Elsevier

Neuroscience

Volume 111, Issue 2, 10 May 2002, Pages 379-387
Neuroscience

Anatomical substrates of orexin–dopamine interactions: lateral hypothalamic projections to the ventral tegmental area

https://doi.org/10.1016/S0306-4522(02)00017-9Get rights and content

Abstract

Dopaminergic projections to the forebrain arising from the mesencephalic ventral tegmentum modulate information processing in cortical and limbic sites. The lateral hypothalamus is crucial for the coordination of behavioral responses to interoceptive cues. The presence of a hypothalamic input to the ventral tegmental area has been known for some time, but the organization of this pathway has received little attention. Among the neuropeptides found in the hypothalamus are the orexins, which are selectively expressed in the lateral hypothalamus and adjacent perifornical area and are critically involved in homeostatic regulatory processes, including arousal and feeding. We examined the anatomical relationships between orexin and dopamine neurons in rats, with particular attention to characterizing the lateral hypothalamic projection to midbrain dopamine neurons.

Iontophoretic deposits of the retrograde tracer FluoroGold into the ventral tegmental area revealed a large number of retrogradely-labeled cells that formed a band extending from the medial perifornical area arching dorsally over the fornix and then ventrolaterally into the lateral hypothalamus; approximately 20% of these cells expressed orexin A-like immunoreactivity. Moreover, axons that were anterogradely labeled from the lateral hypothalamus were seen throughout the ventral tegmental area, and were often in close proximity to the dendrites and somata of dopamine neurons. Dopamine and orexin fibers were found to codistribute in the medial prefrontal cortex; orexin fibers were present in lower density in the medial shell of the nucleus accumbens, and the central and posterior basolateral nuclei of the amygdala.

We conclude that the lateral hypothalamic/perifornical projection represents an anatomical substrate by which interoceptive-related signals may influence forebrain dopamine function.

Section snippets

Animals and surgery

Adult male Sprague–Dawley rats (Harlan; Birmingham, AL, USA) were kept on a 12 h light–dark cycle and allowed free access to food and water. Experimental procedures were conducted in accord with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals.

Rats were deeply anesthetized with pentobarbital and glass pipettes (18–24 μm outer diameter) filled with a 3% solution of the retrograde tracer FluoroGold (FG; Fluorochrome, Inc., Englewood, CO, USA) in 0.1 M cacodylic

Retrograde labeling in the LH/PFA

FG injections of the VTA resulted in retrograde labeling that extended from the preoptic regions to the most caudal portions of the LH. The retrogradely-labeled cells in the LH and surrounding nuclei were organized as a dense band of neurons, which extended from the lateral border of the paraventricular hypothalamic nucleus and arched dorsally over the fornix before curving ventrolaterally into the juxtacapsular LH (see Fig. 1). Retrograde labeling was predominantly ipsilateral, but a small

Discussion

Orexin cells contribute to but are not the sole source of a dense projection from the LH to the VTA. The anatomical distributions of orexin and DA suggest that orexin regulates DA neurons via projections from the LH to the VTA and perhaps at the level of the mesocorticolimbic terminal fields.

Acknowledgements

We appreciate the assistance of Tamara Altman in the preparation of figures, and thank Dr. Lothar Jennes for his generous gift of the guinea-pig anti-FluoroGold antibody. This work was supported in part by a NARSAD Young Investigator Award (J.F.), NIH grants MH 45124 and MH 57995 (A.Y.D.), and the National Parkinson Foundation Center of Excellence at Vanderbilt University.

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