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Fasting Induces a Large, Leptin-Dependent Increase in the Intrinsic Action Potential Frequency of Orexigenic Arcuate Nucleus Neuropeptide Y/Agouti-Related Protein Neurons

Vollum Institute and The Center for the Study of Weight Regulation and Associated Disorders (K.A.T., R.D.C.), Oregon Health & Science University, Portland, Oregon 97239; and Department of Neuroscience (K.A.T.), Albert Einstein College of Medicine, Bronx, New York 10461

Address all correspondence and requests for reprints to: Kanji A. Takahashi, Albert Einstein College of Medicine, Rose F. Kennedy Center, Room 703, 1410 Pelham Parkway South, Bronx, New York 10461. E-mail: katakaha{at}aecom.yu.edu.

The neuropeptide Y (NPY)/Agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus are thought to promote feeding. Here, we demonstrate that feeding state in vivo, through a leptin-dependent process, induces large and persistent changes in the electrophysiological activity of these neurons as measured extracellularly in vitro. Consistent with an orexigenic role, fasting induced a 4-fold increase in the basal action potential frequency of NPY/AgRP neurons. Leptin, when injected into fasted wild-type mice, induced a dose- and time-dependent decrease in spike frequency, which approached fed levels 2–3 h post treatment. In leptin-deficient (lep^ob/lep^ob) and leptin receptor-deficient (lepr^db/lepr^db) mice, NPY/AgRP spike frequency was not significantly increased by fasting, and even in mutant mice fed ad libitum, spike frequency was at least as high as in fasted wild-type mice. All recordings included GABA_A and ionotropic glutamate receptor antagonists, suggesting that expression of this modulation is potentially intrinsic and not synaptically dependent. Recorded neurons were unambiguously identified using NPY-Sapphire transgenic mice. This is a remarkably straightforward example of a very robust in vitro electrophysiogical effect produced by a simple behavioral manipulation, food restriction.

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