Corticofugal Circuits for Active Listening

积极倾听的皮质回路

• 批准号: 10530181
• 负责人: Daniel B. Polley
• 金额: $ 70.34万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530181
• 关键词: Acetylcholine; Active Listening; Acute; Amygdaloid structure; Animals; Arousal; Auditory; Auditory Perception; Auditory area; Award; Awareness; Axon; Basal Ganglia; Basal Nucleus of Meynert; Behavior; Behavioral; Brain; Calcium; Categories; Cell Nucleus; Cholinergic Receptors; Code; Corpus striatum structure; Coupling; Dementia; Desire for food; Detection; Diagonal Band Nucleus; Equilibrium; Failure; Fiber; Genetic; Hearing; Hippocampus (Brain); Image; Learning; Measures; Medial; Medial geniculate body; Mediating; Memory; Modality; Modeling; Monitor; Mus; Neocortex; Neurodegenerative Disorders; Neurons; Operant Conditioning; Output; Phase; Preparation; Presynaptic Terminals; Property; Prosencephalon; Psychological reinforcement; Publishing; Pupil; Rehabilitation therapy; Reporting; Research; Role; Sensory; Sensory Disorders; Slice; Stimulus; Synaptic plasticity; Tail; Testing; Thalamic structure; Transgenic Mice; Whole-Cell Recordings; Work; antagonist; auditory nuclei; auditory stimulus; aversive conditioning; awake; basal forebrain; basal forebrain cholinergic neurons; base; cell type; cholinergic; cholinergic neuron; classical conditioning; conditioning; indexing; memory consolidation; novel strategies; novel therapeutics; optogenetics; receptive field; relating to nervous system; response; sensor; sound; two-photon

Cholinergic basal forebrain (CBF) neurons project throughout the neocortex, hippocampus, and amygdala to modulate perceptual salience and regulate synaptic plasticity underlying learning and memory. CBF research has focused on rostral regions, including the medial septum, nuclei of the diagonal band, and nucleus basalis (NB). The caudal extreme of the basal forebrain has been largely overlooked, yet our research suggests that this caudal tail region – much like the tail of the striatum – can be conceptualized as a distinct functional subdomain with categorically different response properties than more rostral regions. The projections of CBF tail neurons (CBFt) are concentrated in two regions: the auditory cortex (ACtx) and the thalamic reticular nucleus (TRN). Our published and preliminary recordings from CBFt neurons in passively listening mice reveal surprisingly strong, short-latency, low-threshold responses to a broad class of auditory stimuli that have no explicit behavioral relevance. Comparable responses are not observed for stimuli in other modalities or from more rostral CBF neurons. CBFt sound responses are not stable, but instead are rapidly and selectively enhanced for threat-predicting sounds during Pavlovian and instrumental learning paradigms. Thus, our studies of the tail region suggest a different model for cholinergic modulation of cortical sound processing in which the ACtx is continuously bombarded by sound-triggered acetylcholine (ACh) surges that reorganize during learning to highlight relevant sounds and guide cortical receptive field plasticity. Here, we describe three specific aims for the coming project period that will illuminate how the CBFt regulates thalamocortical sound processing, perceptual awareness of sound, and associative plasticity during auditory learning. Studies in Aim 1 will test an inverted-U hypothesis for cholinergic modulation of sound processing, which holds that sensory tuning in the primary ACtx (A1) and TRN become imprecise and unreliable during transient peaks and troughs of local endogenous ACh release. Further, we predict that these effects can be accounted for – in part – by the particularly strong influence of CBFt-mediated ACh release on A1 layer 6 corticothalamic neurons, as tested by studies in both intact and acute thalamocortical brain slice preparations. Aim 2 will extend these ideas to the behavioral domain by showing that occasional lapses in thalamocortical encoding and perceptual awareness of target sounds (i.e., miss trials) can be attributed to stochastic peaks and troughs in CBFt-mediated ACh levels immediately preceding target sound onset. Aim 3 will test the hypothesis that enhanced CBFt responses to sounds associated with aversive – but not appetitive – reinforcement is sufficient to shift A1 sound representations from a mode of net stability to heightened plasticity that supports associative auditory learning. These hypotheses will be tested through the combined application of genetically encoded ACh sensor imaging, optogenetics, multi-regional single unit recordings, and 2-photon calcium imaging of CBFt or NB axons in awake transgenic mice during voluntary and involuntary behavioral reporting of sound perception.

胆碱能基底前脑 (CBF) 神经元投射到整个新皮质、海马体和杏仁核， 调节感知显着性并调节 CBF 研究的突触可塑性。 重点关注吻侧区域，包括内侧隔膜、对角带核和基底核 （注意）基底前脑的尾端在很大程度上被忽视了，但我们的研究表明： 这个尾部区域——很像纹状体的尾部——可以被概念化为一个独特的功能区 与更多的喙部区域相比，具有明显不同响应特性的子域 CBF 的投影。 尾部神经元（CBFt）集中在两个区域：听觉皮层（ACtx）和丘脑网状结构 我们已发表的被动聆听小鼠 CBFt 神经元的初步记录揭示了这一点。 对一大类听觉刺激的反应出人意料地强烈、短延迟、低阈值，而这些刺激没有 对于其他方式或来自其他方式的刺激没有观察到明显的行为相关性。 更多的头侧 CBF 神经元 CBFt 声音反应不稳定，而是快速且有选择性的。 在巴甫洛夫和器乐学习范式中增强了威胁预测声音，因此，我们的。 对尾部区域的研究提出了皮质声音处理的胆碱能调制的不同模型 ACtx 不断受到声音触发的乙酰胆碱 (ACh) 浪涌的轰击，从而重组 在学习过程中突出相关声音并引导皮质感受野可塑性在这里，我们描述了三个。 下一个项目期间的具体目标将阐明 CBFt 如何调节丘脑皮质声音 听觉学习过程中的处理、声音的感知意识和联想可塑性。 1 将测试声音处理的胆碱能调制的倒 U 假设，该假设认为感觉 在瞬态峰值和低谷期间，主 ACtx (A1) 和 TRN 的调谐变得不精确且不可靠 此外，我们预测这些影响可以部分归因于 CBFt 介导的乙酰胆碱释放对 A1 层 6 皮质丘脑神经元的影响特别强烈，经测试 对完整和急性丘脑皮质脑切片制剂的研究将把这些想法扩展到 行为领域，通过显示丘脑皮质编码和知觉意识的偶尔失误 目标声音（即错过试验）可归因于 CBFt 介导的 ACh 水平的随机波峰和波谷 目标 3 将测试增强 CBFt 响应的假设。 与厌恶相关的声音 - 但不是食欲 - 强化足以改变 A1 声音 从净稳定模式到支持联想听觉学习的胃肠可塑性的表征。 这些假设将通过基因编码的 ACh 传感器成像的组合应用进行测试， 光遗传学、多区域单单元记录以及 CBFt 或 NB 轴突的 2 光子钙成像 在声音感知的自愿和非自愿行为报告期间唤醒转基因小鼠。