Cholinergic mechanism underlying prepulse inhibition of the startle response in rats
Cholinergic mechanism underlying prepulse inhibition of the startle response in rats
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DOI：
10.1016/j.neuroscience.2008.04.018
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发表时间：
2008-07-31
期刊：
影响因子：
3.3
通讯作者：
Schmid, S.
中科院分区：
文献类型：
--
作者：
Bosch, D.;Schmid, S.
惊吓反应被前脉冲抑制（PPI）减弱，前脉冲抑制被认为反映了感觉运动门控机制，在精神分裂症患者中受损。一个介导PPI在大鼠中脑回路已被提出，行为实验表明，乙酰胆碱和GABA在抑制惊吓的重要作用。我们在这里测试的假设，激活中脑神经元可以抑制惊吓信号通过胆碱能机制。我们已经开发出一个大脑切片，包括惊吓调解巨人。脑桥神经元以及中脑中脑桥神经元需要PPI。膜片钳记录的惊吓介导的脑干神经元结合刺激的感觉传入内的惊吓通路和激活中脑脑桥神经元显示延迟抑制突触传递300毫秒和1秒后中脑激活。后者被毒蕈碱拮抗剂东莨菪碱逆转。此外，在中脑刺激后1 s但不是300 ms，配对脉冲比发生了变化。我们的研究结果表明，有一个直接的胆碱能投射从建议PPI中脑电路惊吓介导的神经元在脑干和该投射抑制突触传递的惊吓通路在一个不同的时间窗口，通过激活突触前毒蕈碱受体。此外，有迹象表明，不同的受体介导的抑制，通过这种投射在一个较短的时间窗口，并位于突触后。我们的研究结果有助于了解PPI的机制，这对于开发治疗伴有前注意认知缺陷的疾病的新靶点非常重要。(C)2008年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Startle responses are attenuated by prepulse inhibition (PPI), which is considered to reflect a sensorimotor gating mechanism and is impaired in patients suffering from schizophrenia. A midbrain circuit that mediates PPI in rats has been proposed and behavioral experiments have indicated an important role of acetylcholine and GABA in inhibiting startle. We here test the hypothesis that activation of the midbrain neurons can inhibit startle signaling through a cholinergic mechanism. We have developed a brain slice that comprises startle mediating giant. pontine neurons as well as midbrain mesopontine neurons required for PPI. Patch clamp recordings of startle mediating brainstem neurons combined with stimulation of sensory afferents within the startle pathway and activation of mesopontine neurons revealed a delayed inhibition of synaptic transmission 300 ms and 1 s after midbrain activation. The latter was reversed by the muscarinic antagonist scopolamine. Further, there was a shift in the paired pulse ratio 1 s but not 300 ms after midbrain stimulation. Our results show that there is a direct cholinergic projection from the proposed PPI midbrain circuit to startle mediating neurons in the brainstem and that this projection inhibits synaptic transmission in the startle pathway in a distinct time window through the activation of presynaptic muscarinic receptors. Moreover, there is indication for a different receptor that mediates inhibition through this projection in a shorter time window and is located postsynaptically. Our results contribute to the understanding of mechanisms underlying PPI, which is important for developing new targets in the treatment of disorders accompanied with pre-attentive cognitive deficits. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.