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2004年8月25日
随着社会的不断进步，生活节奏的加快，人们日益忙碌，加上外在大环境急剧的变化，有些人无法适应，产生压力，压力的不断积累而发生的暂时性失眠，使他们苦不堪言。以至于有些人发出如下感慨：我人生的三大愿望是，吃的下饭，睡得着觉，笑的出来。难道我们真的就对此束手无策吗？
在2004年8月19日的NEURON上，University of California的Rainer Reinscheid 和Yan-Ling Xu 带领的研究小组发表了他们的最新研究结果。他们发现一种新蛋白——神经肽S(neuropeptide S，NPS)，通过激活其同源受体(NPSR)，并引发细胞内 Ca2+动员，进而调控失眠和忧虑，具有提高实验动物的清醒程度以及有减少焦虑的作用。
值得注意的是NPSRmRNA广泛的分布于大脑中，包括类扁桃体(amygdala)和丘脑中线核(midline thalamic nuclei)；而NPS则是由蓝斑(locus coeruleus)和丘脑前核群(Barrington's nucleus)之间的以前未鉴定的一簇细胞分泌。这些结果均表明，NPS是清醒和焦虑的新的调节因子。
为了研究NPS是如何影响小鼠的清醒和焦虑的，他们进行了一系列试验，结果发现没有注射的小鼠，喜欢安全、封闭的区域，而注射过NPS的小鼠，不像没有注射的小鼠那样惧怕探索光线明亮的区域。另外，当他们往笼中投入大理石时(小鼠惧怕异物)，注射过NPS的小鼠比没有注射的小鼠埋藏的大理石要少。
这一研究不仅有助于了解大脑的古老区域，而且也有助于进一步了解睡眠失调。并且NPS也极有可能治疗从抑郁症(depression )到嗜睡症( narcolepsy)到很多疾病，这对于受这类疾病困扰的数百万人来说，其研究意义是十分重大的。
Neuropeptide S: A Neuropeptide Promoting Arousal and Anxiolytic-like Effects
Arousal and anxiety are behavioral responses that involve complex neurocircuitries and multiple neurochemical components. Here, we report that a neuropeptide, neuropeptide S (NPS), potently modulates wakefulness and could also regulate anxiety. NPS acts by activating its cognate receptor (NPSR) and inducing mobilization of intracellular Ca2+. The NPSR mRNA is widely distributed in the brain, including the amygdala and the midline thalamic nuclei. Central administration of NPS increases locomotor activity in mice and decreases paradoxical (REM) sleep and slow wave sleep in rats. NPS was further shown to produce anxiolytic-like effects in mice exposed to four different stressful paradigms. Interestingly, NPS is expressed in a previously undefined cluster of cells located between the locus coeruleus (LC) and Barrington's nucleus. These results indicate that NPS could be a new modulator of arousal and anxiety. They also show that the LC region encompasses distinct nuclei expressing different arousal-promoting neurotransmitters.
Figure 1. Primary Structures of Neuropeptide S from Human, Chimpanzee, Rat, Mouse, Dog, and Chicken
Figure 3. Tissue Distribution of NPS Precursor and NPS Receptor mRNA in Rat Tissues
Quantitative RT-PCR was used to measure transcript levels of NPS precursor (left) and NPS receptor mRNA (right) in 45 rat tissues. Transcript levels were normalized to β-actin. pbl, peripheral blood leucocytes.
Expression of NPS Precursor mRNA in the Pontine Area of the Rat Brain
(A) Schematic drawing of the section shown in (B). The level is at bregma −9.80 mm (Paxinos and Watson, 1997
, reprinted with permission from Elsevier). (B) Representative autoradiogram of NPS mRNA expression in LC area. (C–E) Dark-field images of double in situ hybridization of NPS precursor mRNA (white) and TH mRNA (dark blue) in LC area. (D) Higher magnification of the area indicated by an arrow in (C). (E) Higher magnification of a more caudal section. (F–H) Dark-field images of double in situ hybridization of NPS precursor mRNA (white) and CRF mRNA (dark blue) at mid-level of LC area (F) and rostral LC (G). (H) Higher magnification of the area indicated by an arrow in (G). TH, tyrosine hydroxylase; NPS, neuropeptide S; CRF, corticotropin-releasing factor. Landmarks: Cb, cerebellum; 4V, fourth ventricle. Scale bar, 500 μm in (C), 250 μm in all other pictures.
Distribution of NPS Precursor mRNA Expression in Rat Brain
(A, D, and G) Drawings of the sections illustrated in (B) and (C) (Bregma −9.68 mm), (E) and (F) (Bregma −2.80 mm), and (H) and (I) (Bregma −3.14 mm), respectively (Paxinos and Watson, 1997). (B, C, E, F, H, and I) Dark-field images of NPS precursor mRNA expression in coronal sections of rat brain. (E and H) Expression of NPS precursor mRNA in boxed regions in (D) and (G), respectively. (C, F, and I) Higher magnification of the area indicated by an arrow in (B), (E), and (H), respectively. Arrows in (F) and (I) indicate single cells showing hybridization signals for NPS precursor mRNA. LPB, lateral parabrachial nucleus; Pr5, principle sensory 5 nucleus; DMH, dorsomedial hypothalamic nucleus; Amg, amygdala. Landmarks: Cb, cerebellum; 3V, third ventricle; opt, optic tract. Scale bar, 500 μm.
Distribution of NPS Receptor mRNA Expression in Rat Brain
(A, D, G, and J) Schematic drawings of the sections shown in (B) and (C) (Bregma, 3.20 mm), (E) and (F) (Bregma −1.80 mm), (H) and (I) (Bregma −2.80 mm), and (K) and (L) (Bregma −4.52 mm), respectively (Paxinos and Watson, 1997). (B, E, H, and K) Autoradiograms of NPSR mRNA expression in coronal rat brain sections. Arrows in (B), (E), (H), and (K) indicate endopiriform nucleus (En). Arrowheads in (E), (H), and (K) refer to secondary motor cortex (M2), retrosplenial agranular cortex (RSA)/M2, and RSA, respectively. (C, F, and I) Dark-field images of boxed regions in (B), (E), and (H), respectively. (L) Dark field image of midline thalamic regions of section (K). (M and N) Dark-field image of cortical regions in section (E). Arrows in (N) indicate scattered cells expressing NPSR mRNA in somatosensory cortex. (O) Dark-field image of cortical and subicular regions in section (K). AON, anterior olfactory nucleus; DEn, dorsal endopiriform nucleus; CM, central medial thalamic nucleus; IAM, interanteromedial thalamic nucleus; Rh, rhomboid thalamic nucleus; Re, reuniens thalamic nucleus; Amg, amygdala; Hyp, hypothalamus; S, subiculum; Prc, precommissural nucleus; PVP, paraventricular thalamus nucleus, posterior; PH, posterior hypothalamus. Landmarks: aca, anterior commissure, anterior part; pt, paratenial thalamic nuclei; opt, optic tract; D3V, dorsal third ventricle; 3V, third ventricle; Hip, hippocampus. Scale bar, 500 μm.
Figure 7. Central Administration of NPS Produces Behavioral Arousal and Wakefulness
(A) Hyperlocomotion effects of NPS in naive and habituated mice. Naive mice were new to the test chamber, while habituated animals were acclimatized for 1 hr prior to the injection. In naive mice, 0.1 and 1 nmole NPS induce significant hyperlocomotion (F3,324 = 92.83, p < 0.0001, two-way ANOVA for repeated measures). The same doses of NPS also produced significant effects in habituated animals (F3,336 = 135.59, p < 0.0001).
(B) Arousal promoting effects of NPS in rats. NPS increases the amount of wakefulness and decreases SWS1, SWS2, and REM sleep in rats (n = 8 for each dose). **p < 0.01, 0.1 nmole and 1.0 nmole compared with saline; *p < 0.01, 1.0 nmole compared with saline (ANOVA followed by Scheffe's post hoc test).
Figure 8. Anxiolytic-like Effects of NPS in Mice
NPS produces dose-dependent anxiolytic-like effects in C57Bl/6 mice exposed to the open field (A), light-dark box (B), elevated plus maze (C), and marble burying paradigm (D). Doses and groups: all doses are in nmole per animal; open field (n = 8 for each dose); light-dark box (PBS, n = 10; 0.01 nmole, n = 5; 0.03 nmole, n = 5; 0.1 nmole, n = 5; 0.3 nmole, n = 11; 1 nmole, n = 5; 3 nmole, n = 8); elevated plus maze (n = 5 for all doses); marble burying (PBS and 0.01 nmole, n = 10; 0.1 and 1 nmole, n = 9). **p < 0.01, *p < 0.05 compared to PBS control, ANOVA followed by Dunnett's test for multiple comparisons. All data are presented as means ± SEM.
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生物谷严正声明：转载生物谷文章请注明来自生物谷 (wangchangwei)
在2004年8月19日的NEURON上，University of California的Rainer Reinscheid 和Yan-Ling Xu 带领的研究小组发表了他们的最新研究结果。他们发现一种新蛋白——神经肽S(neuropeptide S，NPS)，通过激活其同源受体(NPSR)，并引发细胞内 Ca2+动员，进而调控失眠和忧虑，具有提高实验动物的清醒程度以及有减少焦虑的作用。
值得注意的是NPSRmRNA广泛的分布于大脑中，包括类扁桃体(amygdala)和丘脑中线核(midline thalamic nuclei)；而NPS则是由蓝斑(locus coeruleus)和丘脑前核群(Barrington's nucleus)之间的以前未鉴定的一簇细胞分泌。这些结果均表明，NPS是清醒和焦虑的新的调节因子。
为了研究NPS是如何影响小鼠的清醒和焦虑的，他们进行了一系列试验，结果发现没有注射的小鼠，喜欢安全、封闭的区域，而注射过NPS的小鼠，不像没有注射的小鼠那样惧怕探索光线明亮的区域。另外，当他们往笼中投入大理石时(小鼠惧怕异物)，注射过NPS的小鼠比没有注射的小鼠埋藏的大理石要少。
这一研究不仅有助于了解大脑的古老区域，而且也有助于进一步了解睡眠失调。并且NPS也极有可能治疗从抑郁症(depression )到嗜睡症( narcolepsy)到很多疾病，这对于受这类疾病困扰的数百万人来说，其研究意义是十分重大的。
Neuropeptide S: A Neuropeptide Promoting Arousal and Anxiolytic-like Effects
Arousal and anxiety are behavioral responses that involve complex neurocircuitries and multiple neurochemical components. Here, we report that a neuropeptide, neuropeptide S (NPS), potently modulates wakefulness and could also regulate anxiety. NPS acts by activating its cognate receptor (NPSR) and inducing mobilization of intracellular Ca2+. The NPSR mRNA is widely distributed in the brain, including the amygdala and the midline thalamic nuclei. Central administration of NPS increases locomotor activity in mice and decreases paradoxical (REM) sleep and slow wave sleep in rats. NPS was further shown to produce anxiolytic-like effects in mice exposed to four different stressful paradigms. Interestingly, NPS is expressed in a previously undefined cluster of cells located between the locus coeruleus (LC) and Barrington's nucleus. These results indicate that NPS could be a new modulator of arousal and anxiety. They also show that the LC region encompasses distinct nuclei expressing different arousal-promoting neurotransmitters.
Figure 1. Primary Structures of Neuropeptide S from Human, Chimpanzee, Rat, Mouse, Dog, and Chicken
Figure 3. Tissue Distribution of NPS Precursor and NPS Receptor mRNA in Rat Tissues
Quantitative RT-PCR was used to measure transcript levels of NPS precursor (left) and NPS receptor mRNA (right) in 45 rat tissues. Transcript levels were normalized to β-actin. pbl, peripheral blood leucocytes.
Expression of NPS Precursor mRNA in the Pontine Area of the Rat Brain
(A) Schematic drawing of the section shown in (B). The level is at bregma −9.80 mm (Paxinos and Watson, 1997
, reprinted with permission from Elsevier). (B) Representative autoradiogram of NPS mRNA expression in LC area. (C–E) Dark-field images of double in situ hybridization of NPS precursor mRNA (white) and TH mRNA (dark blue) in LC area. (D) Higher magnification of the area indicated by an arrow in (C). (E) Higher magnification of a more caudal section. (F–H) Dark-field images of double in situ hybridization of NPS precursor mRNA (white) and CRF mRNA (dark blue) at mid-level of LC area (F) and rostral LC (G). (H) Higher magnification of the area indicated by an arrow in (G). TH, tyrosine hydroxylase; NPS, neuropeptide S; CRF, corticotropin-releasing factor. Landmarks: Cb, cerebellum; 4V, fourth ventricle. Scale bar, 500 μm in (C), 250 μm in all other pictures.Distribution of NPS Precursor mRNA Expression in Rat Brain
(A, D, and G) Drawings of the sections illustrated in (B) and (C) (Bregma −9.68 mm), (E) and (F) (Bregma −2.80 mm), and (H) and (I) (Bregma −3.14 mm), respectively (Paxinos and Watson, 1997
). (B, C, E, F, H, and I) Dark-field images of NPS precursor mRNA expression in coronal sections of rat brain. (E and H) Expression of NPS precursor mRNA in boxed regions in (D) and (G), respectively. (C, F, and I) Higher magnification of the area indicated by an arrow in (B), (E), and (H), respectively. Arrows in (F) and (I) indicate single cells showing hybridization signals for NPS precursor mRNA. LPB, lateral parabrachial nucleus; Pr5, principle sensory 5 nucleus; DMH, dorsomedial hypothalamic nucleus; Amg, amygdala. Landmarks: Cb, cerebellum; 3V, third ventricle; opt, optic tract. Scale bar, 500 μm.Distribution of NPS Receptor mRNA Expression in Rat Brain
(A, D, G, and J) Schematic drawings of the sections shown in (B) and (C) (Bregma, 3.20 mm), (E) and (F) (Bregma −1.80 mm), (H) and (I) (Bregma −2.80 mm), and (K) and (L) (Bregma −4.52 mm), respectively (Paxinos and Watson, 1997
). (B, E, H, and K) Autoradiograms of NPSR mRNA expression in coronal rat brain sections. Arrows in (B), (E), (H), and (K) indicate endopiriform nucleus (En). Arrowheads in (E), (H), and (K) refer to secondary motor cortex (M2), retrosplenial agranular cortex (RSA)/M2, and RSA, respectively. (C, F, and I) Dark-field images of boxed regions in (B), (E), and (H), respectively. (L) Dark field image of midline thalamic regions of section (K). (M and N) Dark-field image of cortical regions in section (E). Arrows in (N) indicate scattered cells expressing NPSR mRNA in somatosensory cortex. (O) Dark-field image of cortical and subicular regions in section (K). AON, anterior olfactory nucleus; DEn, dorsal endopiriform nucleus; CM, central medial thalamic nucleus; IAM, interanteromedial thalamic nucleus; Rh, rhomboid thalamic nucleus; Re, reuniens thalamic nucleus; Amg, amygdala; Hyp, hypothalamus; S, subiculum; Prc, precommissural nucleus; PVP, paraventricular thalamus nucleus, posterior; PH, posterior hypothalamus. Landmarks: aca, anterior commissure, anterior part; pt, paratenial thalamic nuclei; opt, optic tract; D3V, dorsal third ventricle; 3V, third ventricle; Hip, hippocampus. Scale bar, 500 μm.Figure 7. Central Administration of NPS Produces Behavioral Arousal and Wakefulness
(A) Hyperlocomotion effects of NPS in naive and habituated mice. Naive mice were new to the test chamber, while habituated animals were acclimatized for 1 hr prior to the injection. In naive mice, 0.1 and 1 nmole NPS induce significant hyperlocomotion (F3,324 = 92.83, p < 0.0001, two-way ANOVA for repeated measures). The same doses of NPS also produced significant effects in habituated animals (F3,336 = 135.59, p < 0.0001).
(B) Arousal promoting effects of NPS in rats. NPS increases the amount of wakefulness and decreases SWS1, SWS2, and REM sleep in rats (n = 8 for each dose). **p < 0.01, 0.1 nmole and 1.0 nmole compared with saline; *p < 0.01, 1.0 nmole compared with saline (ANOVA followed by Scheffe's post hoc test).
Figure 8. Anxiolytic-like Effects of NPS in Mice
NPS produces dose-dependent anxiolytic-like effects in C57Bl/6 mice exposed to the open field (A), light-dark box (B), elevated plus maze (C), and marble burying paradigm (D). Doses and groups: all doses are in nmole per animal; open field (n = 8 for each dose); light-dark box (PBS, n = 10; 0.01 nmole, n = 5; 0.03 nmole, n = 5; 0.1 nmole, n = 5; 0.3 nmole, n = 11; 1 nmole, n = 5; 3 nmole, n = 8); elevated plus maze (n = 5 for all doses); marble burying (PBS and 0.01 nmole, n = 10; 0.1 and 1 nmole, n = 9). **p < 0.01, *p < 0.05 compared to PBS control, ANOVA followed by Dunnett's test for multiple comparisons. All data are presented as means ± SEM.
全文
生物谷严正声明：转载生物谷文章请注明来自生物谷 (wangchangwei)