Journal
JOURNAL OF NEUROSCIENCE
Volume 24, Issue 14, Pages 3527-3536Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5364-03.2004
Keywords
theta rhythm; hypocretin; orexin; sleep; memory; cognition; acetylcholine; cataplexy; narcolepsy
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Funding
- NIMH NIH HHS [MH61465, R01 MH061465] Funding Source: Medline
- NINDS NIH HHS [NS32945, NS37788, R01 NS037788] Funding Source: Medline
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Hypothalamic fibers containing the wake-promoting peptides, hypocretins (Hcrts) or orexins, provide a dense innervation to the medial septum-diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics. The MSDB, via its cholinergic and GABAergic projections to the hippocampus, controls the hippocampal theta rhythm and associated learning and memory functions. Neurons of the MSDB express very high levels of the Hcrt receptor 2, which is mutated in canine narcoleptics. In the present study, we investigated the electrophysiological effects of Hcrt peptides on septohippocampal cholinergic neurons that were identified in living brain slices of the MSDB using a selective fluorescent marker. Hcrt activation of septohippocampal cholinergic neurons was reversible, reproducible, and concentration dependent and mediated via a direct postsynaptic mechanism. Both Hcrt1 and Hcrt2 activated septohippocampal cholinergic neurons with similar EC50 values. The Hcrt effect was dependent on external Na+, reduced by external Ba2+, and also reduced in recordings with CsCl-containing electrodes, suggesting a dual underlying ionic mechanism that involved inhibition of a K+ current, presumably an inward rectifier, and a Na+-dependent component. The Na+ component was dependent on internal Ca2+, blocked by replacing external Na+ with Li+, and also blocked by bath-applied Ni2+ and KB-R7943, suggesting involvement of the Na+-Ca2+ exchanger. Using double-immunolabeling studies at light and ultrastructural levels, we also provide definitive evidence for a hypocretin innervation of cholinergic neurons. Thus Hcrt effects within the septum should increase hippocampal acetylcholine release and thereby promote hippocampal arousal.
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