Physiological Changes in Glucose Differentially Modulate the Excitability of Hypothalamic Melanin-Concentrating Hormone and Orexin Neurons<i>In Situ</i>

Burdakov, Denis; Gerasimenko, Oleg Vsevolodovich; Verkhratsky, Alexei

doi:10.1523/jneurosci.4925-04.2005

Cited by 313 publications

(323 citation statements)

References 32 publications

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“…1 A, n ϭ 15 cells). This electrical fingerprint was previously described for orexin neurons (21,22). In contrast, adapting orexin cells exhibited a strikingly different type of rebound potential: a transient depolarization crowned with spikes; we called this new type of orexin cell fingerprint ''Type-D'' (Fig.…”

Section: Transient and Sustained Glucose Sensors Among Orexin Neuronsmentioning

confidence: 56%

“…6 A and B), cells were injected every 20 -40 s with a fixed-amplitude (10 -40 pA, 1-s duration) square pulse of hyperpolarizing current (22). The amplitude of the resulting downward deflections in membrane potential is proportional to membrane resistance (Ohm's law).…”

Section: Methodsmentioning

confidence: 99%

“…Both partial and complete adaptation in Type-D cells was minimal or absent when the neurons were stimulated with glucose at 22°C instead of 35°C (cells monitored for up to 1 h, n ϭ 10). This temperature dependence presumably explains why adaptation was not apparent when glucose-sensing in orexin cells was previously studied at room temperature (15,22).…”

Section: Membrane Properties and Anatomical Location Of Adapting Andmentioning

confidence: 99%

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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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Section: Transient and Sustained Glucose Sensors Among Orexin Neuronsmentioning

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: Membrane Properties and Anatomical Location Of Adapting Andmentioning

confidence: 99%

See 1 more Smart Citation

Adaptive sugar sensors in hypothalamic feeding circuits

Williams

Alexopoulos

Jensen

et al. 2008

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

111

107

View full text Add to dashboard Cite

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“…OX neuron activation is to be expected in this model due to at least two mechanisms. First, in vitro electrophysiological studies indicate that OX cells are directly stimulated by low glucose [28]. Second, activation of corticotrophin-releasing factor (CRF) neurons in response to stressors such as restraint and footshock is implicated in producing behavioral activation and Fos expression in OX neurons [29,30].…”

Section: Discussionmentioning

confidence: 99%

Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

Tkacs

Pan

Sawhney

et al. 2007

Physiology & Behavior

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Hypoglycemia resulting from excess of exogenous or endogenous insulin elicits central nervous system activation that contributes to counterregulatory hormone secretion. In adult humans without diabetes, hypoglycemia occurring during sleep usually produces cortical activation with awakening. However, in adult humans with type 1 diabetes, hypoglycemic arousal appears blunted or absent. We hypothesized that insulin injection sufficient to produce hypoglycemia would induce awakening in adult male rats. Polysomnographic studies were carried out to characterize the effect of insulin injection on measures of sleep and waking during a circadian time of increased sleep. Compared to a baseline day, insulin treatment more than doubled the time spent awake, from 18.4 ± 2.6% after saline injection to 48.0 ± 5.5% after insulin. Insulin injection also reduced rapid eye movement sleep (REMS) from 27.3 ± 1.8% to 5.6 ± 1.3%. The percent of time in non-REM sleep (NREMS) sleep was not different between saline and insulin days, however, NREMS after insulin was fragmented, with increased number and decreased duration of episodes. These electrophysiological data indicate that insulin-induced hypoglycemia is an arousing stimulus in rats, as in nondiabetic adult humans. We also studied the effect of insulin on activation of selected arousal-related neurons using immunohistochemical detection of Fos. Fos-immunoreactivity increased in orexin (OX) neurons after insulin, from 8.7 ± 4.9% after saline injection to 37 ± 9% after insulin. Basal forebrain cholinergic nuclei also showed increased Fos-immunoreactivity after insulin. These correlated behavioral and histological data provide targets for future studies of the neural pathways underlying hypoglycemic arousal.

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“…Orexin neurons are localised in the posterolateral hypothalamus and project into the entire brain except the cerebellum [1]. Electrophysiological studies on hypothalamic slices have shown that orexin neurons are responsive to peripheral metabolic cues [4,5]. The excitability of orexin neurons was inhibited by glucose and leptin, indicators of high energy levels, whereas ghrelin, a signal for energy depletion, caused a stimulatory effect.…”

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confidence: 99%

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

et al. 2008

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Aims/hypothesis Orexin/hypocretin is a hypothalamic neuropeptide that regulates motivated behaviours, such as feeding and arousal, and, importantly, is also involved in energy homeostasis. The aim of this study was to reveal the role of orexin in the regulation of insulin sensitivity for glucose metabolism. Methods Orexin knockout mice fasted overnight underwent oral glucose tolerance testing and insulin tolerance testing. The impact of orexin deficiency on insulin signalling was studied by Western blotting to measure levels of Akt phosphorylation and its upstream and downstream molecules in the hypothalamus, muscle and liver in orexin knockout mice. Results We found that orexin deficiency caused the agerelated development of impaired glucose tolerance and insulin resistance in both male mice without obesity and female mice with mild obesity, fed a normal chow diet. When maintained on a high-fat diet, these abnormalities became more pronounced exclusively in female orexin knockout mice that developed severe obesity. Insulin signalling through Akt was disrupted in peripheral tissues of middle-aged (9-month-old) but not young adult (2-to-3-month-old) orexin knockout mice fed a normal chow diet. Moreover, basal levels of hypothalamic Akt phosphorylation were abnormally elevated in orexin knockout mice at every age studied, and insulin stimulation failed to increase the level of phosphorylation. Similar abnormalities were observed with respect to GSK3β phosphorylation in the hypothalamus and peripheral tissues of middle-aged orexin knockout mice. Conclusions/interpretation Our results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age.

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Physiological Changes in Glucose Differentially Modulate the Excitability of Hypothalamic Melanin-Concentrating Hormone and Orexin NeuronsIn Situ

Cited by 313 publications

References 32 publications

Adaptive sugar sensors in hypothalamic feeding circuits

Adaptive sugar sensors in hypothalamic feeding circuits

Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

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