探索神经精神疾病的发生发展机制及其诊治技术具有重要意义。中脑的多巴胺神经元投射到广泛的前脑区域，所释放的多巴胺调控许多重要功能的过程，例如运动、认识、意识和学习过程等。其变异带来许多神经精神疾病，如帕金森氏症、精神分裂症、注意力缺乏多动症等，而相关的多巴胺拮抗剂、激动剂和重新摄取抑制剂等常常被用于治疗这些疾病。因此，研究中脑中多巴胺的调控不仅可以帮助人们理解大脑工作的神经生物学机制，也能为发展神经精神疾病病理及诊疗研究提供新的思路。
最近，中科院武汉物理与数学研究所徐富强研究员所领导的小组与北京生命科学研究所的合作者，利用多模态的手段和转基因动物，揭示了鸟苷酰环化酶-C（guanylyl cyclase-C，GC-C)的激活，通过cGMP依赖蛋白激酶（PKG），强化由谷氨酸和乙酰胆碱受体导致的多巴胺神经元的兴奋性活动；GC-C敲除动物的确展现了过高的活动和注意力缺乏，而且，这些行为可以被相应的治疗注意力缺乏多动症的药物和PKG的兴奋剂所逆转。
这些结果不仅揭示了GC-C/PKG通路在重要脑功能中的角色，而且提供了一个研发治疗相应神经精神疾病药物的新靶点。这一研究成果发表在《科学》杂志上。
该研究小组此前在神经生物学领域独立完成了通过对麻醉的深度操控，使动物大脑处于不同的运行状态，研究动物嗅觉系统的第一中枢嗅球如何编码同一气味刺激的信息。该项研究成果发表在美国《国家科学院院刊》上。
这些研究受到国家杰出青年科学基金和中科院“百人计划”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.
