探索神經(jīng)精神疾病的發(fā)生發(fā)展機(jī)制及其診治技術(shù)具有重要意義,。中腦的多巴胺神經(jīng)元投射到廣泛的前腦區(qū)域,，所釋放的多巴胺調(diào)控許多重要功能的過程，例如運動,、認(rèn)識,、意識和學(xué)習(xí)過程等。其變異帶來許多神經(jīng)精神疾病,，如帕金森氏癥,、精神分裂癥、注意力缺乏多動癥等,，而相關(guān)的多巴胺拮抗劑,、激動劑和重新攝取抑制劑等常常被用于治療這些疾病。因此,，研究中腦中多巴胺的調(diào)控不僅可以幫助人們理解大腦工作的神經(jīng)生物學(xué)機(jī)制,，也能為發(fā)展神經(jīng)精神疾病病理及診療研究提供新的思路。
最近,，中科院武漢物理與數(shù)學(xué)研究所徐富強(qiáng)研究員所領(lǐng)導(dǎo)的小組與北京生命科學(xué)研究所的合作者,，利用多模態(tài)的手段和轉(zhuǎn)基因動物，揭示了鳥苷酰環(huán)化酶-C（guanylyl cyclase-C,，GC-C)的激活,，通過cGMP依賴蛋白激酶（PKG），強(qiáng)化由谷氨酸和乙酰膽堿受體導(dǎo)致的多巴胺神經(jīng)元的興奮性活動,；GC-C敲除動物的確展現(xiàn)了過高的活動和注意力缺乏,，而且，這些行為可以被相應(yīng)的治療注意力缺乏多動癥的藥物和PKG的興奮劑所逆轉(zhuǎn),。
這些結(jié)果不僅揭示了GC-C/PKG通路在重要腦功能中的角色,，而且提供了一個研發(fā)治療相應(yīng)神經(jīng)精神疾病藥物的新靶點。這一研究成果發(fā)表在《科學(xué)》雜志上,。
該研究小組此前在神經(jīng)生物學(xué)領(lǐng)域獨立完成了通過對麻醉的深度操控,，使動物大腦處于不同的運行狀態(tài)，研究動物嗅覺系統(tǒng)的第一中樞嗅球如何編碼同一氣味刺激的信息。該項研究成果發(fā)表在美國《國家科學(xué)院院刊》上,。
這些研究受到國家杰出青年科學(xué)基金和中科院“百人計劃”的支持,。(生物谷 Bioon.com)
doi:10.1126/science.1207675
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Role for the Membrane Receptor Guanylyl Cyclase-C in Attention Deficiency and Hyperactive Behavior
Rong Gong, Cheng Ding, Ji Hu2,, Yao Lu, Fei Liu, Elizabeth Mann, Fuqiang Xu, Mitchell B. Cohen, Minmin Luo
Midbrain dopamine neurons regulate many important behavioral processes, and their dysfunctions are associated with several human neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD) and schizophrenia. Here, we report that these neurons in mice selectively express guanylyl cyclase-C (GC-C), a membrane receptor previously thought to be expressed mainly in the intestine. GC-C activation potentiates the excitatory responses mediated by glutamate and acetylcholine receptors via the activity of guanosine 3′,5′-monophosphate–dependent protein kinase (PKG). Mice in which GC-C has been knocked out exhibit hyperactivity and attention deficits. Moreover, their behavioral phenotypes are reversed by ADHD therapeutics and a PKG activator. These results indicate important behavioral and physiological functions for the GC-C/PKG signaling pathway within the brain and suggest new therapeutic targets for neuropsychiatric disorders related to the malfunctions of midbrain dopamine neurons.
doi:10.1073/pnas.1013814108
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Brain-state–independent neural representation of peripheral stimulation in rat olfactory bulb
Anan Li, Ling Gong, and Fuqiang Xu
It is critical for normal brains to perceive the external world precisely and accurately under ever-changing operational conditions, yet the mechanisms underlying this fundamental brain function in the sensory systems are poorly understood. To address this issue in the olfactory system, we investigated the responses of olfactory bulbs to odor stimulations under different brain states manipulated by anesthesia levels. Our results revealed that in two brain states, where the spontaneous baseline activities differed about twofold based on the local field potential (LFP) signals, the levels of neural activities reached after the same odor stimulation had no significant difference. This phenomenon was independent of anesthetics (pentobarbital or chloral hydrate), stimulating odorants (ethyl propionate, ethyl butyrate, ethyl valerate, amyl acetate, n-heptanal, or 2-heptanone), odor concentrations, and recording sites (the mitral or granular cell layers) for LFPs in three frequency bands (12–32 Hz, 33–64 Hz, and 65–90 Hz) and for multiunit activities. Furthermore, the activity patterns of the same stimulation under these two brain states were highly similar at both LFP and multiunit levels. These converging results argue the existence of mechanisms in the olfactory bulbs that ensure the delivery of peripheral olfactory information to higher olfactory centers with high fidelity under different brain states.
