev.neuro.051508.135535 PubMedCrossRefGoogle Scholar
  65. Robinson ESJ, Eagle DM, Mar AC, Bari A, Banerjee G, Jiang X, Dalley JW, Robbins TW (2008) Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat. Neuropsychopharmacology 33:1028–1037. doi:10.1038/sj.npp.1301487 PubMedCrossRefGoogle Scholar
  66. Rudebeck PH, Walton ME, Smyth AN, Bannerman DM, Rushworth MFS (2006) Separate neural pathways process different decision costs. Nat Neurosci 9:1161–1168. doi:10.1038/nn1756 PubMedCrossRefGoogle Scholar
  67. Sallee F, McGough J, Wigal T, Donahue J, Lyne A, Biederman J, For the SPD503 Study Group (2009) Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 48:155–165. doi:10.1097/CHI.0b013e318191769e PubMedCrossRefGoogle Scholar
  68. Samejima K, Ueda Y, Doya K, Kimura M (2005) Representation of action-specific reward values in the striatum. Science 310:1337–1340. doi:10.1126/science.1115270 PubMedCrossRefGoogle Scholar
  69. Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950PubMedCrossRefGoogle Scholar
  70. Scheres A, Tontsch C, Thoeny AL, Kaczkurkin A (2010) Temporal reward discounting in attention-deficit/hyperactivity disorder: the contribution of symptom domains, reward magnitude, and session length. Biol Psychiatry 67:641–648. doi:10.1016/j.biopsych.2009.10.033 PubMedCrossRefGoogle Scholar
  71. Schuck-Paim C, Pompilio L, Kacelnik A (2004) State-dependent decisions cause apparent violations of rationality in animal choice. PLoS Biol 2:e402. doi:10.1371/journal.pbio.0020402 PubMedCrossRefGoogle Scholar
  72. Schultz W (1998) Predictive reward signal of dopamine neurons. J Neurophysiol 80:1–27PubMedGoogle Scholar
  73. Schweitzer J, Sulzer-Azaroff B (1995) Self-control in boys with attention deficit hyperactivity disorder: effects of added stimulation and time. J Child Psychol Psychiatry 36:671–686PubMedGoogle Scholar
  74. Sellitto M, Ciaramelli E, di Pellegrino G (2010) Myopic discounting of future rewards after medial orbitofrontal damage in humans. J Neurosci 30:16429–16436. doi:10.1523/jneurosci.2516-10.2010 PubMedCrossRefGoogle Scholar
  75. Seo H, Lee D (2009) Behavioral and neural changes after gains and losses of conditioned reinforcers. J Neurosci 29:3627–3641. doi:10.1523/JNEUROSCI.4726-08.2009 PubMedCrossRefGoogle Scholar
  76. Sinha R (2001) How does stress increase risk of drug abuse and relapse. Psychopharmacology 158:343–359. doi:10.1007/s002130100917 PubMedCrossRefGoogle Scholar
  77. Stephens DW (1981) The logic of risk-sensitive foraging preferences. Anim Behav 29:628–629CrossRefGoogle Scholar
  78. Stephens DW, Krebs JR (1986) Foraging theory. Princeton Univ Press, PrincetonGoogle Scholar
  79. Venkatraman V, Huettel SA, Chuah LYM, Payne JW, Chee MWL (2011) Sleep deprivation biases the neural mechanisms underlying economic preferences. J Neurosci 31:3712–3718. doi:10.1523/JNEUROSCI.4407-10.2011 PubMedCrossRefGoogle Scholar
  80. Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AFT (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 10:376–384. doi:10.1038/nn1846 PubMedCrossRefGoogle Scholar
  81. von Neumann J, Morgenstern O (1944) The theory of games and economic behavior. Princeton Univ Press, PrincetonGoogle Scholar
  82. Vuchinich RE, Simpson CA (1998) Hyperbolic temporal discounting in social drinkers and problem drinkers. Exp Clin Psychopharmacol 6:292–305PubMedCrossRefGoogle Scholar
  83. Wade TR, de Wit H, Richards JB (2000) Effects of dopaminergic drugs on delayed reward as a measure of impulsive behavior in rats. Psychopharmacology 150:90–101PubMedCrossRefGoogle Scholar
  84. Wallis JD, Kennerley SW (2010) Heterogeneous reward signals in the prefrontal cortex. Curr Opin Neurobiol 20:191–198. doi:10.1016/j.conb.2010.02.009 PubMedCrossRefGoogle Scholar
  85. Wang M, Ramos BP, Paspalas C, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Nou E, Mazer JA, McCormick DA, Arnsten AFT (2007) α2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397–410. doi:10.1016/j.cell.2007.03.015 PubMedCrossRefGoogle Scholar
  86. Wang M, Gamo NJ, Yang Y, Jin LE, Wang XJ, Laubach M, Mazer JA, Lee D, Arnsten AFT (2011) Neuronal basis of age-related working memory decline. Nature 476:210–213. doi:10.1038/nature10243 PubMedCrossRefGoogle Scholar
  87. Watanabe M (1996) Reward expectancy in primate prefrontal neurons. Nature 382:629–632. doi:10.1038/382629a0 PubMedCrossRefGoogle Scholar
  88. Weber BJ, Huettel SA (2008) The neural substrates of probabilistic and intertemporal decision making. Brain Res 1234:104–115. doi:10.1016/j.brainres.2008.07.105 PubMedCrossRefGoogle Scholar
  89. Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575PubMedCrossRefGoogle Scholar
  90. Winstanley CA, Theobald DEH, Cardinal RN, Robbins TW (2004) Contrasting roles of basolateral amygdala and orbitofrontal cortex in impulsive choice. J Neurosci 24:4718–4722. doi:10.1523/JNEUROSCI.5606-03.2004 PubMedCrossRefGoogle Scholar
  91. Winstanley CA, Theobald DEH, Dalley JW, Cardinal RN, Robbins TW (2006) Double dissociation between serotonergic and dopaminergic modulation of medial prefrontal and orbitofrontal cortex during a test of impulsive choice. Cereb Cortex 16:106–114. doi:10.1093/cercor/bhi088 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Soyoun Kim
    • 1
  • Irina Bobeica
    • 1
  • Nao J. Gamo
    • 1
  • Amy F. T. Arnsten
    • 1
  • Daeyeol Lee
    • 1
  1. 1.Department of NeurobiologyYale University School of MedicineNew HavenUSA

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