Akira Terao - Academia.edu (original) (raw)

Papers by Akira Terao

Journal of Neuroscience, 2014

Recent studies have reported that MCH neurons are active during rapid eye movement (REM) sleep, b... more Recent studies have reported that MCH neurons are active during rapid eye movement (REM) sleep, but their physiological role in the regulation of sleep/wakefulness is not fully understood. To determine the physiological role of MCH neurons, newly developed transgenic mouse strains that enable manipulation of the activity and fate of MCH neurons in vivo were generated using the recently developed knockin-mediated enhanced gene expression by improved tetracycline-controlled gene induction system. The activity of these cells was controlled by optogenetics by expressing channelrhodopsin2 (E123T/T159C) or archaerhodopsin-T in MCH neurons. Acute optogenetic activation of MCH neurons at 10 Hz induced transitions from non-REM (NREM) to REM sleep and increased REM sleep time in conjunction with decreased NREM sleep. Activation of MCH neurons while mice were in NREM sleep induced REM sleep, but activation during wakefulness was ineffective. Acute optogenetic silencing of MCH neurons using archaerhodopsin-T had no effect on any vigilance states. Temporally controlled ablation of MCH neurons by cell-specific expression of diphtheria toxin A increased wakefulness and decreased NREM sleep duration without affecting REM sleep. Together, these results indicate that acute activation of MCH neurons is sufficient, but not necessary, to trigger the transition from NREM to REM sleep and that MCH neurons also play a role in the initiation and maintenance of NREM sleep.

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1998

To determine the site of action of the sleep-promoting effect of interleukin-1 (IL-1), we continu... more To determine the site of action of the sleep-promoting effect of interleukin-1 (IL-1), we continuously infused (between 11 P.M. and 5 A.M.) murine recombinant IL-1beta into seven different locations in the ventricular and subarachnoid systems of the brain in freely moving rats. When IL-1 was infused at 10 ng/6 hr into the subarachnoid space underlying the ventral surface of the rostral basal forebrain, which previously was defined as the "prostaglandin (PG) D2-sensitive sleep-promoting zone" (PGD2-SZ), the total amount of slow-wave sleep (SWS) increased by 110.7 min (IL-1 was 208.1 +/- 14.3 min vs control at 97.4 +/- 9.3 min; n = 8; p < 0.01 by paired Student's t test) from the baseline control level obtained under continuous infusion of saline vehicle. The hourly SWS during the infusion period reached the level of daytime SWS, the physiological maximum, whereas paradoxical sleep (PS) was decreased transiently. This site of action for the SWS promotion was dissociat...

Bmc Neuroscience, 2002

The cryptochrome 1 and 2 genes (cry1 and cry2) are necessary for the generation of circadian rhyt... more The cryptochrome 1 and 2 genes (cry1 and cry2) are necessary for the generation of circadian rhythms, as mice lacking both of these genes (cry1,2 -/-) lack circadian rhythms. We studied sleep in cry1,2 -/mice under baseline conditions as well as under conditions of constant darkness and enforced wakefulness to determine whether cryptochromes influence sleep regulatory processes.

Neuroscience, 2003

To determine whether the synthesis of macromolecules is increased in the cerebral cortex during s... more To determine whether the synthesis of macromolecules is increased in the cerebral cortex during sleep, we subjected C57BL/6 mice to 6 hours of sleep deprivation and then screened the expression of 1176 genes of known function by using cDNA arrays. The expression of the heat shock proteins (HSP), endoplasmic reticulum protein (ERp72) and glucose-regulated protein (GRp78), was among the genes whose expression was significantly elevated in the cortex during sleep deprivation, whereas GRp78 and GRp94 mRNAs were elevated in the cortex during recovery sleep after sleep deprivation, as confirmed by conventional and quantitative realtime polymerase chain reaction and/or Northern analyses. A systematic evaluation of the expression of six heat shock protein family members in seven brain regions revealed in-creased mRNA levels in cortex, basal forebrain, hypothalamus, cerebellum and medulla during sleep deprivation, whereas increased mRNA levels during recovery sleep were limited to the cortex and medulla. Immunohistochemical studies identified increased numbers of GRp78-, GRp94-, and ERp72-immunoreactive cells in the dorsal and lateral cortex during sleep deprivation but, during recovery sleep, elevated numbers of these cells were found only in the lateral cortex. In the medulla, increased numbers of GRp94-immunoreactive cells were observed in nucleus tractus solitarius, dorsal motor nucleus of the vagus and the rostroventrolateral medulla during recovery sleep. The widespread increase of heat shock protein family mRNAs in brain during sleep deprivation may be a neuroprotective response to prolonged wakefulness. In contrast, the relatively limited heat shock protein family mRNA expression during recovery sleep may be related to the role of heat shock proteins in protein biogenesis and thus to the restorative function of sleep.

Journal of Neuroscience, 2014

PLoS ONE, 2013

Chronic adrenergic activation leads to the emergence of beige adipocytes in some depots of white ... more Chronic adrenergic activation leads to the emergence of beige adipocytes in some depots of white adipose tissue in mice. Despite their morphological similarities to brown adipocytes and their expression of uncoupling protein 1 (UCP1), a thermogenic protein exclusively expressed in brown adipocytes, the beige adipocytes have a gene expression pattern distinct from that of brown adipocytes. However, it is unclear whether the thermogenic function of beige adipocytes is different from that of classical brown adipocytes existing in brown adipose tissue. To examine the thermogenic ability of UCP1 expressed in beige and brown adipocytes, the adipocytes were isolated from the fat depots of C57BL/6J mice housed at 24uC (control group) or 10uC (cold-acclimated group) for 3 weeks. Morphological and gene expression analyses revealed that the adipocytes isolated from brown adipose tissue of both the control and cold-acclimated groups consisted mainly of brown adipocytes. These brown adipocytes contained large amounts of UCP1 and increased their oxygen consumption when stimulated with norepinephirine. Adipocytes isolated from the perigonadal white adipose tissues of both groups and the inguinal white adipose tissue of the control group were white adipocytes that showed no increase in oxygen consumption after norepinephrine stimulation. Adipocytes isolated from the inguinal white adipose tissue of the coldacclimated group were a mixture of white and beige adipocytes, which expressed UCP1 and increased their oxygen consumption in response to norepinephrine. The UCP1 content and thermogenic ability of beige adipocytes estimated on the basis of their abundance in the cell mixture were similar to those of brown adipocytes. These results revealed that the inducible beige adipocytes have potent thermogenic ability comparable to classical brown adipocytes.

Peptides, 2012

The thermogenic function of brown adipose tissue (BAT) is increased by norepinephrine (NE) releas... more The thermogenic function of brown adipose tissue (BAT) is increased by norepinephrine (NE) released from sympathetic nerve endings, but the roles of NPY released along with NE are poorly elucidated. Here, we examined effect of NPY on basal and NE-enhanced thermogenesis in isolated brown adipocytes that express Y1 and Y5 receptor mRNA. Treatment of cells with NPY did not influence the basal and NE-enhanced rates of oxygen consumption and cAMP accumulation. Treatment with NPY also failed to induce ERK (Thr202/Tyr204) phosphorylation in the brown adipocytes. In contrast, treatment with NPY increased ERK phosphorylation in cultured stromal vascular cells from the BAT that express Y1 receptor mRNA. In the latter treatment with NPY also increased STAT3 (Ser727) phosphorylation. These results suggest that NPY mainly acts on stromal vascular cells in BAT and plays roles in the regulation of their gene transcription through ERK and STAT3 pathways, while NPY does not affect the thermogenic function of brown adipocytes.

Neuroscience Letters, 2004

Several lines of evidence indicate that the histaminergic (HA) system is important for wakefulnes... more Several lines of evidence indicate that the histaminergic (HA) system is important for wakefulness and behavioral state regulation. We investigated the hypothesis that age-related changes in HA system occur which may be related to decreased alertness in aging. Although histidine decarboxylase mRNA levels did not change with age in C57BL/6 mice, significant differences were found in histamine H1 receptor (H 1 R), histamine H2 receptor (H 2 R), and histamine H3 receptor (H 3 R) mRNA levels in several brain regions. The most widespread changes were observed in H 1 R mRNA, which were significantly lower (27-38%) in the cortex, hypothalamus, hippocampus and medulla of 24month-old mice relative to 3-month-old animals. Age-related changes in H 2 R mRNA levels were restricted to the pons and cerebellum and decreased H 3 R mRNA was found only in the medulla. In conjunction with the age-related decrease in hypocretin receptor 2 mRNA levels we have previously reported, decreased HA receptor mRNA levels may contribute to diminished alertness, sleep continuity, and diurnal rhythms of sleep and wakefulness in the aged. q

Neuroscience Letters, 2002

The hypocretin (Hcrt; also known as orexin) system has been implicated in arousal state regulatio... more The hypocretin (Hcrt; also known as orexin) system has been implicated in arousal state regulation and energy metabolism. We hypothesize that age-related sleep problems can result from dysfunction of this system and thus measured messenger RNA (mRNA) levels of preprohcrt in the hypothalamus, and hcrt receptor 1 (hcrtr1) and hcrt receptor 2 (hcrtr2) in eight brain regions of 3, 12, 18 and 24 months old C57BL/6 mice. Expression of preprohcrt and the colocalized prodynorphin did not change with age. Whereas an age-related change in hcrtr1 mRNA expression was observed only in the hippocampus, hcrtr2 mRNA levels declined in the hippocampus, thalamus, pons, and medulla; these reductions ranged from 33 to 44%. Declining trends (P , 0:1) in hcrtr2 mRNA levels were also observed in the cortex, basal forebrain and hypothalamus. These results are consistent with the hypothesis that an age-related deterioration occurs in the Hcrt system that may contribute to age-related sleep disorders. q

Neuroscience, 2003

Previous studies have documented changes in expression of the immediate early gene (IEG) c-fos an... more Previous studies have documented changes in expression of the immediate early gene (IEG) c-fos and Fos protein in the brain between sleep and wakefulness. Such expression differences implicate changes in transcriptional regulation across behavioral states and suggest that other transcription factors may also be affected. In the current study, we examined the expression of seven fos/jun family member mRNAs (c-fos, fosB, fos related antigen (fra)1, fra-2, junB, c-jun, and junD) and three other IEG mRNAs (egr-1, egr-3, and nur77) in mouse brain following short-term (6 h) sleep deprivation (SD) and 4 h recovery sleep (RS) after SD. Gene expression was quantified in seven brain regions by real-time reverse transcription-polymerase chain reaction (RT-PCR). Multivariate analysis of variance revealed statistically significant variation in cerebral cortex, basal forebrain, thalamus and cerebellum. Levels of c-fos and fosB mRNA were elevated during SD in all four of these brain regions. In the cerebral cortex, junB mRNA was also elevated during SD whereas, in the basal forebrain, fra-1 and fra-2 mRNA levels increased in this condition. During RS, the only IEG mRNA to undergo significant increase was fra-2 in the cortex. C-jun and junD mRNAs were invariant across experimental conditions. These results indicate that the expression of fos/jun family members is diverse during SD. Among other IEGs, nur77 mRNA expression across conditions was similar to c-fos and fosB, egr-1 mRNA was elevated during SD in the cortex and basal forebrain, and egr-3 mRNA was elevated in the cortex during both SD and RS. The similarity of fosB and nur77 expression to c-fos expression indicates that these genes might also be useful markers of functional activity. Along with our previous results, the increased levels of fra-2 and egr-3 mRNAs during RS reported here suggest that increased mRNA expression during sleep is rare and may be anatomically restricted.

Neuroscience, 2006

Previous studies have demonstrated that macromolecular synthesis in the brain is modulated in ass... more Previous studies have demonstrated that macromolecular synthesis in the brain is modulated in association with the occurrence of sleep and wakefulness. Similarly, the spectral composition of electroencephalographic activity that occurs during sleep is dependent on the duration of prior wakefulness. Since this homeostatic relationship between wake and sleep is highly conserved across mammalian species, genes that are truly involved in the electroencephalographic response to sleep deprivation might be expected to be conserved across mammalian species. Therefore, in the rat cerebral cortex, we have studied the effects of sleep deprivation on the expression of immediate early gene and heat shock protein mRNAs previously shown to be upregulated in the mouse brain in sleep deprivation and in recovery sleep after sleep deprivation. We find that the molecular response to sleep deprivation and recovery sleep in the brain is highly conserved between these two mammalian species, at least in terms of expression of immediate early gene and heat shock protein family members. Using Affymetrix Neurobiology U34 GeneChips ® , we also screened the rat cerebral cortex, basal forebrain, and hypothalamus for other genes whose expression may be modulated by sleep deprivation or recovery sleep. We find that the response of the basal forebrain to sleep deprivation is more similar to that of the cerebral cortex than to the hypothalamus. Together, these results suggest that sleepdependent changes in gene expression in the cerebral cortex are similar across rodent species and therefore may underlie sleep history-dependent changes in sleep electroencephalographic activity. © 2005 Published by Elsevier Ltd on behalf of IBRO.

Journal of Neuroimmunology, 2002

Using GeneChipsR, basal and lipopolysaccharide (LPS)-induced gene expression was examined in the ... more Using GeneChipsR, basal and lipopolysaccharide (LPS)-induced gene expression was examined in the hippocampus of 3-, 12-, 18-and 24-month-old male C57BL/6 mice to identify genes whose altered expression could influence hippocampal function in advanced age. Gene elements that changed with age were selected with a t-statistic and specific expression patterns were confirmed with real-time quantitative PCR. Basal expression of 128 gene elements clearly changed with age in the hippocampus. Fourteen gene elements showed increased expression with age and these increases were validated after LPS stimulation. Major histocompatibility complex (MHC) TL region and thymic shared antigen (TSA-1) gene expression increased, suggesting T cell activation in the hippocampus with age. Cytokine (interleukin (IL)-1h, tumor necrosis factor (TNF)-a) and chemokine (macrophage chemotactic protein-1) expression increased sharply in 24-month-old mice. These findings are in contrast to a decrease in the peripheral immune response, documented by decreased T cell proliferation and decreased ratios of naive to memory T cells. Age-related increases in inflammatory potential in the brain may contribute to neurodegenerative diseases of the aged. D

Journal of Neurochemistry, 2008

Journal of Neurochemistry, 2002

Possible roles of prostaglandins (PGs) in interleukin-1 (IL-1)-induced activation of noradrenergi... more Possible roles of prostaglandins (PGs) in interleukin-1 (IL-1)-induced activation of noradrenergic neurons were examined by assessing norepinephrine (NE) turnover in the brain and peripheral organs of rats. An intraperitoneal injection of human recombinant IL-1 beta accelerated NE turnover in the hypothalamus, spleen, lung, diaphragm, and pancreas. A similar increase in NE turnover was also observed after intracerebroventricular injection of corticotropin-releasing hormone (CRH). Pretreatment with indomethacin (cyclooxygenase inhibitor) abolished the IL-1-induced, but not the CRH-induced, increase in hypothalamic and splenic NE turnover. To elucidate which eicosanoid-cyclooxygenase product(s) is responsible for accelerating NE turnover, PGD2, PGE2, PGF2 alpha, U-46619 (stable thromboxane A2 analogue), or carbacyclin (stable prostacyclin analogue) was administered intracerebroventricularly. Among them, PGE2 was the only eicosanoid effective in increasing NE turnover in spleen, whereas PGD2 was effective in the hypothalamus. The stimulative effect of PGD2 was abolished by pretreatment with intracerebroventricular injection of a CRH antiserum. These results suggest that the action of IL-1 is mediated through PGD2 production to activate the noradrenergic neurons in the hypothalamus, and through PGE2 production to increase sympathetic nerve activity in spleen.

Journal of Dairy Research, 2010

Retinol-binding protein 4 (RBP4) is a plasma protein involved in retinol transportation, and rece... more Retinol-binding protein 4 (RBP4) is a plasma protein involved in retinol transportation, and recent evidence in rodents suggests that RBP4 is also a metabolic regulator that modifies insulin sensitivity. To assess how RBP4 levels are regulated in ruminants, we determined the RBP4 concentrations in bovine plasma and milk using Western blot analysis. Plasma RBP4 levels in non-pregnant non-lactating (control) cows were around 45 microg/ml, which were sustained during 60-h fasting, but decreased significantly 4 h after lipopolysaccharide (LPS) administration. Basal plasma retinol concentration was around 30 microg/dl, but this decreased to approximately one-third and one-half of these values during fasting and 8 h after LPS challenge, respectively. Plasma RBP4 and retinol levels in cows 3-6 d before parturition were comparable to those of the controls. However, on the day of parturition both were significantly decreased and had returned to basal levels by two weeks after calving. Interestingly, RBP4 was clearly detected in colostrum (16.4+/-5.6 microg/ml) but was only faintly detected in milk from cows at 7 d and 15 d after calving. Retinol concentrations in colostrum were almost 10-fold higher than those in plasma, while those in milk were comparable to those in plasma. These results suggest that RBP4 and retinol levels are independently regulated under physiological and pathophysiological conditions and that RBP4, like retinol, is transferred from maternal stores to calves through colostrum.

Gene, 2001

Hypocretins 1 and 2 (also called orexins A and B, respectively) are hypothalamic neuropeptides th... more Hypocretins 1 and 2 (also called orexins A and B, respectively) are hypothalamic neuropeptides that have recently been shown to be involved in the sleep disorder narcolepsy and possibly in the normal regulation of sleep and wake functions. These two peptides are derived from a single precursor molecule called prepro-hypocretin, also known as prepro-orexin. We have cloned a 450 bp fragment from the 5 Hanking region of the human prepro-hypocretin gene and demonstrated that this fragment has promoter activity in vitro. Deletions at the 5 H end from 2450 to 2188 reduced the promoter activity by ,50%. Further deletion from the 5 H -end to 269 almost completely abolished promoter activity. The 450 bp fragment contains a number of potential transcription factor binding sites, including an interferon (IFN) response element. Our studies demonstrate that a-IFN strongly inhibits the promoter activity of both 450 and 188 bp fragments in a dosedependent manner. The inhibitory effect of a-IFN is consistent with recent studies which suggest that hypocretin 1/orexin A may be involved in modulating arousal states and with the literature indicating involvement of immune-related molecules in sleep regulation. q Abbreviations: hcrt, hypocretin gene; a-IFN, a-interferon; ISRE, interferon-stimulated response element; IRF-1, interferon regulatory factor-1; OX 1 R, orexin-1 receptor/hypocretin receptor 1; OX 2 R, orexin-2 receptor/ hypocretin receptor 2; PCR, polymerase chain reaction; 20a-SDH, 20-ahydroxysteroid dehydrogenase; SEM, standard error of the mean; SOCS, suppressors of cytokine signaling; Stats, signal transducers and activators of transcription * Corresponding author.

Gene, 2002

Fatty acid amide hydrolase (FAAH) is a membrane-bound enzyme that inactivates a family of fatty a... more Fatty acid amide hydrolase (FAAH) is a membrane-bound enzyme that inactivates a family of fatty acid amide molecules which are implicated in physiological processes such as pain and sleep. We cloned a 1.9 kb fragment of the 5 0 -untranslated region of the mouse FAAH gene into the pGL3 basic luciferase reporter vector and showed that this sequence has promoter activity in vitro. By primer extension analysis, we have determined the transcription start site to be 200 bases upstream of the ATG initiation codon and found that a TATA motif was absent. A number of putative response elements, including those for estrogen and glucocorticoids, were identified in this sequence. We have demonstrated that the estrogen and glucocorticoid receptors down-regulate transcriptional activity independent of their ligand. These data should help in understanding the mechanisms of FAAH gene transcription. q

Experimental Animals, 2014

Genetic variations in the wild-derived inbred mouse strains are more diverse than that of classic... more Genetic variations in the wild-derived inbred mouse strains are more diverse than that of classical laboratory inbred mouse strains, including C57BL/6J (B6). The sleep/wake and monoamine properties of six wild-derived inbred mouse strains (PGN2, NJL, BLG2, KJR, MSM, HMI) were characterized and compared with those of B6 mice. All examined mice were nocturnal and had a polyphasic sleep pattern with a "main sleep period" identified during the light period. However, there were three sleep/wake phenotypic differences between the wild-derived mouse strains and B6 strain. First, the amount of sleep during the dark phase was comparable with that of B6 mice. However, the amount of sleep during the light phase was more varied among strains, in particular, NJL and HMI had significantly less sleep compared with that of B6 mice. Second, PGN2, NJL, BLG2, and KJR mice showed a "highly awake period" (in which the hourly total sleep time was <10%) immediately after the onset of the dark period, which was not seen in B6 mice. Third, relative to that of B6 mice, PGN2 and KJR mice showed longer duration of wakefulness episodes during the 12-h dark phase. Differences in whole brain noradrenaline, dopamine, and 5-hydroxy-tryptamine contents between the wild-derived mouse strains and B6 strain were also found. These identified phenotypes might be potentially under strong genetic control. Hence, wild-derived inbred mice could be useful for identifying the genetic factors underlying the regulation of sleep and wakefulness.

Journal of Neuroscience, 2014

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1998

Bmc Neuroscience, 2002

Neuroscience, 2003

Journal of Neuroscience, 2014

PLoS ONE, 2013

Peptides, 2012

Neuroscience Letters, 2004

Neuroscience Letters, 2002

Neuroscience, 2003

Neuroscience, 2006

Journal of Neuroimmunology, 2002

Journal of Neurochemistry, 2008

Journal of Neurochemistry, 2002

Journal of Dairy Research, 2010

Gene, 2001

Gene, 2002

Experimental Animals, 2014