Corticofugal Circuits for Active Listening

胆碱能基底前脑（CBF）神经元投射到整个新皮层、海马和杏仁核， 调节知觉的显著性和调节学习和记忆基础的突触可塑性。CBF研究 主要集中在吻侧区域，包括内侧隔、斜角带核和基底核 （注）。基底前脑的尾端在很大程度上被忽视了，然而我们的研究表明， 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， 子域与不同的反应性质比更多的吻部地区。CBF的预测 尾神经元（CBFt）集中在两个区域：听觉皮层（ACtx）和丘脑网状 核（TRN）。我们发表的和初步的记录来自被动倾听小鼠的CBFt神经元， 令人惊讶的是，对一大类听觉刺激的短潜伏期低阈值反应， 外显行为相关性对于其他方式的刺激或来自 更多的嘴侧CBF神经元。CBFt声音反应并不稳定，而是快速和选择性的 在巴甫洛夫和工具学习范式中，威胁预测声音的能力得到了增强。所以我们 对尾区的研究表明，大脑皮层声音处理的胆碱能调制是一种不同的模型， ACtx不断受到声音触发的乙酰胆碱（ACh）激增的轰击， 在学习过程中，突出相关的声音和指导皮层感受野可塑性。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如何调节丘脑皮质音 处理，知觉意识的声音，和联想可塑性在听觉学习。研究目的 1将测试一个倒U型假说的胆碱能调制的声音处理，这认为，感觉 在瞬态波峰和波谷期间，初级ACtx（A1）和TRN中的调谐变得不精确和不可靠 局部内源性乙酰胆碱释放。此外，我们预测，这些影响可以解释-部分-由 CBFt介导的ACh释放对A1层6皮质丘脑神经元的影响特别强烈，如通过 在完整和急性丘脑皮质脑切片制备中的研究。目标2将把这些想法扩展到 行为领域的研究表明，丘脑皮质编码和知觉意识的偶尔失误， 目标声音（即，缺失试验）可归因于CBFt介导的ACh水平的随机峰和谷 就在目标声音开始之前。目的3将检验增强CBFt对以下物质的反应的假设： 与厌恶相关的声音-但不是食欲-强化足以转移A1声音 从网络稳定性模式到支持联想听觉学习的增强可塑性。 这些假设将通过基因编码的乙酰胆碱传感器成像的组合应用进行测试， 光遗传学、多区域单单位记录和CBFt或NB轴突的双光子钙成像， 清醒的转基因小鼠在自愿和非自愿的行为报告的声音感知。

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.