Sutcliffe J G, de Lecea L
Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037, USA.
Results Probl Cell Differ. 1999;26:239-55. doi: 10.1007/978-3-540-49421-8_11.
We have developed methodologies for identifying mRNAs with highly restricted expression within the brain. One postnatal-onset mRNA, restricted to sparse GABAergic interneurons of the cerebral cortex and hippocampus, encodes preprocortistatin, the precursor of a 14-residue peptide that shares 11 amino acids with somatostatin. Cortistatin binds to all five cloned somatostatin receptors when they are expressed in transfected cells and depresses neuronal activity, but, unlike somatostatin, it reduces locomotor activity and induces slow-wave sleep. Cortistatin, whose mRNA accumulates during sleep deprivation, apparently acts by antagonizing the effects of acetylcholine on cortical excitability, thereby causing synchronization brain slow waves. A single amino acid difference with somatostatin accounts for the dramatic differences in the effects of the two peptides on physiology and behavior. A second postnatal-onset mRNA, restricted to 1100 large neuronal cell bodies of the dorsal-lateral hypothalamus, encodes preprohypocretin, the precursor of two peptides that share homology with each other and with members of the secretin peptide family. The peptides are detected immunohistochemically in secretory vesicles at synapses of fibers that project to posterior hypothalamus and diverse targets in other brain regions. The peptides are excitatory when applied to cultured hypothalamic neurons. Recent studies by Sakurai and colleagues (1998) have identified the hypocretin peptides (called the orexins by those workers) as ligands for two orphan receptors at which they stimulate food-intake behavior. Sakurai and collaborators showed that the mRNA for these peptides accumulates during food deprivation. The hypocretin projections suggest additional homeostatic roles for the peptides. These studies suggest the common mechanism of regulation for necessary, but voluntary, behaviors (sleep and feeding) by transcription-based accumulation of peptide transmitters that create a pressure for the voluntary activities.
我们已经开发出了在大脑中识别表达高度受限的mRNA的方法。一种出生后开始表达的mRNA，仅在大脑皮层和海马体中稀疏的γ-氨基丁酸（GABA）能中间神经元中表达，编码前皮质抑素，它是一种14个氨基酸残基的肽的前体，该肽与生长抑素共有11个氨基酸。当在转染细胞中表达时，皮质抑素能与所有5种克隆的生长抑素受体结合，并抑制神经元活动，但与生长抑素不同的是，它会降低运动活性并诱导慢波睡眠。皮质抑素的mRNA在睡眠剥夺期间会积累，它显然是通过拮抗乙酰胆碱对皮层兴奋性的影响来发挥作用，从而导致大脑慢波同步。与生长抑素仅一个氨基酸的差异就导致了这两种肽在生理和行为影响上的巨大差异。另一种出生后开始表达的mRNA，仅在背外侧下丘脑的1100个大神经元细胞体中表达，编码前促食欲素，它是两种相互同源且与促胰液素肽家族成员同源的肽的前体。通过免疫组织化学方法在投射到下丘脑后部和其他脑区不同靶点的纤维突触的分泌小泡中检测到了这些肽。将这些肽应用于培养的下丘脑神经元时具有兴奋性。樱井及其同事（1998年）最近的研究已确定促食欲素肽（这些研究人员称之为食欲素）是两种孤儿受体的配体，它们在这些受体上刺激食物摄取行为。樱井及其合作者表明，这些肽的mRNA在食物剥夺期间会积累。促食欲素的投射表明这些肽还有其他稳态作用。这些研究表明，通过基于转录的肽类递质积累来调节必要但自主的行为（睡眠和进食）存在共同机制，这种积累为自主活动产生了一种驱动力。
