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The Journal of Neuroscience, April 7, 2004, 24(14):3527-3536; doi:10.1523/JNEUROSCI.5364-03.2004

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Behavioral/Systems/Cognitive
Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

Min Wu,¹ Laszlo Zaborszky,⁵ Tibor Hajszan,^4,5 Anthony N. van den Pol,² and Meenakshi Alreja^1,3

Departments of ¹Psychiatry, ²Neurosurgery, and ³Neurobiology, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut 06508, ⁴Center of Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102, and ⁵Laboratory of Molecular Neurobiology, Biological Research Center, Szeged, Hungary 6726

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.

Key words: theta rhythm; hypocretin; orexin; sleep; memory; cognition; acetylcholine; cataplexy; narcolepsy

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Received July 30, 2003; revised February 20, 2004; accepted February 28, 2004.

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