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Orexin (hypocretin) neurons contain dynorphin
1Department of Neurobiology and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Orexins (also called hypocretins) are peptide neurotransmitters expressed in neurons of the lateral hypothalamic area (LHA). Mice lacking the orexin peptides develop narcolepsy-like symptoms, whereas mice with a selective loss of the orexin neurons develop hypophagia and severe obesity in addition to the narcolepsy phenotype. These different phenotypes suggest that orexin neurons may contain neurotransmitters besides orexin that regulate feeding and energy balance. Dynorphin neurons are common in the LHA, and dynorphin has been shown to influence feeding; hence, we studied whether dynorphin and orexin are colocalized. In rats, double-label in situ hybridization revealed that nearly all (94%) neurons expressing prepro-orexin mRNA also expressed prodynorphin mRNA. The converse was also true: 96% of neurons in the LHA containing prodynorphin mRNA also expressed prepro-orexin mRNA. Double-label immunohistochemistry confirmed that orexin-A and dynorphin-A peptides were highly colocalized in the LHA. Wild-type mice and orexin knock-out mice showed abundant prodynorphin mRNA-expressing neurons in the LHA, but orexin/ataxin-3 mice with a selective loss of the orexin neurons completely lacked prodynorphin mRNA in this area, further confirming that within the LHA, dynorphin expression is restricted to the orexin neurons. These findings suggest that dynorphin-A may play an important role in the function of the orexin neurons.
Insights
Orexin neurons in the brain
Area of Science:
- Neuroscience
- Neuroendocrinology
Background:
- Orexins (hypocretins) are crucial neurotransmitters produced in the lateral hypothalamic area (LHA).
- Loss of orexin function leads to narcolepsy, while selective loss of orexin neurons causes obesity and hypophagia, suggesting other neurotransmitters are involved.
Purpose of the Study:
- To investigate the potential colocalization of dynorphin within orexin neurons in the LHA.
- To determine if dynorphin plays a role in the function of orexin neurons.
Main Methods:
- Utilized double-label in situ hybridization in rats to examine mRNA colocalization.
- Employed double-label immunohistochemistry to confirm peptide colocalization.
- Analyzed gene expression in wild-type, orexin knock-out, and orexin/ataxin-3 mice.
Main Results:
- Nearly all orexin neurons (94%) co-expressed prodynorphin mRNA, and vice versa (96%).
- Orexin-A and dynorphin-A peptides were found to be highly colocalized in the LHA.
- Selective loss of orexin neurons in orexin/ataxin-3 mice resulted in a complete absence of prodynorphin mRNA in the LHA.
Conclusions:
- Dynorphin expression in the LHA is predominantly restricted to orexin neurons.
- Dynorphin-A likely plays a significant role in the physiological functions regulated by orexin neurons.