Input of Orexin/Hypocretin Neurons Revealed by a Genetically Encoded Tracer in Mice

Sakurai, Takeshi; Nagata, Ruby; Yamanaka, Akihiro; Kawamura, Hiroko; Tsujino, Natsuko; Muraki, Yo; Kageyama, Haruaki; Kunita, Satoshi; Takahashi, Satoru; Goto, Katsutoshi; Koyama, Yoshimasa; Shioda, Seiji; Yanagisawa, Masashi

doi:10.1016/j.neuron.2005.03.010

Cited by 413 publications

(208 citation statements)

References 45 publications

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“…This phenotype indicates that conditional targeting of Lmx1b with the ePet-Cre lines will be essential for understanding the role of Lmx1b in the development of postnatal 5HT-modulated behaviors. These lines will also enable studies of 5HT neuron circuits in the behaving animal such as the reciprocal orexinergic-serotonergic negative feedback circuit that appears to be involved in stabilizing sleep͞wakefulness states (38)(39)(40). The ePet-Cre lines could also be crossed to the lacZ wheat germ agglutinin (41) transgenic line for anterograde transneuronal tracing of 5HT circuits.…”

Section: Discussionmentioning

confidence: 99%

A genetic approach to access serotonin neurons forin vivoandin vitrostudies

Scott

Wylie

Lerch

et al. 2005

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

209

237

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Serotonin (5HT) is a critical modulator of neural circuits that support diverse behaviors and physiological processes, and multiple lines of evidence implicate abnormal serotonergic signaling in psychiatric pathogenesis. The significance of 5HT underscores the importance of elucidating the molecular pathways involved in serotonergic system development, function, and plasticity. However, these mechanisms remain poorly defined, owing largely to the difficulty of accessing 5HT neurons for experimental manipulation. To address this methodological deficiency, we present a transgenic route to selectively alter 5HT neuron gene expression. This approach is based on the ability of a Pet-1 enhancer region to direct reliable 5HT neuron-specific transgene expression in the CNS. Its versatility is illustrated with several transgenic mouse lines, each of which provides a tool for 5HT neuron studies. Two lines allow Cre-mediated recombination at different stages of 5HT neuron development. A third line in which 5HT neurons are marked with yellow fluorescent protein will have numerous applications, including their electrophysiological characterization. To demonstrate this application, we have characterized active and passive membrane properties of midbrain reticular 5HT neurons, which heretofore have not been reported to our knowledge. A fourth line in which Pet-1 loss of function is rescued by expression of a Pet-1 transgene demonstrates biologically relevant levels of transgene expression and offers a route for investigating serotonergic protein structure and function in a behaving animal. These findings establish a straightforward and reliable approach for developing an array of tools for in vivo and in vitro studies of 5HT neurons.Cre recombinase ͉ pet-1 ͉ transgenic ͉ yellow fluorescent protein ͉ monoamine S erotonin (5HT) is a transmitter of broad relevance to nervous system development and function (1-4). Serotonergic pathways innervate most cytoarchitectonic structures of the CNS, and accordingly they have been implicated in the modulation of circuitry involved in nearly all behaviors and physiological processes (3, 5-7). Additionally, 5HT neurotransmission is modulated through abundant afferent information arising from, for example, other monoaminergic systems (8, 9) and from orexinergic, glutamatergic, and GABAergic pathways (10-12). The remarkably expansive neuromodulatory influence of 5HT is the product of a complex transcriptional cascade that generates 5HT-synthesizing neurons in the ventral hindbrain (13-18). 5HT also figures prominently in mental health disorders as a number of lines of evidence provide strong support for the hypothesis that altered serotonergic signaling contributes to neurological and psychiatric pathogenesis (19)(20)(21)(22). Despite considerable progress in understanding the importance of 5HT neurotransmission, however, the mechanisms governing 5HT neuron development and the precise physiological roles of 5HT in the modulation of CNS circuitry are not yet clear.Studies of 5HT neurons are hind...

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Section: Discussionmentioning

confidence: 99%

A genetic approach to access serotonin neurons forin vivoandin vitrostudies

Scott

Wylie

Lerch

et al. 2005

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

209

237

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“…Degeneration of Hcrt neurons underlies the sleep disorder narcolepsy, underscoring the importance of this system for the regulation of sleep and wakefulness (Hara et al, 2001;Thannickal et al, 2000). Hcrt neurons receive afferents from several brain regions involved in homeostatic processes (Sakurai et al, 2005;Yoshida et al, 2006), indicating that these cells may integrate arousal with other physiological functions.…”

Section: Introductionmentioning

confidence: 99%

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

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The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wakepromoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH-or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos + cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH-and ALMtreated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL-but not in VEH-or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.

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“…1). This notion is further supported by recent systematic searches of afferent pathways to orexin neurons (Sakurai et al, 2005;Yoshida et al, 2006). Understanding the connectome of orexin neurons more precisely might provide…”

Section: Mmandts 12mentioning

confidence: 85%

Overview of orexin/hypocretin system

Mieda

Sakurai

2012

Progress in Brain Research

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A series of recent studies has established the orexin/hypocretin system as a critical regulator of sleep/wake states. Its deficiency results in the sleep disorder narcolepsy in humans, dogs, and rodents. These findings have brought about the possibility of novel therapies for sleep disorders including narcolepsy and insomnia. Moreover, accumulating evidence indicates that the orexin/hypocretin system regulates sleep and wakefulness through interactions with neuronal systems that regulate emotion, reward, and energy homeostasis. Here, we briefly summarize the progress of orexin/hypocretin studies and future perspectives.

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Input of Orexin/Hypocretin Neurons Revealed by a Genetically Encoded Tracer in Mice

Cited by 413 publications

References 45 publications

A genetic approach to access serotonin neurons forin vivoandin vitrostudies

A genetic approach to access serotonin neurons forin vivoandin vitrostudies

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Overview of orexin/hypocretin system

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