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两条主要通路上的许多递质系统的相互作用，一条依靠丘脑将感觉输入传递到大脑皮层，另一条绕过丘脑激活皮质和下丘脑外侧神经元。后一种通路起源于单胺能神经元，包括中缝背核(DR)的5-羟色胺能神经元和蓝斑(LC)的去甲肾上腺素能神经元。两个单胺能核与组胺能结节乳头核(TMN-Haas等人)。2008)在清醒状态下高频开火。相反，所有三组神经元分别在NREM和REM睡眠期间放慢并几乎停止放电(Saper等人。2001)。清醒和睡眠状态之间的转换依赖于对TMN神经元的抑制，TMN神经元的很大一部分来自VLPO的“促进睡眠”的GABA能神经元。在相反的情况下，这些神经元在睡眠中以高频发出信号，并受到LC和DR的支配。虽然丘脑介导的觉醒系统的神经递质调节已受到广泛研究(Llinas&Steriade，2006；Franks，2008)，但调节下丘脑睡眠中心的机制和神经元输入才刚刚开始阐明(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同一性受到的关注有限。同样，尽管5-羟色胺和组胺可以深刻影响TMN和DR神经元的兴奋性(Eriksson等人)。2001年；Barbara等人。2002)，组胺能调节5-羟色胺能传递和5-羟色胺能调节觉醒-睡眠周期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-羟色胺拮抗剂(如5-HT2AR和5HT6R类)促进动物和人类的睡眠(Morairty等)。2008年：；兰道特等人。1999年)。使用以前使用的方法来更好地理解支持GABAAR活性催眠剂丘脑活动的分子机制(Belelli等人。2005年)，我们最近研究了GABA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)。该项目旨在扩展这一研究路线，并结合转基因小鼠和应用于啮齿动物脑片的电生理技术，以：1)表征DR和TMN神经元的抑制性和兴奋性传递；2)研究5-羟色胺和组胺受体对DR和TMN活性的调节作用。3)利用脑电记录结合体外电生理技术，阐明5-羟色胺和组胺受体在睡眠-觉醒控制中的作用。参考文献：Barbara A，Acefes J&Arias-Montano JA(2002)。脑研究报告954,247-255。2.Belelli D，Peden Dr，Rosahl TW，Wafard Ka&Lambert JJ(2005)。J.Neurosci25,11513-11520。3.Eriksson KS，Stevens Dr&Haas HL(2001)神经药理学40,345-351。4.Franks NP(2008年)。纳特·纽伦西牧师。9,370-386。5.Haas HL，Sergeeva OA&Selbach O(2008年)。PhysIOL Rev.88,1183-1241.6.Landolt HP，Meier V，Burgess HJ，et al.(1999年)。神经精神药理学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)。睡31，34-44。9.Saper CB，Chou TC&Scammell TE(2001)。趋势神经科学。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.