Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada
J Neurosci. 2018 Oct 10;38(41):8798-8808. doi: 10.1523/JNEUROSCI.0984-18.2018. Epub 2018 Aug 31.
One of the two major cholinergic centers of the mammalian brain is located in the midbrain, i.e., the pedunculopontine tegmentum (PPTg) and the adjacent laterodorsal tegmentum. These cholinergic neurons have been shown to be important for e.g., arousal, reward associations, and sleep. They also have been suggested to mediate sensorimotor gating, measured as prepulse inhibition of startle (PPI). PPI disruptions are a hallmark of schizophrenia and are observed in various other psychiatric disorders, where they are associated with, and often predictive of, other cognitive symptoms. PPI has been proposed to be mediated by a short midbrain circuitry including inhibitory cholinergic projections from PPTg to the startle pathway. Although the data indicating the involvement of the PPTg is very robust, some more recent evidence challenges that there is a cholinergic contribution to PPI. We here use transient optogenetic activation of specifically the cholinergic PPTg neurons in male and female rats to address their role in startle modulation in general, and in PPI specifically. Although we could confirm the crucial role of PPTg cholinergic neurons in associative reward learning, validating our experimental approach, we found that activation of cholinergic PPTg neurons did not inhibit startle responses. In contrast, activation of cholinergic PPTg neurons enhanced startle, which is in accordance with their general role in arousal and indicate a potential involvement in sensitization of startle. We conclude that noncholinergic PPTg neurons mediate PPI in contrast to the longstanding hypothetical view that PPI is mediated by cholinergic PPTg neurons. Activation of cholinergic neurons in the midbrain has been assumed to mediate prepulse inhibition of startle (PPI), a common measure of sensorimotor gating that is disrupted in schizophrenia and other psychiatric disorders. We here revisit this long-standing hypothesis using optogenetic activation of these specific neurons combined with startle testing in rats. In contrast to the hypothetical role of these neurons in startle modulation, we show that their activation leads to an increase of baseline startle and to prepulse facilitation. This supports recent data by others that have started to cast some doubt on the cholinergic hypothesis of PPI, and calls for a revision of the theoretical construct of PPI mechanisms.
哺乳动物大脑中的两个主要胆碱能中枢之一位于中脑，即脑桥被盖（PPTg）和相邻的外侧背盖。这些胆碱能神经元对于觉醒、奖励关联和睡眠等非常重要。它们也被认为介导感觉运动门控，表现为惊吓前脉冲抑制（PPI）。PPI 中断是精神分裂症的一个标志，在各种其他精神疾病中也有观察到，它们与其他认知症状有关，并且常常可以预测其他认知症状。PPI 被认为是由包括 PPTg 中的抑制性胆碱能投射到惊吓途径的短中脑回路介导的。尽管表明 PPTg 参与的证据非常可靠，但一些最新的证据挑战了 PPI 存在胆碱能贡献的观点。我们在这里使用雄性和雌性大鼠中特定的 PPTg 胆碱能神经元的瞬时光遗传学激活来解决它们在一般惊吓调制和特定 PPI 中的作用。尽管我们可以确认 PPTg 胆碱能神经元在联想性奖励学习中的关键作用，验证了我们的实验方法，但我们发现激活 PPTg 胆碱能神经元不会抑制惊吓反应。相反，激活 PPTg 胆碱能神经元增强了惊吓反应，这与它们在觉醒中的一般作用一致，并表明它们可能参与了惊吓反应的敏化。我们得出的结论是，非胆碱能 PPTg 神经元介导 PPI，与长期以来假设的 PPI 由 PPTg 胆碱能神经元介导的观点相反。中脑胆碱能神经元的激活被认为介导了惊吓前脉冲抑制（PPI），这是一种常见的感觉运动门控测量方法，在精神分裂症和其他精神疾病中受到破坏。我们在这里使用这些特定神经元的光遗传学激活结合大鼠的惊吓测试重新检验了这一长期存在的假设。与这些神经元在惊吓调制中的假设作用相反，我们表明它们的激活导致基础惊吓增加和前脉冲促进。这支持了其他人最近的数据，这些数据开始对 PPI 的胆碱能假说产生一些怀疑，并呼吁对 PPI 机制的理论构建进行修订。
