Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. Deficits of PPI are a hallmark of schizophrenia and associated with several other psychiatric illnesses such as e.g. autism spectrum disorder, yet the mechanisms underlying PPI are still not fully understood. There is growing evidence contradicting the long-standing hypothesis that PPI is mediated by a short feed-forward midbrain circuitry including inhibitory cholinergic projections from the pedunculopontine tegmental nucleus (PPTg) to the startle pathway. Here, we employed a chemogenetic approach to explore the involvement of the PPTg in general, and cholinergic neurons specifically, in PPI. Activation of inhibitory DREADDs (designer receptors exclusively activated by designer drugs) in the PPTg by systemic administration of clozapine-N-oxide (CNO) disrupted PPI, confirming the involvement of the PPTg in PPI. In contrast, chemogenetic inhibition of specifically cholinergic PPTg neurons had no effect on PPI, but inhibited morphine-induced conditioned place preference (CPP) in the same animals, showing that the DREADDs were effective in modulating behavior. These findings support a functional role of the PPTg and/or neighboring structures in PPI in accordance with previous lesion studies, but also provide strong evidence against the hypothesis that specifically cholinergic PPTg neurons are involved in mediating PPI, implicating rather non-cholinergic midbrain neurons.

中文翻译：

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惊吓脉冲抑制前的中脑机制的破译。

前脉冲抑制（PPI）是感觉运动门控的一种操作措施。PPI的缺乏是精神分裂症的标志，并与其他几种精神疾病有关，例如自闭症谱系障碍，但PPI的潜在机制仍未完全了解。越来越多的证据与长期以来的假说矛盾，即PPI是由短前馈中脑回路介导的，该回路包括从足小脑桥骨被盖核（PPTg）到惊吓途径的抑制性胆碱能投射。在这里，我们采用了一种化学生成方法来探索PPTg的参与，特别是胆碱能神经元在PPI中的参与。通过全身性施用氯氮平-N-氧化物（CNO）破坏的PPI激活PPTg中抑制性DREADDs（被设计药物独家激活的设计受体），确认PPTg参与了PPI。相比之下，化学胆碱能PPTg神经元的抑制作用对PPI没有影响，但在相同的动物中抑制了吗啡诱导的条件性位置偏爱（CPP），表明DREADDs在调节行为方面有效。这些发现支持了PPTg和/或邻近结构在PPI中的功能作用，这与先前的病灶研究一致，但也提供了强有力的证据来反对这一假设，即胆碱能PPTg神经元参与介导PPI的假设，这牵涉到非胆碱能中脑神经元。表明DREADD在调节行为方面有效。这些发现支持了PPTg和/或邻近结构在PPI中的功能作用，这与先前的病灶研究一致，但也提供了强有力的证据来反对这一假设，即胆碱能PPTg神经元参与介导PPI的假设，这牵涉到非胆碱能的中脑神经元。表明DREADD在调节行为方面有效。这些发现支持了PPTg和/或邻近结构在PPI中的功能作用，这与先前的病灶研究一致，但也提供了强有力的证据来反对这一假设，即胆碱能PPTg神经元参与介导PPI的假设，这牵涉到非胆碱能的中脑神经元。