title: Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry.
abstract: Lateral hypothalamic area (LHA) orexin neurons modulate reward-based feeding by activating ventral tegmental area (VTA) dopamine (DA) neurons. We hypothesize that signals of peripheral energy status influence reward-based feeding by modulating the glucose sensitivity of LHA orexin glucose-inhibited (GI) neurons. This hypothesis was tested using electrophysiological recordings of LHA orexin-GI neurons in brain slices from 4 to 6week old male mice whose orexin neurons express green fluorescent protein (GFP) or putative VTA-DA neurons from C57Bl/6 mice. Low glucose directly activated ~60% of LHA orexin-GFP neurons in both whole cell and cell attached recordings. Leptin indirectly reduced and ghrelin directly enhanced the activation of LHA orexin-GI neurons by glucose decreases from 2.5 to 0.1mM by 53±12% (n=16, P<0.001) and 41±24% (n=8, P<0.05), respectively. GABA or neurotensin receptor blockade prevented leptin's effect on glucose sensitivity. Fasting increased activation of LHA orexin-GI neurons by decreased glucose, as would be predicted by these hormonal effects. We also evaluated putative VTA-DA neurons in a novel horizontal slice preparation containing the LHA and VTA. Decreased glucose increased the frequency of spontaneous excitatory post-synaptic currents (sEPSCs; 125 ± 40%, n=9, P<0.05) and action potentials (n=9; P<0.05) in 45% (9/20) of VTA DA neurons. sEPSCs were completely blocked by AMPA and NMDA glutamate receptor antagonists (CNQX 20 μM, n=4; APV 20μM, n=4; respectively), demonstrating that these sEPSCs were mediated by glutamatergic transmission onto VTA DA neurons. Orexin-1 but not 2 receptor antagonism with SB334867 (10μM; n=9) and TCS-OX2-29 (2μM; n=5), respectively, blocks the effects of decreased glucose on VTA DA neurons. Thus, decreased glucose increases orexin-dependent excitatory glutamate neurotransmission onto VTA DA neurons. These data suggest that the glucose sensitivity of LHA orexin-GI neurons links metabolic state and reward-based feeding.
authors.affiliation: New Jersey Med. Sch., Rutgers University, Newark, NJ 07103, United States.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: New Jersey Med. Sch., Rutgers University, Newark, NJ 07103, United States.
authors.forename: Ammy M
authors.initials: AM
authors.lastname: Santiago
authors.affiliation: Univ. Northern Colorado, Greeley, CO 80639, United States.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.affiliation: New Jersey Med. Sch., Rutgers University, Newark, NJ 07103, United States. Electronic address: routhvh@njms.rutgers.edu.
authors.forename: Vanessa H
authors.initials: VH
authors.lastname: Routh
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008636:Mesencephalon / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009287:Naphthyridines; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D012201:Reward; D009435:Synaptic Transmission / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000378:metabolism
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068797:Orexins; D014508:Urea; D005947:Glucose
keywords: Dopamine; Electrophysiology; Energy balance; Ghrelin; Leptin; Ventral tegmental area
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