Cholinergic Modulation of VIP Neurons in the Auditory Midbrain and its Impact on the Excitability of Thalamic Neurons

摘要 我们的大脑是如何识别和响应语音和其他听觉提示的，目前还不清楚。下部的神经元 位于中脑的听觉处理中枢丘(IC)对光谱表现出选择性反应 以及语音和其他复杂声音的时间特征。先前的研究结果表明，乙酰胆碱(ACh)， 一种与注意力和突触可塑性相关的神经调节剂，可能提供一种基于注意力的机制 来改变IC中的听觉处理。此外，IC中的神经元表达不同的尼古丁组合 乙酰胆碱受体(NAChR)亚单位。然而，胆碱能调节的细胞机制 IC及其对听觉丘脑下游靶点的影响尚不清楚。我们最近发现， 短暂的ACh脉冲可延长IC内血管活性肠肽(VIP)神经元的放电周期。 此外，VIP神经元投射到听觉丘脑(内侧膝状体，MG)，我们初步获得了 数据表明，短暂的VIP脉冲促进了MG神经元子集的强烈去极化。我们 假设ACh通过nAChR依赖的信号通路增强VIP神经元的兴奋性 VIP神经元反过来使用谷氨酸和VIP信号来驱动突触后长时间的兴奋性 MG内的神经元。为了解决这个问题，我们正在使用脑片电生理学和药理学来确定 ACh对VIP神经元和VIP对MG神经元的调制作用机制。我们的 初步结果表明，短脉冲ACh诱发的VIP神经元的长时间放电依赖于 激活α4β2 nAChRs。此外，我们发现，这种作用并不能通过阻断谷氨酸能来消除， GABA能和甘氨酸能突触传递或通过减少细胞外钙离子，提示ACh通过 激活血管活性肠肽神经元自身表达的α-4-β-2nAChRs，而不是通过激活突触前神经元 到VIP神经元。此外，我们的初步数据显示，VIP的短暂脉冲在脑内引起长时间的去极化 Mg神经元。这项提案的总体目标是首次确定胆碱能调节 改变一类已确定的IC主神经元的活动，以及这些变化如何反过来影响 Mg.在目标1中，我们将结合脑片电生理学和药理学和光遗传学来确定 参与ICVIP神经元胆碱能调节的受体和机制。在目标2中，我们将使用大脑 切片电生理学、药理学和通道视紫红质辅助电路标测(CRACM)以确定 VIP神经元的突触传递如何影响MG神经元的兴奋性。总体而言，我们的结果将 为IC中胆碱能调节如何影响IC和MG的神经元兴奋性提供了机制基础 这将为确定胆碱能调节如何用于促进适应性 听力损失患者的可塑性。

Abstract How our brains identify and respond to speech and other auditory cues remains unclear. Neurons in the inferior colliculus (IC), a hub for auditory processing located in the midbrain, exhibit selective responses to the spectral and temporal features of speech and other complex sounds. Previous findings suggest that acetylcholine (ACh), a neuromodulator associated with attention and synaptic plasticity, may provide an attention-based mechanism to alter auditory processing in the IC. Furthermore, neurons in the IC express different combinations of nicotinic acetylcholine receptor (nAChR) subunits. However, the cellular mechanisms underlying cholinergic modulation in the IC and its impact on downstream targets in the auditory thalamus remain unknown. We recently found that brief pulses of ACh drive prolonged periods of firing in Vasoactive Intestinal Peptide (VIP) neurons in the IC. Moreover, VIP neurons project to the auditory thalamus (medial geniculate, MG), and we obtained preliminary data suggesting that brief pulses of VIP promote strong depolarization in a subset of MG neurons. We hypothesize that ACh enhances excitability of VIP neurons through a nAChR-dependent signaling pathway and that VIP neurons in turn use glutamatergic and VIP signaling to drive prolonged excitability of postsynaptic neurons in the MG. To address this, we are using brain slice electrophysiology and pharmacology to determine the mechanisms that govern the modulatory effects of ACh on VIP neurons and VIP on MG neurons. Our preliminary results show that the prolonged firing of VIP neurons elicited by brief pulses of ACh depends on activation of α4β2 nAChRs. Furthermore, we found that this effect is not abolished by blocking glutamatergic, GABAergic, and glycinergic synaptic transmission or by reducing extracellular Ca2+, suggesting that ACh acts by activating α4β2 nAChRs expressed on VIP neurons themselves and not through activation of neurons presynaptic to VIP neurons. Additionally, our preliminary data show that brief pulses of VIP elicit prolonged depolarization in MG neurons. The overall objective of this proposal is to determine for the first time how cholinergic modulation alters activity in an identified class of IC principal neurons and how these alterations in turn affect activity in the MG. In Aim 1, we will combine brain slice electrophysiology with pharmacology and optogenetics to determine the receptors and mechanisms involved in cholinergic modulation of IC VIP neurons. In Aim 2, we will use brain slice electrophysiology, pharmacology and channelrhodopsin-assisted circuit mapping (CRACM) to determine how synaptic transmission from VIP neurons affects the excitability of MG neurons. Overall, our results will provide a mechanistic basis for how cholinergic modulation in the IC shapes neuron excitability in the IC and MG and will provide a foundation for determining how cholinergic modulation can be used to promote adaptive plasticity in people with hearing loss.