Abstract：
Cholinergic signaling is essential to mediate the auditory prepulse inhibition (PPI), an operational measure of sensorimotor gating, that refers to the reduction of the acoustic startle reflex (ASR) when a low-intensity, non-startling acoustic stimulus (the prepulse) is presented just before the onset of the acoustic startle stimulus. The cochlear root neurons (CRNs) are the first cells of the ASR circuit to receive cholinergic inputs from non-olivocochlear neurons of the ventral nucleus of the trapezoid body (VNTB) and subsequently decrease their neuronal activity in response to auditory prepulses. Yet, the contribution of the VNTB-CRNs pathway to the mediation of PPI has not been fully elucidated. In this study, we used the immunotoxin anti-choline acetyltransferase (ChAT)-saporin as well as electrolytic lesions of the medial olivocochlear bundle to selectively eliminate cholinergic VNTB neurons, and then assessed the ASR and PPI paradigms. Retrograde track-tracing experiments were conducted to precisely determine the site of lesioning VNTB neurons projecting to the CRNs. Additionally, the effects of VNTB lesions and the integrity of the auditory pathway were evaluated via auditory brain responses tests, ChAT- and FOS-immunohistochemistry. Consequently, we established three experimental groups: 1) intact control rats (non-lesioned), 2) rats with bilateral lesions of the olivocochlear bundle (OCB-lesioned), and 3) rats with bilateral immunolesions affecting both the olivocochlear bundle and the VNTB (OCB/VNTB-lesioned). All experimental groups underwent ASR and PPI tests at several interstimulus intervals before the lesion and 7, 14, and 21 days after it. Our results show that the ASR amplitude remained unaffected both before and after the lesion across all experimental groups, suggesting that the VNTB does not contribute to the ASR. The%PPI increased across the time points of evaluation in the control and OCB-lesioned groups but not in the OCB/VNTB-lesioned group. At the ISI of 50 ms, the OCB-lesioned group exhibited a significant increase in%PPI (p < 0.01), which did not occur in the OCB/VNTB-lesioned group. Therefore, the ablation of cholinergic non-olivocochlear neurons in the OCB/VNTB-lesioned group suggests that these neurons contribute to the mediation of auditory PPI at the 50 ms ISI through their cholinergic projections to CRNs. Our study strongly reinforces the notion that auditory PPI encompasses a complex mechanism of top-down cholinergic modulation, effectively attenuating the ASR across different interstimulus intervals within multiple pathways.
摘要：
胆碱能信号传导对于介导听觉前脉冲抑制（PPI）至关重要，感觉运动门控的操作措施，这是指在低强度时声学惊吓反射(ASR)的减少，非惊人的声学刺激（前脉冲）出现在声学惊吓刺激开始之前。耳蜗根神经元（CRN）是ASR回路的第一个细胞，可以接收来自梯形体（VNTB）腹核的非耳蜗神经元的胆碱能输入，并随后响应于听觉前脉冲而降低其神经元活动。然而，VNTB-CRNs通路对PPI介导的贡献尚未完全阐明.在这项研究中,我们使用免疫毒素抗胆碱乙酰转移酶（ChAT）-saporin以及内侧耳蜗束的电解损伤选择性消除胆碱能VNTB神经元，然后评估ASR和PPI范式。进行逆行追踪实验以精确确定损伤投射到CRN的VNTB神经元的位点。此外,通过听觉脑反应测试评估VNTB病变的影响和听觉通路的完整性，ChAT和FOS免疫组织化学。因此,我们建立了三个实验组：1）完整的对照大鼠（无损伤），2）双侧耳蜗束损伤的大鼠（OCB损伤），和3）双侧免疫损伤同时影响橄榄耳蜗束和VNTB（OCB/VNTB损伤）的大鼠。所有实验组在病变前和病变后第7、14和21天进行了几个刺激间隔的ASR和PPI测试。我们的结果表明，在所有实验组的病变之前和之后，ASR幅度都不受影响。这表明VNTB对ASR没有贡献。在对照组和OCB损伤组的整个评估时间点的%PPI增加,但在OCB/VNTB损伤组中没有增加。在50毫秒的ISI时，OCB损伤组PPI%显著增加(p<0.01)，这在OCB/VNTB病变组中没有发生。因此,OCB/VNTB病变组中胆碱能非橄榄耳蜗神经元的消融表明,这些神经元通过对CRN的胆碱能投射,在50msISI处促进听觉PPI的介导.我们的研究强烈加强了这样的观念，即听觉PPI包含自上而下的胆碱能调节的复杂机制，有效地衰减跨多个途径内的不同刺激间隔的ASR。
