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

听觉中脑 VIP 神经元的胆碱能调节及其对丘脑神经元兴奋性的影响

• 批准号: 10267691
• 负责人: Luis Miguel Rivera-Perez
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2023-09-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267691
• 关键词: Acetylcholine; Address; Affect; Attention; Auditory; Auditory area; Auditory system; Brain; Brain region; Cells; Complex; Cues; Data; Dendrites; Electric Stimulation; Electrophysiology (science); Exhibits; Foundations; Glutamates; Goals; Inferior Colliculus; Knowledge; Lead; Medial; Messenger RNA; Midbrain structure; Molecular; N-Methyl-D-Aspartate Receptors; Neuromodulator; Neurons; Nicotinic Receptors; Outcomes Research; Output; Peptide Signal Sequences; Pharmacology; Physiologic pulse; Play; Research; Role; Sensory; Shapes; Signal Pathway; Slice; Sound Localization; Speech; Synaptic Transmission; Synaptic plasticity; System; Tegmentum Mesencephali; Testing; Thalamic structure; The Sun; Time; Vasoactive Intestinal Peptide; auditory processing; auditory thalamus; base; cholinergic; experimental study; extracellular; hearing impairment; hearing loss treatment; hearing restoration; improved; insight; millisecond; neuroregulation; neurotransmission; novel; optogenetics; postsynaptic; postsynaptic neurons; presynaptic neurons; receptor; response; somatosensory; sound; speech processing

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.

摘要 我们的大脑如何识别和回应语音和其他听觉线索仍然不清楚。下丘脑神经元 丘（IC）是位于中脑的听觉处理中枢，对频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。以前的研究结果表明，乙酰胆碱（ACh）， 一种与注意力和突触可塑性相关的神经调质，可能提供一种基于注意力的机制 来改变大脑皮层的听觉处理此外，IC中的神经元表达不同的烟碱酸组合。 乙酰胆碱受体（nAChR）亚单位。然而，胆碱能调节的细胞机制 在IC及其对听觉丘脑下游靶点的影响仍然未知。我们最近发现， ACh的短暂脉冲驱动IC中血管活性肠肽（VIP）神经元的长时间放电。 此外，VIP神经元投射到听丘脑（内侧膝状体，MG），我们获得了初步的 数据表明VIP的短暂脉冲促进MG神经元亚组中的强去极化。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神经元反过来又使用突触能和VIP信号来驱动突触后神经元的长期兴奋性。 MG中的神经元为了解决这个问题，我们正在使用脑切片电生理学和药理学来确定 ACh对VIP神经元和VIP对MG神经元调节作用的机制。我们 初步结果表明，ACh短脉冲引起的VIP神经元放电延长依赖于 激活α4β2 nAChR。此外，我们发现，这种作用并没有被阻断多巴胺能， GABA能和甘氨酸能突触传递或通过减少细胞外Ca2+，表明ACh的作用是 激活VIP神经元自身表达的α4β2 nAChRs，而不是通过激活突触前神经元， VIP神经元。此外，我们的初步数据表明，VIP的短暂脉冲引起长时间的去极化， MG神经元。这项提议的总体目标是首次确定胆碱能调节 改变了IC主要神经元的活动，以及这些改变如何反过来影响IC主要神经元的活动。 MG.在目标1中，我们将联合收割机脑切片电生理学与药理学和光遗传学相结合， 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。总的来说，我们的结果将 为IC中的胆碱能调节如何影响IC和MG中的神经元兴奋性提供了机制基础 并将提供一个基础，以确定如何胆碱能调节可用于促进适应性 听力损失患者的可塑性。