Effects of lesions of the histaminergic tuberomammillary nucleus on spontaneous sleep in rats.
OBJECTIVE
Extensive evidence suggests that histaminergic neurons promote wakefulness. Histaminergic neurons are found exclusively in the tuberomammillary nucleus (TMN), and electrolytic lesions of the posterior hypothalamus, where the TMN resides, produce intense hypersomnolence. However, electrolytic lesions disrupt fibers of passage, and the effects of fiber-sparing, cell-specific TMN lesions on sleep and wakefulness are unknown. Hence, we placed cell-specific lesions in the TMN to determine its role in spontaneous wakefulness.


METHODS
TMN neurons in rats are relatively resistant to excitotoxins. Hence, we ablated them using saporin conjugated to hypocretin 2, which ablates hypocretin receptor-bearing neurons such as TMN neurons. One to 2 weeks after bilateral injections of Hcrt2-SAP into Sprague-Dawley rats, we correlated loss of TMN neurons with changes in sleep.


METHODS
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METHODS
N/A.


METHODS
N/A.


RESULTS
Four days after injections with hypocretin-2-saporin, the number of TMN neurons was markedly decreased, and most were lost after 12 days, as determined by immunohistochemistry for adenosine deaminase, a marker of TMN neurons. Nearby nonhistaminergic neurons were similarly ablated. Rats with an average 82.5% loss of TMN cells (determined 2 weeks after injection) did not have marked changes in total sleep amounts compared to saline-treated rats 1 or 2 weeks following the injection, except for a slight decrease in rapid eye movement sleep during the lights-on period for the first week only. The percentage of remaining TMN neurons positively correlated with the average duration of wake bouts during the lights-off period.


CONCLUSIONS
The absence of gross changes in sleep after extensive loss of histaminergic neurons suggests that this system is not critical for spontaneous wakefulness.
Gerashchenko
Dmitry
D
West Roxbury Veterans Affairs Medical Center, West Roxbury, Massachusetts 02132, USA.
Chou
Thomas C
TC
Blanco-Centurion
Carlos A
CA
Saper
Clifford B
CB
Shiromani
Priyattam J
PJ
D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001931:Brain Mapping; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D004292:Dominance, Cerebral / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000502:physiology*; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D007034:Hypothalamus, Posterior / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000502:physiology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
D006632:Histamine; D000243:Adenosine Deaminase