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

ArticleinThe Journal of Neuroscience : The Official Journal of the Society for Neuroscience 24(40):8741-51 · November 2004with9 Reads
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.
    • "In the arcuate nucleus (ARC), NPY and AgRP neurons can be conditionally activated by Hcrt and ghrelin and inhibited by leptin, suggesting a role for Hcrt in satiety and hunger [65], and microinjection of Hcrt into the ARC increases food intake behaviorally and increases cytosolic calcium in NPY neurons via a Hcrt-1 receptor-dependent pathway [66, 67] . Conversely, as NPY is able to reduce the activity of Hcrt neurons by multiple pre-and postsynaptic mechanisms, it may tonically attenuate Hcrtregulated behavioral arousal [68] . Intracerebroventricular administration of ghrelin stimulates feeding behavior and induces c-Fos expression in Hcrt neurons; ghrelin mRNA levels also peak in the dark phase of activity just prior to sleep, further suggesting an interaction with Hcrt and arousal [69, 70]. "
    [Show abstract] [Hide abstract] ABSTRACT: The hypocretins (Hcrts), also known as orexins, have been among the most intensely studied neuropeptide systems since their discovery about two decades ago. Anatomical evidence shows that the hypothalamic neurons that produce hypocretins/orexins project widely throughout the entire brain, innervating the noradrenergic locus coeruleus, the cholinergic basal forebrain, the dopaminergic ventral tegmental area, the serotonergic raphe nuclei, the histaminergic tuberomammillary nucleus, and many other brain regions. By interacting with other neural systems, the Hcrt system profoundly modulates versatile physiological processes including arousal, food intake, emotion, attention, and reward. Importantly, interruption of the interactions between these systems has the potential to cause neurological and psychiatric diseases. Here, we review the modulation of diverse neural systems by Hcrts and summarize potential therapeutic strategies based on our understanding of the Hcrt system’s role in physiology and pathophysiological processes.
    Full-text · Article · Jan 2016
    • "In view of these arguments, we hypothesize that NPYpositive , orexin-sensitive neurons could collect and integrate information on the metabolic state and locomotor activity and transmit it to the SCN. It has been also suggested that the IGL is a part of the negative-feedback loop with the lateral hypothalamus because NPY tonically inhibits orexinergic neurons (Fu et al., 2004). Although orexins act upon the NPY-positive neurons in the IGL, the complex effect is not cell-type specific. "
    [Show abstract] [Hide abstract] ABSTRACT: Orexins/hypocretins (OXA and OXB) are two hypothalamic peptides involved in the regulation of many physiological processes including the sleep-wake cycle, food intake and arousal. The orexinergic system of the lateral hypothalamus is considered a non-specific peptidergic system, and its nerve fibres innervate numerous brain areas. Among many targets of orexinergic neurons is the intergeniculate leaflet (IGL) of the thalamus - a small but important structure of the mammalian biological clock. In rats, the IGL consists of GABAergic cells which also synthesise different neuropeptides. One group of neurons produces neuropeptide Y (NPY) and sends its axons to the master biological clock known as the suprachiasmatic nuclei. Another neuronal group produces enkephalin and is known to connect contralateral IGLs. This study evaluated the effects of orexins on identified IGL neurons revealing that 58% of the recorded neurons were sensitive to OXA (200 nM) and OXB (200 nM) administration. Both NPY-positive and -negative neurons were depolarised by these neuropeptides. Experiments using selective orexin receptor antagonists (SB-334867, 10 μM and TCS-OX2-29, 10 μM) suggested that both orexin receptors participate in the recorded OXA effects. In addition, IGL neurons were either directly depolarised by OXA or their activity was altered by changes in presynaptic inputs. We observed an increase of GABA release onto the investigated IGL neuron after OXA application, consistent with a presynaptic localisation of the orexin receptors. An increase in miniature excitatory postsynaptic current frequency was not observed within the IGL. Our findings reinforce the connection between circadian clock physiology and the orexinergic system. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · May 2015
    • "Related neuropeptides mediate quiescence and arousal/ motivation in worms, flies, and rodents. Peptides homologous to NPY induce locomotion quiescence in C. elegans (FLP-18 and FLP-21), inhibit locomotion and foraging for food in Drosophila (NPF) (Wu et al., 2003), and inhibit the arousing effects of hypocretin-expressing neurons in mice (NPY) (Fu et al., 2004). By contrast, peptides homologous to PDF arouse locomotion in C. elegans (PDF-1), arouse circadian locomotor activity, and decrease sleep duration in Drosophila (PDF) (Parisky et al., 2008; Renn et al., 1999), and regulate circadian behaviors and sleep in rodents (VIP) (Hu et al., 2011; Maywood et al., 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Animals undergo periods of behavioral quiescence and arousal in response to environmental, circadian, or developmental cues. During larval molts, C. elegans undergoes a period of profound behavioral quiescence termed lethargus. Locomotion quiescence during lethargus was abolished in mutants lacking a neuropeptide receptor (NPR-1) and was reduced in mutants lacking NPR-1 ligands (FLP-18 and FLP-21). Wild-type strains are polymorphic for the npr-1 gene, and their lethargus behavior varies correspondingly. Locomotion quiescence and arousal were mediated by decreased and increased secretion of an arousal neuropeptide (PDF-1) from central neurons. PDF receptors (PDFR-1) expressed in peripheral mechanosensory neurons enhanced touch-evoked calcium transients. Thus, a central circuit stimulates arousal from lethargus by enhancing the sensitivity of peripheral mechanosensory neurons in the body. These results define a circuit mechanism controlling a developmentally programmed form of quiescence.
    Full-text · Article · Jun 2013
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