Effects of serotonin on perifornical‐lateral hypothalamic area neurons in rat

Kumar, Sunil; Szymusiak, Ronald; Bashir, Tariq; Rai, Seema; McGinty, Dennis; Alam, Md. Noor

doi:10.1111/j.1460-9568.2006.05268.x

Cited by 31 publications

(31 citation statements)

References 41 publications

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“…The predictions about the monoamines, Avp, Ntsr, Trh, and Cck are supported by the literature (Bayer et al 2005;Tsujino et al 2005;Kumar et al 2007;Hara et al 2009), while the others are novel. Finally, we identify a novel set of transcription factors-including Elk3, Hmx2, Fosl1, Creb3l1, Rfx4, Stat5b, and Lhx9-that may be important for the specification of these cells.…”

Section: à5supporting

confidence: 60%

Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation

et al. 2013

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Hypocretin (orexin; Hcrt)-containing neurons of the hypothalamus are essential for the normal regulation of sleep and wake behaviors and have been implicated in feeding, anxiety, depression, and reward. The absence of these neurons causes narcolepsy in humans and model organisms. However, little is known about the molecular phenotype of these cells; previous attempts at comprehensive profiling had only limited sensitivity or were inaccurate. We generated a Hcrt translating ribosome affinity purification (bacTRAP) line for comprehensive translational profiling of all ribosome-bound transcripts in these neurons in vivo. From this profile, we identified >6000 transcripts detectably expressed above background and 188 transcripts that are highly enriched in these neurons, including all known markers of the cells. Blinded analysis of in situ hybridization databases suggests that 60% of these are expressed in a Hcrt marker-like pattern. Fifteen of these were confirmed with double labeling and microscopy, including the transcription factor Lhx9. Ablation of this gene results in a >30% loss specifically of Hcrt neurons, without a general disruption of hypothalamic development. Polysomnography and activity monitoring revealed a profound hypersomnolence in these mice. These data provide an in-depth and accurate profile of Hcrt neuron gene expression and suggest that Lhx9 may be important for specification or survival of a subset of these cells.[Keywords: translational profiling; hypocretin; orexin; bacTRAP; Lhx9; narcolepsy] Supplemental material is available for this article. Narcolepsy is a profound disorder of sleep regulation, characterized by excessive daytime sleepiness, sleep attacks, cataplexy, and sleep-onset REM (rapid eye movement) periods. Studies indicate that narcolepsy, especially when accompanied by cataplexy, is due to the absence of hypocretinergic neurons and signaling (Nishino et al. 2000;Thannickal et al. 2000;Bourgin et al. 2008). The hypocretins (Hcrts; also called orexins) are peptidergic neurotransmitters used by a discrete population of neurons in the lateral hypothalamus Sakurai et al. 1998). In model organisms, disruption of the gene encoding the Hcrt peptides or a Hcrt receptor (Chemelli et al. 1999;Lin et al. 1999) or, alternatively, the ablation of the neurons producing Hcrt (Gerashchenko et al. 2001;Hara et al. 2001;Zhang et al. 2007) recapitulates features of narcolepsy. In humans, there are two variations of the disorder: narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwoC). NC is strongly linked and associated with the HLA DQB1*0602 allele, a T-cell receptor locus, and P2RY11, a receptor that can regulate immune cell survival (Hallmayer et al. 2009;Kornum et al. 2011). This strongly suggests involvement of the immune system in the etiology of NC, while the involvement in NwoC is less clear. Cold Spring Harbor Laboratory Press on May 13, 2018 -Published by genesdev.cshlp.org Downloaded from

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Section: à5supporting

confidence: 60%

Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation

et al. 2013

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“…This finding is supported by a recent report (Kaur et al, 2009) that identified the Hcrt -vPAG circuit, whose activity suppresses REM sleep but not non- REM sleep. On the other hand, Hcrt neurons receive inhibition innervation from noradrenergic (Li et al, 2002), serotoninergic (Yamanaka et al, 2003; Kumar et al, 2007) and dopaminergic (Yamanaka et al, 2006) inputs whereas the histamine has little, if any, effect (Yamanaka et al, 2003). The role of noradrenergic innervation to Hcrt cells remains controversial, as some reports show excitatory effects in rats and others demonstrate inhibitory action (Grivel et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Hypocretin (orexin) regulation of sleep-to-wake transitions

2014

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The hypocretin (Hcrt), also known as orexin, peptides are essential for arousal stability. Here we discuss background information about the interaction of Hcrt with other neuromodulators, including norepinephrine and acetylcholine probed with optogenetics. We conclude that Hcrt neurons integrate metabolic, circadian and limbic inputs and convey this information to a network of neuromodulators, each of which has a different role on the dynamic of sleep-to-wake transitions. This model may prove useful to predict the effects of orexin receptor antagonists in sleep disorders and other conditions.

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“…The placement of the microdialysis probe was such that it was adjacent to the microwire bundles and the extracellular environment of the recorded neurons was within the estimated diffusion field of the microdialysis probe (Alam et al, 2005, Kumar et al, 2007). The microdialysis probe was fixed and microwire bundles were advanced adjacent to the side of the exposed microdialysis membrane to minimize the tissue trauma and to ensure maximum stability of the unit recording.…”

Section: Methodsmentioning

confidence: 99%

Nitric oxide production in the perifornical-lateral hypothalamic area and its influences on the modulation of perifornical-lateral hypothalamic area neurons

et al. 2011

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The perifornical-lateral hypothalamic area (PF-LHA) is a major wake-promoting structure. It predominantly contains neurons that are active during behavioral and cortical activation. PF-LHA stimulation produces arousal and PF-LHA lesions produce somnolence. Nitric oxide (NO) is a gaseous neurotransmitter that has been implicated in the regulation of multiple pathological and physiological processes including the regulation of sleep. NO levels are higher in the cortex and in the basal forebrain (BF) during arousal. In this study we determined whether NO levels increase in the PF-LHA during prolonged arousal and whether increased NO modulates the discharge activity of PF-LHA neurons. Experiments were conducted during lights-on phase between 8.00 – 20.00h (lights-on at 8.00h). First, we quantified levels of NO metabolites, NO2− and NO3− (collectively called NOx−) in the microdialysis dialysates collected from the PF-LHA during baseline (undisturbed rats), 6h of sleep deprivation (SD), and recovery after SD. We further determined the effects of a NO donor, NOC-18, on the discharge activity of PF-LHA neurons in urethane-anesthetized rats. Overall, SD significantly affected NOx− production in the PF-LHA (one way repeated measures ANOVA, F=7.827, p=0.004). The levels of NOx− increased progressively in animals that were subjected to prolonged arousal as compared to the undisturbed predominantly sleeping animals and decreased during the recovery period. Local application of NOC-18 significantly suppressed the discharge of PF-LHA neurons including a majority of stimulus-on neurons or neurons exhibiting activation during EEG desynchronization. The findings of this study suggest that in the PF-LHA, NO production is elevated during prolonged waking and that NO exerts predominantly inhibitory effects on PF-LHA neurons, especially on those neurons that are active during cortical activation. These findings are consistent with a hypothesis that NO in the PF-LHA plays a role in sleep regulation by inhibiting its neurons.

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Effects of serotonin on perifornical‐lateral hypothalamic area neurons in rat

Cited by 31 publications

References 41 publications

Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation

Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation

Hypocretin (orexin) regulation of sleep-to-wake transitions

Nitric oxide production in the perifornical-lateral hypothalamic area and its influences on the modulation of perifornical-lateral hypothalamic area neurons

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