Abstract
Until recently, hypocretin (Hcrt) neurons were the only known wake-promoting neuronal population in the lateral hypothalamus (LH), but subpopulations of inhibitory neurons in this area and glutamatergic neurons in the nearby supramammillary nucleus (SuM) have recently been found that also promote wakefulness. We performed chemogenetic excitation of LH neurons in mice and observed increased wakefulness that lasted more than 4h without unusual behavior or EEG anomalies. The increased wakefulness was similar in the presence or absence of the dual orexin receptor blocker almorexant (ALM). Analysis of hM3Dq transfection and c-FOS expression in LH inhibitory neurons and in the SuM failed to confirm that the increased wakefulness was due to these wake-promoting populations, although this possibility cannot be completely excluded. To evaluate the relationship to the Hcrt system, we repeated the study in Orexin-tTA mice in the presence or absence of dietary doxycycline (DOX), which enabled us to manipulate the percentage of Hcrt neurons that expressed hM3Dq. In DOX-fed mice, 18% of Hcrt neurons as well as many other LH neurons expressed hM3Dq; these mice showed a profound increase in wake after hM3Dq activation even in the presence of ALM. In mice switched to normal chow, 62% of Hcrt neurons expressed hM3Dq along with other LH cells; chemogenetic activation produced even more sustained arousal which could be reduced to previous levels by ALM treatment. Together, these results indicate an LH neuron population that promotes wakefulness through an Hcrt-independent pathway that can act synergistically with the Hcrt system to prolong arousal.
Significance Despite nearly a century of evidence suggesting that the lateral hypothalamus contains neurons essential to sustain wakefulness, the primary wake-promoting cells in this brain region studied to date have been the hypocretin/orexin neurons. Here, we show that chemogenetic excitation of lateral hypothalamus neurons can induce sustained wakefulness even in absence of hypocretin signaling and that concurrent hypocretin neuron activation can prolong arousal. These results indicate the existence of parallel arousal pathways in the lateral hypothalamus and suggest a new therapeutic target for disorders of excessive sleepiness such as hypersomnia and narcolepsy.
Footnotes
Authors report no conflicts of interest.
Research was supported by R01NS077408 and R01NS098813 from the National Institutes of Health and by KAKENHI grants (16H01271, 15H01428 to A.Y.) from Ministry of Education, Culture, Sports Science, MEXT, Japan. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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