Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: Tonic depression of the hypothalamic arousal system

Yale University, New Haven, Connecticut, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2004; 24(40):8741-51. DOI: 10.1523/JNEUROSCI.2268-04.2004
Source: PubMed


Neurons that release neuropeptide Y (NPY) have important effects on hypothalamic homeostatic regulation, including energy homeostasis, and innervate hypocretin neurons. Using whole-cell patch-clamp recording, we explored NPY actions on hypocretin cells identified by selective green fluorescent protein expression in mouse hypothalamic slices. NPY reduced spike frequency and hyperpolarized the membrane potential of hypocretin neurons. The NPY hyperpolarizing action persisted in tetrodotoxin (TTX), was mimicked by Y1 receptor-selective agonists [Pro34]-NPY and [D-Arg25]-NPY, and was abolished by the Y1-specific antagonist BIBP3226 [(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-amide], consistent with a direct activation of postsynaptic Y1 receptors. NPY induced a current that was dependent on extracellular potassium, reversed near the potassium equilibrium potential, showed inward rectification, was blocked by extracellular barium, and was abolished by GDP-betaS in the recording pipette, consistent with a G-protein-activated inwardly rectifying K+ (GIRK) current. [Pro34]-NPY evoked, and BIBP3226 blocked, the activation of the GIRK-type current, indicating mediation by a Y1 receptor. NPY attenuated voltage-dependent calcium currents mainly via a Y1 receptor subtype. BIBP3226 increased spontaneous spike frequency, suggesting an ongoing Y1 receptor-mediated NPY inhibition. In TTX, miniature EPSCs were reduced in frequency but not amplitude by NPY, NPY13-36, and [D-Trp32]-NPY, but not by [Pro34]-NPY, suggesting the presynaptic inhibition was mediated by a Y2/Y5 receptor. NPY had little effect on GABA-mediated miniature IPSCs but depressed spontaneous IPSCs. Together, these data support the view that NPY reduces the activity of hypocretin neurons by multiple presynaptic and postsynaptic mechanisms and suggest NPY axons innervating hypocretin neurons may tonically attenuate hypocretin-regulated arousal.

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    • "Activity of orexin neurons is regulated by a number of factors, including cholecystokinin, neurotensin, vasopressin, oxytocin, neuropeptide Y (NPY), adenosine, serotonin, and noradrenaline [18]–[22]. In addition, orexin neurons contain other peptides including dynorphin, and neuronal activity-regulated pentraxin (Narp) [23]–[25]. "
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    ABSTRACT: Both orexin and neurotensin are expressed in the lateral hypothalamic area (LHA) and have been implicated in the regulation of feeding, motor activity and the reward system. A double label immunofluorescence and in situ hybridization studies showed that neurotensin colocalizes with orexin in neurons of the LHA. Pharmacological studies suggested that neurotensin excites orexin-producing neurons (orexin neurons) through activation of neurotensin receptor-2 (NTSR-2) and non-selective cation channels. In situ hybridization study showed that most orexin neurons express neurotensin receptor-2 mRNA but not neurotensin receptor-1 (Ntsr-1) mRNA. Immunohistochemical studies showed that neurotensin-immunoreactive fibers make appositions to orexin neurons. A neurotensin receptor antagonist decreased Fos expression in orexin neurons and wakefulness time in wild type mice when administered intraperitoneally. However, the antagonist did not evoke any effect on these parameters in orexin neuron-ablated mice. These observations suggest the importance of neurotensin in maintaining activity of orexin neurons. The evidence presented here expands our understanding of the regulatory mechanism of orexin neurons.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "its absence, narcolepsy with cataplexy occurs, marked by the sudden passage from waking to REMS with muscle atonia (Dauvilliers et al., 2007). Although known to be modulated by multiple neurotransmitters , including GABA and glutamate (Li et al., 2002; Eggermann et al., 2003; Horvath & Gao, 2005; Jones & Muhlethaler, 2005; Henny & Jones, 2006) and several peptides (Fu et al., 2004; Winsky- Sommerer et al., 2004; Tsunematsu et al., 2008; Gonzalez et al., 2009), the Orx neurons are not yet known to be innervated or modulated by SST, which would presumably exert an inhibitory effect in a manner that could attenuate wakefulness, unless the SST terminals also utilize glutamate as a neurotransmitter. "
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    Full-text · Article · Aug 2012 · European Journal of Neuroscience
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    • "Orexin neurons in the PeF are known to express NPY Y4 receptors, and cFos expression is increased in orexin neurons following application of NPY or a Y4-specific agonist (Niimi et al. 2001a; Campbell et al. 2003a). While central orexin injection increases food intake, the effect is at least partly dependent on activation of NPY neurons, as orexin-induced intake is attenuated (but not blocked) by administration of an NPY Y1 receptor antagonist (Yamanaka et al. 2000); this effect is complicated by the finding that NPY tonically pre-and postsynaptically inhibits orexin neurons via a Y1-specific pathway (Fu et al. 2004). Interestingly, NPY-induced food intake appears to be partly dependent on orexin, as treatment with an orexin antibody reduces (but does not eliminate) NPY-induced food intake (Niimi et al. 2001a), and anatomical evidence suggests orexin neurons may be a downstream target of NPY action in feeding (Broberger et al. 1998). "
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