Convergent inputs from electrically and topographically distinct orexin cells to locus coeruleus and ventral tegmental area

Eur J Neurosci. 2012 May;35(9):1426-32. doi: 10.1111/j.1460-9568.2012.08057.x. Epub 2012 Apr 16.


Orexin/hypocretin (orx/hcrt) neurons are thought to ensure that reward-seeking is accompanied by alertness, but the underlying circuit organization is unclear. Reports of differential regulation of lateral versus medial orx/hcrt cells produced a hypothesis of 'efferent dichotomy', in which lateral orx/hcrt cells innervate the ventral tegmental area (VTA) and control reward, while medial orx/hcrt cells innervate locus coeruleus (LC) and control arousal. Two distinct types of orx/hcrt cells also emerged from analysis of intrinsic and input-driven single-cell electrical activity. To examine the projections of these emerging orx/hcrt subtypes to LC and VTA, we injected retrograde tracer into these regions in the mouse brain in vivo, and then examined the properties of tracer-containing orx/hcrt cells in hypothalamic slices. VTA- and LC-projecting orx/hcrt cells were found across the entire orx/hcrt field, including the zona incerta, perifornical area, dorsomedial/anterior and lateral hypothalamus. Within these areas, orx/hcrt cells had similar probabilities of projecting to VTA or LC. Examination of lateral versus medial sections revealed that VTA and LC received inputs from both lateral and medial orx/hcrt cells, but, unexpectedly, lateral orx/hcrt cells were more likely to project to LC than medial orx/hcrt cells. Finally, patch-clamp recordings revealed that VTA and LC received projections from both electrical classes of orx/hcrt cells, which had similar likelihoods of projecting to VTA or LC. Contrary to previous predictions, our data suggest that medial and lateral orx/hcrt cells, and the different electrical and morphological subclasses of orx/hcrt cells identified to date, send projections to both LC and VTA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Mapping*
  • Cell Count
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hypothalamus / cytology
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / physiology*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Locus Coeruleus / cytology*
  • Mice
  • Mice, Transgenic
  • Microscopy, Confocal
  • Microspheres
  • Neural Pathways / physiology
  • Neurons / metabolism*
  • Neuropeptides / metabolism*
  • Orexins
  • Rhodamines
  • Ventral Tegmental Area / cytology*


  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins
  • Rhodamines
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins