The lateral hypothalamus and orexinergic transmission in the paraventricular thalamus promote the attribution of incentive salience to reward-associated cues

Psychopharmacology (Berl). 2020 Dec;237(12):3741-3758. doi: 10.1007/s00213-020-05651-4. Epub 2020 Aug 27.


Rationale: Prior research suggests that the neural pathway from the lateral hypothalamic area (LHA) to the paraventricular nucleus of the thalamus (PVT) mediates the attribution of incentive salience to Pavlovian reward cues. However, a causal role for the LHA and the neurotransmitters involved have not been demonstrated in this regard.

Objectives: To examine (1) the role of LHA in the acquisition of Pavlovian conditioned approach (PavCA) behaviors, and (2) the role of PVT orexin 1 receptors (OX1r) and orexin 2 receptors (OX2r) in the expression of PavCA behaviors and conditioned reinforcement.

Methods: Rats received excitotoxic lesions of the LHA prior to Pavlovian training. A separate cohort of rats characterized as sign-trackers (STs) or goal-trackers (GTs) received the OX1r antagonist SB-334867, or the OX2r antagonist TCS-OX2-29, into the PVT, to assess their effects on the expression of PavCA behavior and on the conditioned reinforcing properties of a Pavlovian reward cue.

Results: LHA lesions attenuated the development of sign-tracking behavior. Administration of either the OX1r or OX2r antagonist into the PVT reduced sign-tracking behavior in STs. Further, OX2r antagonism reduced the conditioned reinforcing properties of a Pavlovian reward cue in STs.

Conclusions: The LHA is necessary for the development of sign-tracking behavior; and blockade of orexin signaling in the PVT attenuates the expression of sign-tracking behavior and the conditioned reinforcing properties of a Pavlovian reward cue. Together, these data suggest that LHA orexin inputs to the PVT are a key component of the circuitry that encodes the incentive motivational value of reward cues.

Keywords: Incentive salience; Lateral hypothalamus; Orexin/hypocretin; Paraventricular nucleus of the thalamus; Sign-tracking.

MeSH terms

  • Animals
  • Benzoxazoles / administration & dosage
  • Choice Behavior / drug effects
  • Choice Behavior / physiology
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology
  • Cues*
  • Hypothalamic Area, Lateral / drug effects
  • Hypothalamic Area, Lateral / physiology*
  • Isoquinolines / administration & dosage
  • Male
  • Midline Thalamic Nuclei / drug effects
  • Midline Thalamic Nuclei / physiology*
  • Motivation / drug effects
  • Motivation / physiology*
  • Naphthyridines / administration & dosage
  • Orexin Receptor Antagonists / administration & dosage
  • Orexin Receptors / physiology*
  • Pyridines / administration & dosage
  • Rats
  • Rats, Sprague-Dawley
  • Reward*
  • Urea / administration & dosage
  • Urea / analogs & derivatives


  • 1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
  • 1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone
  • Benzoxazoles
  • Isoquinolines
  • Naphthyridines
  • Orexin Receptor Antagonists
  • Orexin Receptors
  • Pyridines
  • Urea