Alien Registration- Estabrooke, Hilda (Baldwin, Cumberland County)

https://digitalmaine.com/alien_docs/32893/thumbnail.jp

The Sweet Long Ago : \b Song And Chorus

https://digitalcommons.library.umaine.edu/mmb-vp/2553/thumbnail.jp

Dear Heart, We\u27re Growing Old : Song And Chorus

https://digitalcommons.library.umaine.edu/mmb-vp/5148/thumbnail.jp

Circadian regulation of mouse suprachiasmatic nuclei neuronal states shapes responses to orexin.

This is the final version of the article. Available from Wiley via the DOI in this record.Our knowledge of how circadian and homeostatic brain circuits interact to temporally organize physiology and behavior is limited. Progress has been made with the determination that lateral hypothalamic orexin (OXA) neurons control arousal and appetitive states, while suprachiasmatic nuclei (SCN) neurons function as the master circadian clock. During the day, SCN neurons exhibit heterogeneity in spontaneous resting membrane potential (RMP), with some neurons becoming severely depolarized (hyperexcited) and ceasing to fire action potentials (APs), while other neurons rest at moderate RMP and fire APs. Intriguingly, the day phase is when the SCN clock is most readily influenced by arousal, but it is unclear if and how heterogeneity in the excitability state of SCN neurons shapes their response to arousal signals, such as OXA. In whole-cell recordings we show that during the day OXA recruits GABA-GABAAreceptor signaling to suppress the RMP of hyperexcited silent as well as moderately hyperpolarized AP-firing SCN neurons. In the AP-firing neurons, OXA hyperpolarized and silenced these SCN cells, while in the hyperexcited silent neurons OXA suppressed the RMP of these cells and evoked either AP-firing, depolarized low-amplitude membrane oscillations, or continued silence at a reduced RMP. These results demonstrate how the resting state of SCN neurons determines their response to OXA, and illustrate that the inhibitory action of this neurochemical correlate of arousal can trigger paradoxical AP firing.We thank the BBSRC (BB/L007665/1) and the Wellcome Trust (WT092319MA) for project grant funding to H.D.P and M.D.C.B

HLA-DQB1 Allele and Hypocretin in Korean Narcoleptics with Cataplexy

Cataplexy is one of the most pathognomonic symptoms in narcolepsy. This study was designed to investigate the frequency of the HLA-DQB1 allele and cerebrospinal fluid (CSF) hypocretin levels in Korean narcoleptics with cataplexy as compared with those who do not have cataplexy. Seventy-two narcoleptics were selected based on polysomnography and multiple sleep latency test as well as their history and clinical symptoms at Sleep Disorders Clinic. The patients were divided into a narcolepsy with cataplexy group (n=56) and a narcolepsy without cataplexy group (n=16). All patients were subjected to HLA typing to determine the frequency of DQB1 allele and to spinal tapping to measure the level of CSF hypocretin. In cataplexy-positive patients, as compared with cataplexy-negative patients, the frequency of HLA-DQB1*0602 was found to be significantly high (89.3% vs. 50.0%) (p=0.003). On the other hand, the frequency of HLA-DQB1*0601 was found to be significantly low (0% vs. 43.8%) (p<0.001). In 48 of 56 cataplexy-positive patients (85.7%), hypocretin levels were decreased (≤110 pg/mL). However, only 6 of 16 cataplexy-negative patients (37.5%) exhibited a decreased hyopcretin level (p<0.001). The high frequency of HLA-DQB1*0602, low frequency of HLA-DQB1*0601 and low hypocretin levels in cataplexy-positive groups suggest that cataplexy-positive narcolepsy might be an etiologically different disease entity from the cataplexy-negative

A Major Role for Perifornical Orexin Neurons in the Control of Glucose Metabolism in Rats

OBJECTIVE-The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS-We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS-Hypothalamic disinhibition of neuronal activity by the gamma-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone-containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS-Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis. Diabetes 58:1998-2005, 200

Pharmacogenetic Modulation of Orexin Neurons Alters Sleep/Wakefulness States in Mice

Hypothalamic neurons expressing neuropeptide orexins are critically involved in the control of sleep and wakefulness. Although the activity of orexin neurons is thought to be influenced by various neuronal input as well as humoral factors, the direct consequences of changes in the activity of these neurons in an intact animal are largely unknown. We therefore examined the effects of orexin neuron-specific pharmacogenetic modulation in vivo by a new method called the Designer Receptors Exclusively Activated by Designer Drugs approach (DREADD). Using this system, we successfully activated and suppressed orexin neurons as measured by Fos staining. EEG and EMG recordings suggested that excitation of orexin neurons significantly increased the amount of time spent in wakefulness and decreased both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep times. Inhibition of orexin neurons decreased wakefulness time and increased NREM sleep time. These findings clearly show that changes in the activity of orexin neurons can alter the behavioral state of animals and also validate this novel approach for manipulating neuronal activity in awake, freely-moving animals

Diurnal rhythms in neural activation in the mesolimbic reward system: critical role of the medial prefrontal cortex

Previous evidence suggests a circadian modulation of drug‐seeking behavior and responsiveness to drugs of abuse. To identify potential mechanisms for rhythmicity in reward, a marker of neural activation (c F os) was examined across the day in the mesolimbic reward system. Rats were perfused at six times during the day [zeitgeber times ( ZT s): 2, 6, 10, 14, 18, and 22], and brains were analysed for c F os and tyrosine hydroxylase ( TH )‐immunoreactive ( IR ) cells. Rhythmic expression of c F os was observed in the nucleus accumbens ( NA c) core and shell, in the medial prefrontal cortex (m PFC ), and in TH ‐ IR and non‐ TH ‐ IR cells in the ventral tegmental area ( VTA ), with peak expression during the late night and nadirs during the late day. No significant rhythmicity was observed in the basolateral amgydala or the dentate gyrus. As the m PFC provides excitatory input to both the NA c and VTA , this region was hypothesised to be a key mediator of rhythmic neural activation in the mesolimbic system. Hence, the effects of excitotoxic m PFC lesions on diurnal rhythms in c F os immunoreactivity at previously observed peak ( ZT 18) and nadir ( ZT 10) times were examined in the NA c and VTA . m PFC lesions encompassing the prelimbic and infralimbic subregions attenuated peak c F os immunoreactivity in the NA c, eliminating the diurnal rhythm, but had no effect on VTA rhythms. These results suggest that rhythmic neural activation in the mesolimbic system may contribute to diurnal rhythms in reward‐related behaviors, and indicate that the m PFC plays a critical role in mediating rhythmic neural activation in the NA c. Previous evidence suggests a circadian modulation of drug‐seeking behavior and responsiveness to drugs of abuse. To identify potential mechanisms for rhythmicity in reward, a maker of neural activation (c F os) was examined across the day in the mesolimbic reward system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99016/1/ejn12224.pd

Expression patterns of corticotropin-releasing factor, arginine vasopressin, histidine decarboxylase, melanin-concentrating hormone, and orexin genes in the human hypothalamus

The hypothalamus regulates numerous autonomic responses and behaviors. The neuroactive substances corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), histidine decarboxylase (HDC), melanin-concentrating hormone (MCH), and orexin/hypocretins (ORX) produced in the hypothalamus mediate a subset of these processes. Although the expression patterns of these genes have been well studied in rodents, less is known about them in humans. We combined classical histological techniques with in situ hybridization histochemistry to produce both 2D and 3D images and to visually align and quantify expression of the genes for these substances in nuclei of the human hypothalamus. The hypothalamus was arbitrarily divided into rostral, intermediate, and caudal regions. The rostral region, containing the paraventricular nucleus (PVN), was defined by discrete localization of CRF- and AVP-expressing neurons, whereas distinct relationships between HDC, MCH, and ORX mRNA-expressing neurons delineated specific levels within the intermediate and caudal regions. Quantitative mRNA signal intensity measurements revealed no significant differences in overall CRF or AVP expression at any rostrocaudal level of the PVN. HDC mRNA expression was highest at the level of the premammillary area, which included the dorsomedial and tuberomammillary nuclei as well as the dorsolateral hypothalamic area. In addition, the overall intensity of hybridization signal exhibited by both MCH and ORX mRNA-expressing neurons peaked in distinct intermediate and caudal hypothalamic regions. These results suggest that human hypothalamic neurons involved in the regulation of the HPA axis display distinct neurochemical patterns that may encompass multiple local nuclei. J. Comp. Neurol. 518:4591–4611, 2010. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78077/1/22480_ftp.pd

Orexin Neurons Receive Glycinergic Innervations

Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM) sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2)-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation