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.

整个新皮层，海马和杏仁核的胆碱能力前脑（CBF）神经元项目 调节知觉显着性，并调节学习和记忆的基础突触可塑性。 CBF研究 专注于主缘区域，包括内侧隔膜，对角线带的核和基础核基础。 （NB）。基本前脑的尾端极端被大大忽略了，但我们的研究表明 这个尾尾区域（就像纹状体的尾巴）可以被概念化为独特的功能 与更多的鼻部区域相比，子域具有明确不同的响应特性。 CBF的项目 尾神经元（CBFT）集中在两个区域：听觉皮层（ACTX）和丘脑网状 核（TRN）。我们在被动倾听的小鼠中发表的CBFT神经元发表的初步录音揭示了 出乎意料的强，短期，阈值低的反应 明确的行为相关性。对于其他方式或从 更多的CBF神经元。 CBFT的声音响应不稳定，而是迅速，有选择性的 在Pavlovian和器乐学习范式中，增强了预测威胁的声音。那，我们的 对尾部区域的研究提出了一个不同的模型，用于对皮质声音处理的胆碱能调节 actx不断被声音触发的乙酰胆碱（ACH）轰炸，重组 在学习以突出相关声音并指导皮质接受场可塑性时。在这里，我们描述了三个 在即将到来的项目期间的具体目标，该目标将阐明CBFT如何调节丘脑皮质声音 在听觉学习过程中处理，对声音的感知意识和关联可塑性。瞄准中的研究 1将检验倒立的假设，用于对声音处理的胆碱能调节，这使得有感觉 在瞬态峰和硬质期间，在初级ACTX（A1）和TRN中进行调整变得暗示和不可靠 局部内源性ACH释放。此外，我们预测这些效果可以部分地解释 CBFT介导的ACH释放对A1第6层皮质丘脑神经元的影响特别强，如 对完整和急性丘脑皮层脑切片制剂的研究。 AIM 2将把这些想法扩展到 行为领域通过表明偶尔在丘脑皮质编码和感知意识中的失误 目标声音（即错过试验）可以归因于CBFT介导的ACH水平的随机峰和麻烦 立即在目标声音发作之前。 AIM 3将检验以下假设，即增强了CBFT对 声音与厌恶（但不开胃）相关的声音足以移动A1声音 从净稳定模式到增强的可塑性的表示形式支持关联听觉学习。 这些假设将通过一般编码的ACH传感器成像的联合应用来测试， CBFT或NB轴突的光遗传学，多区域单位记录和2光子钙成像 在自愿和非自愿行为报告中清醒的转基因小鼠。