1 / 23

Orexin neurons, reward and addiction: It all comes together in the lateral hypothalamus

Orexin neurons, reward and addiction: It all comes together in the lateral hypothalamus. Gary Aston-Jones, Ph.D. Department of Neurosciences Medical University of South Carolina. Orexin (hypocretin) neurons:. Peyron et al. J. Neurosci. 1998;18:9996-10015. - located only in hypothalamus

hua
Download Presentation

Orexin neurons, reward and addiction: It all comes together in the lateral hypothalamus

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Orexin neurons, reward and addiction: It all comes together in the lateral hypothalamus Gary Aston-Jones, Ph.D. Department of Neurosciences Medical University of South Carolina

  2. Orexin (hypocretin) neurons: Peyron et al. J. Neurosci. 1998;18:9996-10015 • - located only in hypothalamus • widespread projections • mutations produce narcolepsy symptoms • prominent hypothesis: arousal

  3. Not all orexin neurons are created equal

  4. Activity of orexin neurons in LH does not correspond to arousal rhythm Estabrooke, I. V. et al. J. Neurosci. 2001;21:1656-1662

  5. LH orexin neurons: Possible role in reward processing • Orexin administration increases feeding • • Orexin neurons send projections to brain areas involved in reward (e.g., PFC, Nac, VTA) • Lateral hypothalamus long implicated in reward functions • •Q: Are LH orexin neurons important in reward processing and addiction?

  6. Place conditioning procedureConditioned place preference (CPP) 3 drug or food pairing days, balanced design Preference tested next day, drug-free Brains taken 2 hr after preference test for Fos measurements

  7. Fos activation in orexin neurons with exposure to morphine environment Morphine-conditioned Non-conditioned Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)

  8. Preference scores correlate with percentage of LH orexin cells that are Fos+ Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)

  9. Conclusion: LH orexin neurons are potently activated in proportion to reward preference Q: Could activation of LH orexin neurons be involved in drug-seeking and relapse?

  10. Orexin antagonist attenuates expression of CPP Preference score (sec) * Saline SB334867

  11. Brains taken for Fos staining 2 h after test for reinstate. CPP extinguished for 2 consecutive days Repeated testing for 1 to 3 weeks daily without drug to extinguish preference 3 days of morphine CPP conditioning Stimulate LH orexin neurons to test for reinstatement (rat pancreatic polypeptide, rPP, microinjection in LH) Drug-seeking during protracted withdrawal: Animal Model of Relapse

  12. rPP in LH reinstates morphine preference -effective -ineffective Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)

  13. Correlation: rPP-induced reinstatement and % LH orexin neurons with Fos r = 0.99 Reinstatement score (sec) time in morphine side - saline side % orexin neurons with Fos Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)

  14. Reinstatement score (sec) time in morphine side - saline side rPP-induced reinstatement is blocked by selective orexin antagonist - Test Day 1 - Test Day 2 Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)

  15. Orexin injected into VTA reinstates morphine preference Preference score (sec) time in orexin side - saline side Harris, Wimmer and Aston-Jones, Nature 437: 556-9 (2005)

  16. Orexin is also involved in plasticity and learning Borgland et al, Neuron 49 (2006) Narita et al, J. Neurosci 29 (2006)

  17. LH orexin neurons are stimulated during drug pairing

  18. Bilateral disconnection of LH orexin projections to VTA blocks acquisition of a morphine CPPUnilateral excitotoxic lesion of LH + SB in contra VTA Go see: Wimmer et al., poster 00-74 Monday PM

  19. SUMMARY • LH orexin neurons (but not other orexin neurons) are stimulated in proportion to reward preference. • Blockade of orexin receptors attenuates expression of drug preference. • Exogenous stimulation of LH orexin neurons reinstates extinguished drug preference (relapse). • Orexin in VTA dopamine neuron area reinstates extinguished drug preference (relapse). • Orexin projections from LH to VTA are critical for learning stimulus-drug relationships. Hypothesis: LH orexin neurons are involved in reward-based learning and memory

  20. Projections to brainstem • arousal areas: • LC • TMN • PPT/LDT • Projections to forebrain and • midbrain reward areas: • VTA • NAc • Amy LH DMH/PFA • Arousal-related inputs: • Waking • Stress • Reward-related inputs: • Morphine • Cocaine • Food Functionally distinct orexin neuron groups

  21. Collaborators Matt Wimmer Toastmaster Glenda Harris

  22. Role of LH orexin neurons in reward-based learning and memory circuitry Harris and Aston-Jones, TINS 29: 571-7 (2006)

  23. Bilateral neurotoxic lesions of LH orexin neurons blocks acquistion of a morphine CPP

More Related