The Wake-Promoting Hypocretin–Orexin Neurons Are in an Intrinsic State of Membrane Depolarization

Eggermann, Emmanuel; Bayer, Laurence; Serafin, Mauro; Saint-Mleux, Benoı̂t; Bernheim, Laurent; Machard, Danièle; Jones, Barbara E.; Mühlethaler, Michel

doi:10.1523/jneurosci.23-05-01557.2003

Cited by 160 publications

(155 citation statements)

References 41 publications

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“…The outward shift of resting currents on replacing Na ϩ with NMDG ϩ is consistent with a resting sodium conductance (with TTX present), similar to previous results in deep cerebellar nuclear cells (Raman et al, 2000) and orexinergic neurons (Eggermann et al, 2003). The outward shift of currents after Na ϩ removal could also represent enhancement of an outward Na/K ATPase electrogenic pump current (owing to reduction of the sodium gradient) or elimination of Na/Ca exchanger current.…”

Section: Resting Potential and Background Conductancesupporting

confidence: 88%

Mechanism of Spontaneous Firing in Dorsomedial Suprachiasmatic Nucleus Neurons

Jackson¹,

Yao²,

Bean³

2004

J. Neurosci.

164

218

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We studied acutely dissociated neurons from the dorsomedial (shell) region of the rat suprachiasmatic nucleus (SCN) with the aim of determining the ionic conductances that underlie spontaneous firing. Most isolated neurons were spontaneously active, firing rhythmically at an average frequency of 8 Ϯ 4 Hz. After application of TTX, oscillatory activity generally continued, but more slowly and at more depolarized voltages; these oscillations were usually blocked by 2 M nimodipine. To quantify the ionic currents underlying normal spontaneous activity, we voltage clamped cells using a segment of the spontaneous activity of each cell as voltage command and then used ionic substitution and selective blockers to isolate individual currents. TTX-sensitive sodium current flowed throughout the interspike interval, averaging Ϫ3 pA at Ϫ60 mV and Ϫ11 pA at Ϫ55 mV. Calcium current during the interspike interval was, on average, fourfold smaller. Except immediately before spikes, calcium current was outweighed by calcium-activated potassium current, and in current clamp, nimodipine usually depolarized cells and slowed firing only slightly (average, ϳ8%). Thus, calcium current plays only a minor role in pacemaking of dissociated SCN neurons, although it can drive oscillatory activity with TTX present. During normal pacemaking, the early phase of spontaneous depolarization (Ϫ85 to Ϫ60 mV) is attributable mainly to background conductance; cells have relatively depolarized resting potentials (with firing stopped by TTX and nimodipine) of Ϫ55 to Ϫ50 mV, although input resistance is high (9.5 Ϯ 4.1 G⍀). During the later phase of pacemaking (positive to Ϫ60 mV), TTX-sensitive sodium current is dominant.

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Section: Resting Potential and Background Conductancesupporting

confidence: 88%

Mechanism of Spontaneous Firing in Dorsomedial Suprachiasmatic Nucleus Neurons

Jackson¹,

Yao²,

Bean³

2004

J. Neurosci.

164

218

View full text Add to dashboard Cite

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“…We find a similar fraction of PF LH neurons to be MCH positive by single-cell PCR analysis (Pakkanen et al, 2005). Previous reports from other laboratories have associated the bipolar morphology and tonic firing rate profile as seen in our type 3 neurons with orexin-expressing cells in LH slices (Li et al, 2002;Eggermann et al, 2003;Gao et al, 2003). Also, van den Pol and colleagues demonstrated that MCHpositive neurons in culture, as well as in brain slice preparations, show spikefrequency adaptation with sustained depolarization and responses to hyperpolarizing current that are similar to that of our type 1 neurons (Gao et al, 2003;van den Pol et al, 2004).…”

Section: Basic Characteristics Of Lh Neurons Studiedsupporting

confidence: 83%

Cholinergic Modulation of Appetite-Related Synapses in Mouse Lateral Hypothalamic Slice

Jo¹,

Wiedl²,

Role³

2005

J. Neurosci.

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Nicotine administration reduces appetite and alters feeding patterns; a major deterrent to smoking cessation is hyperphagia and resultant weight gain. We demonstrate here that lateral hypothalamic (LH) circuits involving melanin-concentrating hormone (MCH) neurons are subject to cholinergic modulation that may be related to the effects of nicotine on appetite control. Cholinergic input to the perifornical LH area of the mouse is confirmed by examination of immunostaining for vesicular acetylcholine (

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“…These differences in membrane potential response to depolarization indicate differences in the expression of depolarization-activated ion channels. For example, postinhibitory hyperpolarization of orexin cells is likely to be caused by A-type K ϩ channels (21), while postinhibitory excitation could theoretically be due to I CAN channels present in orexin cells (25). However, our voltageclamp analysis (Fig.…”

Section: Discussionmentioning

confidence: 94%

Adaptive sugar sensors in hypothalamic feeding circuits

Williams

Alexopoulos

Jensen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

111

107

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Brain glucose sensing is critical for healthy energy balance, but how appropriate neurocircuits encode both small changes and large background values of glucose levels is unknown. Here, we report several features of hypothalamic orexin neurons, cells essential for normal wakefulness and feeding: (i) A distinct group of orexin neurons exhibits only transient inhibitory responses to sustained rises in sugar levels; (ii) this sensing strategy involves time-dependent recovery from inhibition via adaptive closure of leak-like K ؉ channels; (iii) combining transient and sustained glucosensing allows orexin cell firing to maintain sensitivity to small fluctuations in glucose levels while simultaneously encoding a large range of baseline glucose concentrations. These data provide insights into how vital behavioral orchestrators sense key features of the internal environment while sustaining a basic activity tone required for the stability of consciousness.brain ͉ glucose ͉ hypocretin ͉ orexin ͉ hypothalamus T o survive, living organisms need to vary their behavior according to internal energy levels. In mammals, this involves translating the hormone and nutrient content of the extracellular fluid into appropriate combinations of brain states such as hunger, arousal, and motivation (1). This translation critically relies on neurons producing the peptide neurotransmitters orexins/ hypocretins (orexin neurons) (2, 3). Orexin neurons are located in the hypothalamus but innervate most of the brain, with major inputs to arousal and reward centers, where orexins are released and act on two specific G protein coupled receptors (4, 5). The firing of orexin neurons promotes wakefulness (6) and is so important for maintaining normal consciousness that loss of orexin cells causes severe narcolepsy/cataplexy (7,8). Orexins are also a powerful stimulus for reward-seeking behavior, and destruction of orexin neurons prevents fasting from stimulating foraging (9-12). Besides promoting wakefulness and reward-seeking, orexin cells are involved in memory, stress, and cardiovascular control (reviewed in ref. 5).Recent data show that orexin neurons are not only key effectors of vital behaviors but are also specialized sensors of the body's internal environment. In particular, they act as electrical detectors of glucose, a fundamental signal informing the brain of changes in body energy reserves (12-14). Small physiological rises in ambient [glucose] are sufficient to trigger large K ϩ currents in orexin cell bodies, causing hyperpolarization and suppression of action potential firing (15). Presumably, it is this combination of critical ''sensor'' and ''effector'' tasks that makes the orexin system such a prominent link between body energy status and behavior (12). However, this multitasking also poses an unsolved paradox. If orexin cells are shut down by even a small rise in glucose and loss of their activity causes narcolepsy, how is narcolepsy-free consciousness maintained after a meal or during diabetic hyperglycemia? One theoretical solu...

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The Wake-Promoting Hypocretin–Orexin Neurons Are in an Intrinsic State of Membrane Depolarization

Cited by 160 publications

References 41 publications

Mechanism of Spontaneous Firing in Dorsomedial Suprachiasmatic Nucleus Neurons

Mechanism of Spontaneous Firing in Dorsomedial Suprachiasmatic Nucleus Neurons

Cholinergic Modulation of Appetite-Related Synapses in Mouse Lateral Hypothalamic Slice

Adaptive sugar sensors in hypothalamic feeding circuits

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