The role of serotonin and histamine receptors in the regulation of the sleep-wake cycle

睡眠-觉醒周期的调节依赖于沿着两条主要途径的许多传递系统的相互作用，一条途径依赖于丘脑将感觉输入传递到大脑皮层，而另一条途径绕过丘脑激活皮层和外侧下丘脑神经元。后一种途径起源于单胺能神经元，分别包括中背（DR）的血清素能神经元和蓝斑（LC）的去甲肾上腺素能神经元。两个单胺能核与组胺能结节性乳核（TMN- Haas et al. 2008）串联在一起，在清醒时以高频放电。相反，这三组神经元分别在非快速眼动和快速眼动睡眠期间减慢并几乎停止放电（Saper et al. 2001）。清醒和睡眠状态之间的切换依赖于TMN神经元的抑制，其中很大一部分来自VLPO的“促进睡眠”gaba能神经元。在相反的情况下，这些神经元在睡眠期间以高频率放电，并受到LC和dr的支配。尽管丘脑介导的唤醒系统的神经递质调节已经受到了广泛的研究（Llinas & Steriade, 2006; Franks, 2008），调节下丘脑睡眠中心的机制和神经元输入才刚刚开始被阐明（Saper等人，2005）。特别是，gaba能和谷氨酸能传递在TMN和DR的兴奋性中所起的作用以及支持其活性调节的受体的分子特性受到的关注有限。同样，尽管5-羟色胺和组胺可以深刻地影响颞下颌神经网络和颞下颌神经神经元的兴奋性（Eriksson等人2001；Barbara等人2002），但在清醒-睡眠周期中，组胺能调节5-羟色胺能传递和5-羟色胺能调节组胺能传递的具体分子机制尚不完全清楚。然而，这两种神经递质的相互作用可能具有临床意义，因为H1R拮抗剂和选择性5-HT拮抗剂（例如5-HT2AR和5HT6R类）在动物和人类中都能促进睡眠（Morairty等）。2008:;Landolt et al. 1999)。使用先前用于更好地理解GABAAR活性催眠药物丘脑作用的分子机制的方法（Belelli等人，2005），我们最近研究了GABAAR能和5 -羟色胺能机制在调节DR活性中的作用（Maguire， Lambert和Belelli未发表）。拟议的项目打算扩展这条研究线，并使用选择性药理学工具结合转基因小鼠和应用于啮齿动物脑切片的电生理技术：1)表征DR和TMN神经元的抑制性和兴奋性传递；2)研究5-羟色胺和组胺受体调节对DR和TMN活性的作用。3)利用脑电图记录结合体外电生理技术，阐明5-HT和组胺受体在睡眠-觉醒控制中的作用。引用:1。Barbara A， Aceves J和Arias-Montano JA（2002）。脑科学进展，1994,24(4):247-255。2. Belelli D, Peden DR, Rosahl TW, Wafford KA & Lambert JJ（2005）。J.Neurosci。25日,11513 - 11520。3. Eriksson KS, Stevens DR & Haas HL（2001）神经药理学40,345-351。4. Franks NP（2008）。Nat.Rev.Neurosci。9日,370 - 386。5. Haas HL， Sergeeva OA和Selbach O（2008）。中国生物医学工程学报（英文版），32(1):481 - 481。6. Landolt HP, Meier V， Burgess HJ等。（1999）。神经精神药理学21,455-466。7. Llinas RR & Steriade M（2006）。J.Neurophysiol。95年,3297 - 3308。8. 刘建军，刘建军，刘建军（2008）。睡31,34 -44。9. 张国强，周国强，陈国强（2001）。神经科学动态，24,726-731。10. Saper CB, Scammell TE & Lu J（2005）。自然，437,1257-1263。

Regulation of the sleep-wake cycle relies on the interaction of a number of transmitter systems along two main pathways, one relying on the thalamus for the transmission of sensory inputs to the cerebral cortex whereas the other bypasses the thalamus to activate both cortical and lateral hypothalamic neurones. This latter pathway originates from monaminergic neurones including the serotonergic and noradrenergic neurones of the dorsal raphe (DR) and locus coeruleus (LC) respectively. Both monaminergic nuclei in tandem with the histaminergic tuberomammilary nucleus (TMN- Haas et al. 2008) fire at high frequency during wakefulness. Conversely, all three groups of neurones slow down and almost stop firing during NREM and REM sleep respectively (Saper et al. 2001). The switch between the awake and sleep state is dependent upon inhibition of the TMN neurones, a large component of which originates from the 'sleep promoting' GABAergic neurones of the VLPO. These neurones, in a reverse scenario, fire at a high frequency during sleep and are innervated by both the LC and the DR. While neurotransmitter modulation of the thalamic mediated arousal system has been subject to extensive investigation (Llinas & Steriade, 2006; Franks, 2008), the mechanisms and neuronal inputs regulating the hypothalamic sleep centres are only beginning to be elucidated (Saper et al 2005). In particular, the role played by both GABAergic and glutamatergic transmission in the excitability of both TMN and DR and the molecular identity of the receptors underpinning regulation of their activity have received limited attention. Similarly, although 5-HT and histamine can profoundly affect the excitability of the TMN and DR neurones (Eriksson et al. 2001; Barbara et al. 2002), the specific molecular mechanisms underpinning histaminergic regulation of serotonergic transmission and serotonergic regulation of histaminergic transmission in the wake-sleep cycle are yet to be fully understood. Nevertheless, the interaction of these two neurotransmitters is likely to be clinically significant, because H1R antagonists and selective 5-HT antagonist (e.g.of the 5-HT2AR and 5HT6R classes) promote sleep both in animals and in humans (Morairty e tal. 2008:; Landolt et al. 1999). Using an approach previously utilised to better understand the molecular mechanisms underpinning the thalamic actions of GABAAR active hypnotic agents (Belelli et al. 2005), we have recently investigated the role of GABAergic and serotonergic mechanisms in the regulation of DR activity (Maguire, Lambert and Belelli unpublished). The proposed project intends to extend this line of research and employ selective pharmacological tools in combination with transgenic mice and electrophysiological techniques applied to rodent brain slices to: 1) characterise inhibitory and excitatory transmission in both DR and TMN neurones 2) investigate the actions of 5-HT and histamine receptor modulation upon the activity of both DR and TMN. 3) utilize EEG recording in combination with in vitro electrophysiological techniques to elucidate the role played by 5-HT and histamine receptors in sleep-wake control. References: 1. Barbara A, Aceves J & Arias-Montano JA (2002). Brain Res. 954, 247-255. 2. Belelli D, Peden DR, Rosahl TW, Wafford KA & Lambert JJ (2005). J.Neurosci. 25, 11513-11520. 3. Eriksson KS, Stevens DR & Haas HL (2001) Neuropharmacology 40, 345-351. 4. Franks NP (2008). Nat.Rev.Neurosci. 9, 370-386. 5. Haas HL, Sergeeva OA & Selbach O (2008). Physiol Rev. 88, 1183-1241. 6. Landolt HP, Meier V, Burgess HJ, et al. (1999). Neuropsychopharmacology 21, 455-466. 7. Llinas RR & Steriade M (2006). J.Neurophysiol. 95, 3297-3308. 8. Morairty SR, Hedley L, Flores J, Martin R & Kilduff TS (2008). Sleep 31, 34-44. 9. Saper CB, Chou TC & Scammell TE (2001). Trends Neurosci. 24, 726-731. 10. Saper CB, Scammell TE & Lu J (2005). Nature 437, 1257-1263.