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.
    PLoS ONE 04/2013; 8(4):e62391. DOI:10.1371/journal.pone.0062391 · 3.23 Impact Factor
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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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    ABSTRACT: Somatostatin (SST) is a neuropeptide with known inhibitory actions in the hypothalamus, where it inhibits release of growth hormone-releasing hormone (GHRH), while also influencing the sleep-wake cycle. Here we investigated in the rat whether SST neurons might additionally release GABA (gamma-aminobutyric acid) or glutamate in different regions and whether they might contact orexin neurons that play an important role in the maintenance of wakefulness. In dual-immunostained sections viewed by epifluorescence microscopy, we examined if SST varicosities were immunopositive for the vesicular transporter for GABA (VGAT) or glutamate (VGLUT2) in the posterolateral hypothalamus and neighboring arcuate nucleus and median eminence. Of the SST varicosities in the posterolateral hypothalamus, 18% were immunopositive for VGAT, whereas ≤ 1% were immunopositive for VGLUT2. In the arcuate and median eminence, 26 and 64% were VGAT+ and < 3% VGLUT2 + , respectively. In triple-immunostained sections viewed by epifluorescence and confocal microscopy, SST varicosities were seen in contact with orexin somata, and of these varicosities, a significant proportion (23%) contained VGAT along with synaptophysin, the presynaptic marker for small synaptic vesicles, and a similar proportion (25%) abutted puncta that were immunostained for gephyrin, the postsynaptic marker for GABAergic synapses. Our results indicate that a significant proportion of SST varicosities in the hypothalamus have the capacity to release GABA, to form inhibitory synapses upon orexin neurons, and accordingly through their peptide and/or amino acid, to inhibit orexin neurons, as well as GHRH neurons. Thus while regulating GHRH release, SST neurons could serve to attenuate arousal and permit progression through the sleep cycle.
    European Journal of Neuroscience 08/2012; 36(10). DOI:10.1111/j.1460-9568.2012.08253.x · 3.18 Impact Factor
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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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    ABSTRACT: In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus-perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin-producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.
    Handbook of experimental pharmacology 01/2012; 209(209):77-109. DOI:10.1007/978-3-642-24716-3_4
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