, Volume 235, Issue 4, pp 999–1014 | Cite as

Transient inactivation of the paraventricular nucleus of the thalamus enhances cue-induced reinstatement in goal-trackers, but not sign-trackers

  • Brittany N. Kuhn
  • Marin S. Klumpner
  • Ignacio R. Covelo
  • Paolo Campus
  • Shelly B. FlagelEmail author
Original Investigation



The paraventricular nucleus of the thalamus (PVT) has been shown to mediate cue-motivated behaviors, such as sign- and goal-tracking, as well as reinstatement of drug-seeking behavior. However, the role of the PVT in mediating individual variation in cue-induced drug-seeking behavior remains unknown.


This study aimed to determine if inactivation of the PVT differentially mediates cue-induced drug-seeking behavior in sign-trackers and goal-trackers.


Rats were characterized as sign-trackers (STs) or goal-trackers (GTs) based on their Pavlovian conditioned approach behavior. Rats were then exposed to 15 days of cocaine self-administration, followed by a 2-week forced abstinence period and then extinction training. Rats then underwent tests for cue-induced reinstatement and general locomotor activity, prior to which they received an infusion of either saline (control) or baclofen/muscimol (B/M) to inactivate the PVT.


Relative to control animals of the same phenotype, GTs show a robust increase in cue-induced drug-seeking behavior following PVT inactivation, whereas the behavior of STs was not affected. PVT inactivation did not affect locomotor activity in either phenotype.


In GTs, the PVT appears to inhibit the expression of drug-seeking, presumably by attenuating the incentive value of the drug cue. Thus, inactivation of the PVT releases this inhibition in GTs, resulting in an increase in cue-induced drug-seeking behavior. PVT inactivation did not affect cue-induced drug-seeking behavior in STs, suggesting that the role of the PVT in encoding the incentive motivational value of drug cues differs between STs and GTs.


Paraventricular nucleus of the thalamus Reinstatement Individual variation Sign-tracker Goal-tracker Cocaine Relapse Reward cue 



We would like to thank Drs. Jonathan Morrow, Aram Parsegian, and Joshua Haight for their feedback on a previous version of this manuscript. We would also like to thank Drs. Brady West and Corey Powell from the Consulting for Statistics, Computing and Analytics Research team at the University of Michigan for their helpful input on statistical modeling for portions of the data. The experiments were designed by BNK and SBF and conducted by BNK, MSK, IRC, and PC. Data was analyzed by BNK, and BNK and SBF wrote the manuscript.


Funding for this work was provided by the National Institute on Drug Abuse branch of the National Institutes of Health (RO1DA038599) awarded to SBF and training grants T32DA007821 (BNK) and T32DA007268 (IRC).

Compliance with ethical standards

Conflict of interest

The authors declare that the research was conducted in the absence of any financial or commercial relationships that could be construed as a potential conflict of interest.


  1. Ahrens AM, Singer BF, Fitzpatrick CJ, Morrow JD, Robinson TE (2016) Rats that sign-track are resistant to Pavlovian but not instrumental extinction. Behav Brain Res 296:418–430. CrossRefPubMedGoogle Scholar
  2. Barson JR, Leibowitz SF (2015) GABA-induced inactivation of dorsal midline thalamic subregions has distinct effects on emotional behaviors. Neurosci Lett 609:92–96. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Beckmann JS, Marusich JA, Gipson CD, Bardo MT (2011) Novelty seeking, incentive salience and acquisition of cocaine self-administration in the rat. Behav Brain Res 216(1):159–165. CrossRefPubMedGoogle Scholar
  4. Berridge KC, Robinson TE, Aldridge JW (2009) Dissecting components of reward: 'liking', 'wanting', and learning. Curr Opin Pharmacol 9(1):65–73. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bindra D (1978) How adaptive behavior is produced: a perceptual motivation alternative to response reinforcement. Behavior and Brain Sciences 1:41–91CrossRefGoogle Scholar
  6. Bolles R (1972) Reinforcement, expectancy, and learning. Psychol Rev 79(5):394–409. CrossRefGoogle Scholar
  7. Browning JR, Jansen HT, Sorg BA (2014) Inactivation of the paraventricular thalamus abolishes the expression of cocaine conditioned place preference in rats. Drug Alcohol Depend 134:387–390. CrossRefPubMedGoogle Scholar
  8. Childress A, Ehrman R, McLellan AT, O'Brien C (1988) Conditioned craving and arousal in cocaine addiction: a preliminary report. NIDA Res Monogr 81:74–80PubMedGoogle Scholar
  9. Childress A, Ehrman R, McLellan AT, O'Brien CP (1993) Classically conditioned factors in drug dependence. In: Lowinson J, Millman RP (eds) Comprehensive textbook of substance abuse. Williams and Wilkins, Baltimore, pp 56–69Google Scholar
  10. Crombag HS, Badiani A, Maren S, Robinson TE (2000) The role of contextual versus discrete drug-associated cues in promoting the induction of psychomotor sensitization to intravenous amphetamine. Behav Brain Res 116(1):1–22. CrossRefPubMedGoogle Scholar
  11. Crombag HS, Bossert JM, Koya E, Shaham Y (2008) Review. Context-induced relapse to drug seeking: a review. Philos Trans R Soc Lond Ser B Biol Sci 363(1507):3233–3243. CrossRefGoogle Scholar
  12. Deutch AY, Ongur D, Duman RS (1995) Antipsychotic drugs induce Fos protein in the thalamic paraventricular nucleus: a novel locus of antipsychotic drug action. Neuroscience 66(2):337–346. CrossRefPubMedGoogle Scholar
  13. Deutch AY, Bubser M, Young CD (1998) Psychostimulant-induced Fos protein expression in the thalamic paraventricular nucleus. J Neurosci 18(24):10680–10687PubMedGoogle Scholar
  14. Do-Monte FH, Minier-Toribio A, Quinones-Laracuente K, Medina-Colon EM, Quirk GJ (2017) Thalamic regulation of sucrose seeking during unexpected reward omission. Neuron 94(2):388–400 e384. CrossRefPubMedGoogle Scholar
  15. Do-Monte FH, Quinones-Laracuente K, Quirk GJ (2015) A temporal shift in the circuits mediating retrieval of fear memory. Nature 519(7544):460–463. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Dong X, Li S, Kirouac GJ (2017) Collateralization of projections from the paraventricular nucleus of the thalamus to the nucleus accumbens, bed nucleus of the stria terminalis, and central nucleus of the amygdala. Brain Struct Functdoi 222(9):3927–3943. CrossRefGoogle Scholar
  17. Flagel SB, Robinson TE (2017) Neurobiological basis of individual variation in stimulus-reward learning. Curr Opin Behav Sci 13:178–185. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Flagel SB, Vazquez DM, Robinson TE (2003) Manipulations during the second, but not the first, week of life increase susceptibility to cocaine self-administration in female rats. Neuropsychopharmacology 28(10):1741–1751. CrossRefPubMedGoogle Scholar
  19. Flagel SB, Robinson TE, Clark JJ, Clinton SM, Watson SJ, Seeman P, Phillips PE, Akil H (2010) An animal model of genetic vulnerability to behavioral disinhibition and responsiveness to reward-related cues: implications for addiction. Neuropsychopharmacology 35(2):388–400. CrossRefPubMedGoogle Scholar
  20. Flagel SB, Cameron CM, Pickup KN, Watson SJ, Akil H, Robinson TE (2011a) A food predictive cue must be attributed with incentive salience for it to induce c-fos mRNA expression in cortico-striatal-thalamic brain regions. Neuroscience 196:80–96. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Flagel SB, Clark JJ, Robinson TE, Mayo L, Czuj A, Willuhn I, Akers CA, Clinton SM, Phillips PE, Akil H (2011b) A selective role for dopamine in stimulus-reward learning. Nature 469(7328):53–57. CrossRefPubMedGoogle Scholar
  22. Flagel SB, Chaudhury S, Waselus M, Kelly R, Sewani S, Clinton SM, Thompson RC, Watson SJ Jr, Akil H (2016) Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model. Proc Natl Acad Sci U S A 113(20):E2861–E2870. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412(6843):141–142. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Grimm JW, Shaham Y, Hope BT (2002) Effect of cocaine and sucrose withdrawal period on extinction behavior, cue-induced reinstatement, and protein levels of the dopamine transporter and tyrosine hydroxylase in limbic and cortical areas in rats. Behav Pharmacol 13(5–6):379–388. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Haight JL (2016) Elucidating the role of the paraventricular nucleus of the thalamus in cue-motivated behavior. Dissertation, University of Michigan.
  26. Haight JL, Flagel SB (2014) A potential role for the paraventricular nucleus of the thalamus in mediating individual variation in Pavlovian conditioned responses. Front Behav Neurosci 8:79. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Haight JL, Fraser KM, Akil H, Flagel SB (2015) Lesions of the paraventricular nucleus of the thalamus differentially affect sign- and goal-tracking conditioned responses. Eur J Neurosci 42(7):2478–2488. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Haight JL, Fuller ZL, Fraser KM, Flagel SB (2017) A food-predictive cue attributed with incentive salience engages subcortical afferents and efferents of the paraventricular nucleus of the thalamus. Neuroscience 340:135–152. CrossRefPubMedGoogle Scholar
  29. Hamlin AS, Clemens KJ, Choi EA, McNally GP (2009) Paraventricular thalamus mediates context-induced reinstatement (renewal) of extinguished reward seeking. Eur J Neurosci 29(4):802–812. CrossRefPubMedGoogle Scholar
  30. Hsu DT, Kirouac GJ, Zubieta JK, Bhatnagar S (2014) Contributions of the paraventricular thalamic nucleus in the regulation of stress, motivation, and mood. Front Behav Neurosci 8:73. PubMedPubMedCentralGoogle Scholar
  31. James MH, Dayas CV (2013) What about me...? The PVT: a role for the paraventricular thalamus (PVT) in drug-seeking behavior. Front Behav Neurosci 7:18. CrossRefPubMedPubMedCentralGoogle Scholar
  32. James MH, Charnley JL, Jones E, Levi EM, Yeoh JW, Flynn JR, Smith DW, Dayas CV (2010) Cocaine-and amphetamine-regulated transcript (CART) signaling within the paraventricular thalamus modulates cocaine-seeking behaviour. PLoS One 5(9):e12980. CrossRefPubMedPubMedCentralGoogle Scholar
  33. James MH, Charnley JL, Flynn JR, Smith DW, Dayas CV (2011) Propensity to 'relapse' following exposure to cocaine cues is associated with the recruitment of specific thalamic and epithalamic nuclei. Neuroscience 199:235–242. CrossRefPubMedGoogle Scholar
  34. Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162(8):1403–1413. CrossRefPubMedGoogle Scholar
  35. Kawa AB, Bentzley BS, Robinson TE (2016) Less is more: prolonged intermittent access cocaine self-administration produces incentive-sensitization and addiction-like behavior. Psychopharmacology 233(19–20):3587–3602. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Kelley AE, Baldo BA, Pratt WE, Will MJ (2005) Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward. Physiol Behav 86(5):773–795. CrossRefPubMedGoogle Scholar
  37. Khoo SY, Gibson GD, Prasad AA, McNally GP (2017) How contexts promote and prevent relapse to drug seeking. Genes Brain Behav 16(1):185–204. CrossRefPubMedGoogle Scholar
  38. Kirouac GJ (2015) Placing the paraventricular nucleus of the thalamus within the brain circuits that control behavior. Neurosci Biobehav Rev 56:315–329. CrossRefPubMedGoogle Scholar
  39. Kirouac GJ, Parsons MP, Li S (2005) Orexin (hypocretin) innervation of the paraventricular nucleus of the thalamus. Brain Res 1059(2):179–188. CrossRefPubMedGoogle Scholar
  40. Li S, Kirouac GJ (2008) Projections from the paraventricular nucleus of the thalamus to the forebrain, with special emphasis on the extended amygdala. J Comp Neurol 506(2):263–287. CrossRefPubMedGoogle Scholar
  41. Li S, Kirouac GJ (2012) Sources of inputs to the anterior and posterior aspects of the paraventricular nucleus of the thalamus. Brain Struct Funct 217(2):257–273. CrossRefPubMedGoogle Scholar
  42. Li Y, Dong X, Li S, Kirouac GJ (2014) Lesions of the posterior paraventricular nucleus of the thalamus attenuate fear expression. Front Behav Neurosci 8:94. PubMedPubMedCentralGoogle Scholar
  43. Li Y, Li S, Wei C, Wang H, Sui N, Kirouac GJ (2010) Orexins in the paraventricular nucleus of the thalamus mediate anxiety-like responses in rats. Psychopharmacology 212(2):251–265. CrossRefPubMedGoogle Scholar
  44. Lovic V, Saunders BT, Yager LM, Robinson TE (2011) Rats prone to attribute incentive salience to reward cues are also prone to impulsive action. Behav Brain Res 223(2):255–261. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Matzeu A, Weiss F, Martin-Fardon R (2015) Transient inactivation of the posterior paraventricular nucleus of the thalamus blocks cocaine-seeking behavior. Neurosci Lett 608:34–39. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Matzeu A, Kerr TM, Weiss F, Martin-Fardon R (2016) Orexin-a/hypocretin-1 mediates cocaine-seeking behavior in the posterior paraventricular nucleus of the thalamus via orexin/hypocretin receptor-2. J Pharmacol Exp Ther 359(2):273–279. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Matzeu A, Cauvi G, Kerr TM, Weiss F, Martin-Fardon R (2017) The paraventricular nucleus of the thalamus is differentially recruited by stimuli conditioned to the availability of cocaine versus palatable food. Addict Biol 22(1):70–77. CrossRefPubMedGoogle Scholar
  48. Meyer PJ, Lovic V, Saunders BT, Yager LM, Flagel SB, Morrow JD, Robinson TE (2012) Quantifying individual variation in the propensity to attribute incentive salience to reward cues. PLoS One 7(6):e38987. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Millan EZ, Ong Z, McNally GP (2017) Paraventricular thalamus: gateway to feeding, appetitive motivation, and drug addiction. Prog Brain Res 235:113–137. CrossRefPubMedGoogle Scholar
  50. Neumann PA, Wang Y, Yan Y, Wang Y, Ishikawa M, Cui R, Huang YH, Sesack SR, Schluter OM, Dong Y (2016) Cocaine-induced synaptic alterations in thalamus to nucleus accumbens projection. Neuropsychopharmacology 41(9):2399–2410. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Ong ZY, Liu JJ, Pang ZP, Grill HJ (2017) Paraventricular thalamic control of food intake and reward: role of glucagon-like peptide-1 receptor signaling. Neuropsychopharmacology 42(12):2387–2397. CrossRefPubMedGoogle Scholar
  52. Ostlund SB, Balleine BW (2007) Orbitofrontal cortex mediates outcome encoding in Pavlovian but not instrumental conditioning. J Neurosci 27(18):4819–4825. CrossRefPubMedGoogle Scholar
  53. Otis JM, Namboodiri VM, Matan AM, Voets ES, Mohorn EP, Kosyk O, McHenry JA, Robinson JE, Resendez SL, Rossi MA, Stuber GD (2017) Prefrontal cortex output circuits guide reward seeking through divergent cue encoding. Nature 543(7643):103–107. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Paolone G, Angelakos CC, Meyer PJ, Robinson TE, Sarter M (2013) Cholinergic control over attention in rats prone to attribute incentive salience to reward cues. J Neurosci 33(19):8321–8335. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Paxinos GWC (2007) The rat brain in stereotaxic coordinates. Academic Press, Burlington, MAGoogle Scholar
  56. Penzo MA, Robert V, Tucciarone J, De Bundel D, Wang M, Van Aelst L, Darvas M, Parada LF, Palmiter RD, He M, Huang ZJ, Li B (2015) The paraventricular thalamus controls a central amygdala fear circuit. Nature 519(7544):455–459. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Pitchers KK, Phillips KB, Jones JL, Robinson TE, Sarter M (2017) Diverse roads to relapse: a discriminative cue signaling cocaine availability is more effective in renewing cocaine-seeking in goal-trackers than sign-trackers, and depends on basal forebrain cholinergic activity. J Neuroscidoi 37(30):7198–7208. CrossRefGoogle Scholar
  58. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18(3):247–291. CrossRefPubMedGoogle Scholar
  59. Robinson TE, Flagel SB (2009) Dissociating the predictive and incentive motivational properties of reward-related cues through the study of individual differences. Biol Psychiatry 65(10):869–873. CrossRefPubMedGoogle Scholar
  60. Robinson TE, Yager LM, Cogan ES, Saunders BT (2014) On the motivational properties of reward cues: individual differences. Neuropharmacology 76 Pt B:450–459. CrossRefPubMedGoogle Scholar
  61. Saunders BT, Robinson TE (2010) A cocaine cue acts as an incentive stimulus in some but not others: implications for addiction. Biol Psychiatry 67(8):730–736. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Saunders BT, Robinson TE (2011) Individual variation in the motivational properties of cocaine. Neuropsychopharmacology 36(8):1668–1676. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Saunders BT, Yager LM, Robinson TE (2013) Cue-evoked cocaine "craving": role of dopamine in the accumbens core. J Neurosci 33(35):13989–14000. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Saunders BT, O'Donnell EG, Aurbach EL, Robinson TE (2014) A cocaine context renews drug seeking preferentially in a subset of individuals. Neuropsychopharmacology 39(12):2816–2823. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168(1–2):3–20. CrossRefPubMedGoogle Scholar
  66. Stephenson CP, Hunt GE, Topple AN, McGregor IS (1999) The distribution of 3,4-methylenedioxymethamphetamine "Ecstasy"-induced c-fos expression in rat brain. Neuroscience 92(3):1011–1023. CrossRefPubMedGoogle Scholar
  67. Stewart J, de Wit H, Eikelboom R (1984) Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol Rev 91(2):251–268. CrossRefPubMedGoogle Scholar
  68. Toates FM (1981) The control of ingestive behaviour by internal and external stimuli—a theoretical review. Appetite 2(1):35–50. CrossRefPubMedGoogle Scholar
  69. Tomie A, Grimes KL, Pohorecky LA (2008) Behavioral characteristics and neurobiological substrates shared by Pavlovian sign-tracking and drug abuse. Brain Res Rev 58(1):121–135. CrossRefPubMedGoogle Scholar
  70. Wassum KM, Ostlund SB, Balleine BW, Maidment NT (2011) Differential dependence of Pavlovian incentive motivation and instrumental incentive learning processes on dopamine signaling. Learn Mem 18(7):475–483. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Yager LM, Robinson TE (2013) A classically conditioned cocaine cue acquires greater control over motivated behavior in rats prone to attribute incentive salience to a food cue. Psychopharmacology 226(2):217–228. CrossRefPubMedGoogle Scholar
  72. Yager LM, Pitchers KK, Flagel SB, Robinson TE (2015) Individual variation in the motivational and neurobiological effects of an opioid cue. Neuropsychopharmacology 40(5):1269–1277. CrossRefPubMedGoogle Scholar
  73. Yeoh JW, James MH, Graham BA, Dayas CV (2014) Electrophysiological characteristics of paraventricular thalamic (PVT) neurons in response to cocaine and cocaine- and amphetamine-regulated transcript (CART). Front Behav Neurosci 8:280. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Yin HH, Ostlund SB, Balleine BW (2008) Reward-guided learning beyond dopamine in the nucleus accumbens: the integrative functions of cortico-basal ganglia networks. Eur J Neurosci 28(8):1437–1448. CrossRefPubMedPubMedCentralGoogle Scholar
  75. Young CD, Deutch AY (1998) The effects of thalamic paraventricular nucleus lesions on cocaine-induced locomotor activity and sensitization. Pharmacol Biochem Behav 60(3):753–758. CrossRefPubMedGoogle Scholar
  76. Zhu Y, Wienecke CF, Nachtrab G, Chen X (2016) A thalamic input to the nucleus accumbens mediates opiate dependence. Nature 530(7589):219–222. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Brittany N. Kuhn
    • 1
  • Marin S. Klumpner
    • 2
  • Ignacio R. Covelo
    • 2
  • Paolo Campus
    • 2
  • Shelly B. Flagel
    • 1
    • 2
    • 3
    Email author
  1. 1.Neuroscience Graduate ProgramUniversity of MichiganAnn ArborUSA
  2. 2.Department of PsychiatryUniversity of MichiganAnn ArborUSA
  3. 3.Molecular and Behavioral Neuroscience InstituteUniversity of MichiganAnn ArborUSA

Personalised recommendations