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Animal models of narcolepsy
Chen L, Brown RE, McKenna JT, McCarley RW (2009) Animal models of narcolepsy. CNS Neurol Disord Drug Targets 8(4):296-308. doi: 10.2174/187152709788921717 PMID: 19689311
Objective: To provide information to enable a consensus concerning the evaluation of narcoleptic behavioral and EEG phenomenology in these models.
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Cell transplantation: a future therapy for narcolepsy?
Arias-Carrion O, Murillo-Rodriguez E (2009) Cell transplantation: a future therapy for narcolepsy?. CNS Neurol Disord Drug Targets 8:309-314. doi: 10.2174/187152709788921681
Summary: This review covers the current understanding of narcolepsy and discusses the potential for transplants as a therapeutic treatment. Animal models are summarized, including the use of orexin-SAP (Cat. #IT-20) in rats. The review goes on to suggest that production of orexigenic neuroblasts from stem cells may be a useful therapy.
Related Products: Orexin-B-SAP (Cat. #IT-20)
Medullary circuitry regulating rapid eye movement sleep and motor atonia.
Vetrivelan R, Fuller PM, Tong Q, Lu J (2009) Medullary circuitry regulating rapid eye movement sleep and motor atonia. J Neurosci 29:9361-9369. doi: 10.1523/JNEUROSCI.0737-09.2009
Summary: Data concerning rapid-eye movement (REM) motor atonia in rats has not agreed with results seen in large amount of data from cats. Here the authors traced the medullary networks in rats involved with this REM function. 120-300 ng injections of orexin-SAP (Cat. #IT-20) were administered to 6 different sites in the medulla. Ablation of orexin receptor-expressing neurons in one site in the ventromedial medulla resulted in intermittent loss of muscle atonia, indicating that glutaminergic neurons in this area are key components of the REM atonia circuit.
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Hypocretin-2 saporin lesions of the ventrolateral periaquaductal gray (vlPAG) increase REM sleep in hypocretin knockout mice.
Kaur S, Thankachan S, Begum S, Liu M, Blanco-Centurion C, Shiromani PJ (2009) Hypocretin-2 saporin lesions of the ventrolateral periaquaductal gray (vlPAG) increase REM sleep in hypocretin knockout mice. PLoS One 4:e6346. doi: 10.1371/journal.pone.0006346
Summary: Not all connections between narcolepsy and orexin are understood, since orexin neurons are located in the lateral hypothalamus and some sleep functions are controlled by the brainstem. This experiment used 16.5 ng injections of orexin-SAP (Cat. #IT-20) into each side of the ventrolateral periaqueductal gray (v/PAG to) examine these connections. The results indicate that loss of orexin neurons in the v/PAG results in loss of inhibitory control over REM sleep, but does not cause cataplexy.
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The retroabducens region is necessary for rapid eye movement (REM) during REM sleep in the rat
Pedersen NP, Anaclet C, Vetrivelan R, Saper CB, Lu J (2008) The retroabducens region is necessary for rapid eye movement (REM) during REM sleep in the rat. Neuroscience 2008 Abstracts 784.15/RR66. Society for Neuroscience, Washington, DC.
Summary: REM sleep is characterized by REMs, atonia of the non-respiratory musculature, and active dreaming during which the electroencephalogram (EEG) is desynchronized in humans and shows increased theta activity in rodents. Surprisingly, the source of the actual REMs during REM sleep is not known, although Pompeiano and Morrison (1965) described the reduction or absence of phasic REM phenomena after electrolytic lesion of the medial and spinal vestibular nuclei in the cat. Using the neurotoxins ibotenic acid and saporin-conjugated anti-orexin B IgG, we systematically placed cell-specific lesions in brainstem candidate structures for the generation of REMs in rats equipped for chronic recording of EEG, electrooculogram, and electromyogram. Lesion of a ‘retroabducens’ area, located immediately caudal and extending ventrally from the abducens nucleus, although leaving the abducens nucleus intact, abolished REMs (as well as waking saccades), without affecting other aspects of REM sleep. Animals with retroabducens lesions showed maintenance of slow oscillations in eye position, characteristic of non-REM or slow wave sleep, throughout REM sleep. Lesions of the medial vestibular nucleus, nucleus prepositus hypoglossi and immediately rostral to abducens did not affect REMs. We hypothesize that the retroabducens area may be required for the generation of saccadic eye movements, similar to the paramedian pontine reticular formation as described in cats and monkeys. The retroabducens region appears to be critical for generating the REMs that characterize REM sleep, but most likely downstream from the REM sleep generator.
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Medullary circuitry regulating trigeminal motor nucleus phasic activity during rapid eye movement sleep in the rat
Anaclet C, Pedersen NP, Lu J (2008) Medullary circuitry regulating trigeminal motor nucleus phasic activity during rapid eye movement sleep in the rat. Neuroscience 2008 Abstracts 784.16/RR67. Society for Neuroscience, Washington, DC.
Summary: Rapid Eye Movement (REM) sleep or paradoxical sleep is characterized by activation of the cortical and hippocampal EEG, atonia of postural muscles (neck and limbs), and phasic movements of cranial muscles (eyes, chin, ears and whiskers). We have previously established that glutamatergic neurons of the sublaterodorsal tegmentual nucleus (SLD) play a critical role in generating postural muscle atonia during REM sleep. It has been further proposed that the SLD produces REM motor atonia by stimulating spinal inhibitory neurons, which in turn inhibit spinal motor output neurons. It is not known however whether the SLD is also involved in the regulation of tonic and phasic events of cranial muscles during REM sleep (e.g., rapid eye movement, phasic masseter activation). Previous studies have shown that the supraolivary medulla (SOM, dorsal to the inferior olive) and parvocellular reticular (PCRt) nucleus in the medullary reticular formation project to relevant cranial motor nuclei, including: the trigeminal motor nucleus (Mo5), retroabducens region, facial nucleus (Mo7) and hypoglossal nucleus (Mo12). It is therefore possible that either the SOM or the PCRt (or both) may also be involved in regulating cranial muscle activity in REM sleep. To identify the cell groups responsible for REM phasic control of cranial motor nuclei, we examined masseter muscle EMG following cell-specific lesions (anti-orexin B IgG-saporin) of the SLD, SOM or PCRt. Following two weeks of surgical recovery, we recorded the EEG, EMG (neck and masseter muscles) and EOG continuously for two days. Control rats showed significant phasic activation of the masseter muscles, in particular during the second half of REM sleep episodes. This phasic bursting pattern was similar to eye movements during REM sleep. Neither SLD nor PCRt lesions altered the phasic activity of the masseter muscles during REM sleep, although, and as previously reported, SLD lesions did produce REM without atonia in postural muscles. By contrast, lesions in the SOM eliminated phasic activation of the masseter muscles during REM and produced myoclonic twitching of neck muscles. These results indicate that the SOM is involved in the induction of phasic REM activity of masseter muscles, likely via activation of Mo5, whereas SOM projections to the spinal cord are involved in suppression of myoclonic activity of postural muscles.
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Changes in energy metabolism after ventrolateral preoptic lesions in rats
Ramalingam V, Fuller PM, Lu J, Saper CB (2008) Changes in energy metabolism after ventrolateral preoptic lesions in rats. Neuroscience 2008 Abstracts 586.14/SS47. Society for Neuroscience, Washington, DC.
Summary: The ventrolateral preoptic area (VLPO) is critically involved in the regulation of sleep. For example, lesions of the VLPO have been reported to cause profound insomnia and sleep fragmentation in rats. We evaluated possible changes in energy metabolism and motor behaviors secondary to chronic sleep restriction in VLPO lesioned rats. Under anesthesia (chloralhydrate, 350 mg/kg, i.p.), adult male Sprague Dawley rats (n = 17) received stereotaxic injections of orexin-saporin into the VLPO and were also implanted with EEG/EMG electrodes to assess sleep-wakefulness. Food, water, and body mass measurements were collected for 60 post-lesion days. Sleep-wakefulness was recorded on post-lesion Days 20 and 50. On post-lesion Day 60, the animals were deeply anesthetized and transcardially perfused with 10% formaldehyde. The brains were removed and processed for histological verification of the lesion site. VLPO lesions produced a decrease (34%) in non rapid eye movement sleep (NREM) and a decrease in NREM sleep bout duration (115 ± 5 sec in the VLPO lesioned rats Vs 133 ± 2 in control rats, P < 0.01). The VLPO lesioned animals also exhibited increased food intake when compared to the age-matched controls (0.45 ± 0.004 grams per gram of lean body mass Vs 0.39 ± 0.01 grams per gram of lean body mass, P = 0.05). Food intake (r = 0.90, P<0.001), but not water intake was positively correlated with the amount of sleep loss. Although the weight gain in the VLPO lesioned rats was not statistically different from the controls, it was negatively correlated with the amount of sleep loss in those animals (r = 0.51, P = 0.05). Although the VLPO lesioned animals balanced on the rotatrod for 25% less time than the controls, this did not reach statistical significance, perhaps because the variance was so high in both groups (87 ± 23 seconds Vs 116 ± 25 sec in control rats, P>0.05). The close correlation of sleep loss with changes in food intake and body weight after the VLPO lesions suggests that the increased feeding but lower body weight may be due to the sleep loss, rather than a consequence of damaging neurons adjacent to the VLPO, which would not correlate with sleep loss.
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The substantia nigra and the control of sleep
Lai YY, Hsieh KC, Nguyen D, Siegel JM (2008) The substantia nigra and the control of sleep. Neuroscience 2008 Abstracts 586.9/SS42. Society for Neuroscience, Washington, DC.
Summary: It has been established that the substantia nigra (SN) is involved in the control of motor activity. However, its role in the regulation of sleep remains unclear. We have previously found that NMDA lesions in the SN suppress sleep in the cat. A recent study demonstrated that lesions of the SN by hypocretin2-saporin result in severe insomnia in the rat. Thus, we hypothesized that activation of the SN by application of either excitatory transmitter analogs/agonists or GABA receptor blockers would induce sleep. Hypocretin had been reported to exert an excitatory effect on SN neuronal activity. The SN receives dense projections from hypocretin neurons. In the current study, we investigated whether microinfusion of hypocretin into the SN would modulate sleep and wakefulness in freely moving rats. Adult male Sprague-Dawley rats were implanted with EEG and EMG electrodes, and a guide cannula targeting the SN. Experiments were conducted one week after the rat had been implanted. The rats were housed individually in sound-attenuated chambers in LD 12:12. Hypocretin-1 was delivered via microdialysis probes (CMA/11) at a rate of 2 μL/min. Each one-hour of hypocretin infusion (ZT4 to ZT5 in the light period) was preceded by a 2-hour baseline period of artificial cerebrospinal fluid (aCSF) infusion and was followed by a 2-hour aCSF infusion. The lower concentration of hypocretin-1 (36 μM, n=2) reduced wakefulness by 19% ± 9.5% and increased slow wave sleep (SWS) by 12.8% ± 2.3% of the baseline level. The higher concentration of hypocretin-1 (72 μM, n=3) reduced wakefulness by 30.5% ± 16.4% of the baseline level and produced an increase in both SWS and REM sleep, by 10.2% ± 2.2% and 63.7% ± 26.6% respectively. The increased sleep induced by both concentrations of hypocretin were also observed in the first post-infusion hour. In conclusion, we found that hypocretin-1 has a sleep-promoting effect in the SN. Our previous study showed that hypocretin (orexin) neurodegeneration occurred in Parkinson’s disease patients. This finding suggests that sleep difficulties in Parkinson’s disease patients may result from a combination of lesions in the SN and the secondary effects of the loss of hypocretin neurons.
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Unilateral lesions of lateral hypothalamic orexin neurons impair surprise-induced enhancements of learning
Holland PC, Angeli N, Lasseter H, Wheeler DS (2008) Unilateral lesions of lateral hypothalamic orexin neurons impair surprise-induced enhancements of learning. Neuroscience 2008 Abstracts 387.16/SS63. Society for Neuroscience, Washington, DC.
Summary: Recent evidence indicates that hypothalamic orexin (hypocretin) neurons are importantly involved in arousal, aspects of learned motivational function, and the cholinergic mediation of sustained attention and the enhanced detection of weak but significant cues. Here we examined the role of these neurons in the modulation of attention in the associative learning of rats. The surprising omission of an expected event can enhance attention to cues present at the time of surprise, and hence facilitate subsequent learning about those cues. In previous research, we showed that circuitry including the amygdala central nucleus (CeA), the substantia nigra pars compacta, cholinergic neurons in the substantia innominata/nucleus basalis, and portions of the medial prefrontal and posterior parietal cortex, form a network essential for this surprise-enhanced learning. In the present study, rats received orexin-saporin lesions of the lateral hypothalamus (LH) in one hemisphere and ibotenic acid lesions of CeA in the other. Because most projections between LH and CeA are ipsilateral, this combination of lesions functionally disconnects CeA from LH orexin neurons. Rats in three control groups received unilateral lesions of LH or CeA (with sham lesions of the other region) or sham lesions of both regions. The rats were then trained in a task in which attention was manipulated by shifting a predictive relation between two cues. First, all rats received serial light-tone pairings, half of which were followed by food. Next, for half of the rats in each lesion condition the tone was omitted on nonreinforced trials, whereas the remaining rats continued to receive the same light-tone trials as before. Finally, attention to the light was assessed by measuring the rate of learning a new light-food relation. If the rats were surprised by the omission of tone during the previous phase, then attention to the light would be enhanced, resulting in faster acquisition of light-food conditioning. Consistent with previous findings, sham-lesioned rats and rats with unilateral CeA lesions showed this surprise-induced enhancement. By contrast, rats with unilateral LH lesions showed no such enhancement of learning, but otherwise performed comparably to controls. Notably, damage to CeA contralateral to the LH damage produced no additional impairment. Thus, LH orexin neurons play an important role in the surprise-induced enhancement of attention and learning, but not solely by their interactions with CeA.
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The role of orexin in sexual behavior and sexual reward of the male rat
Di Sebastiano AR, Yong-yow S, Coolen LM (2008) The role of orexin in sexual behavior and sexual reward of the male rat. Neuroscience 2008 Abstracts 97.4/UU18. Society for Neuroscience, Washington, DC.
Summary: The hypothalamic neuropeptide orexin has been demonstrated to play a role in reward related to drugs of abuse and is potentially involved in regulation of natural rewarding behaviors. Male sexual behavior has been shown to activate orexin neurons and this behavior is altered by administration of orexin receptor agonists or antagonists. However, the exact role of orexin in male sexual performance, sexual motivation and reward is currently unclear. Therefore, the goal of the current study was to test the hypothesis that orexin plays a critical role in sexual behavior, motivation and reward. First, using Fos as a marker for neural activation, we investigated activation of orexin neurons following different parameters of sexual behavior in sexually naïve and experienced male rats. It was demonstrated that orexin neurons in the lateral hypothalamic area (LHA) and in the dorsal medial hypothalamus/perifornical (PFA-DMH) region become activated with presentation of the female and there is no further increase in activation with other components of mating (15-30% in LHA; 65-80% in PFA-DMH). Next, we tested the functional role of orexin utilizing orexin-cell body specific lesions. Adult male rats underwent lesion or sham surgery using the targeted toxin orexin-saporin or blank-saporin respectively. Following two weeks recovery, sexual behavior was recorded over the course of four mating trials. During the first mating trial, males with complete lesions showed significantly shorter latencies to mount and intromit. This suggests that lesions facilitated sexual performance in naïve animals. This facilitation was attenuated by sexual experience as lesions did not affect any parameter of sexual behavior in experienced animals. Next, runway tests were conducted to determine motivation to run towards a potential partner over two conditioning trials. Lesions did not alter sexual motivation, as lesion and sham males all demonstrated increased speed to run towards an estrous female during the second trial. Finally, a conditioned place preference (CPP) paradigm was conducted as a measure of sexual reward. All groups formed a conditioned preference for the mating-paired chamber, indicating that lesions did not significantly disrupt sexual reward. Overall, these findings suggest that orexin does not play a critical role in male sexual performance, motivation, and reward, however may be involved in general arousal related to sexual behavior.
Related Products: Orexin-B-SAP (Cat. #IT-20), Blank-SAP (Cat. #IT-21)