Corticofugal Circuits for Active Listening

胆碱能基底前脑(CBF)神经元投射到新皮质、海马体和杏仁核 调节知觉突显，调节学习和记忆背后的突触可塑性。CBF研究 集中在吻部区域，包括内侧隔核、斜角带核和基底核。 (NB)。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 与更多的嘴区域相比，具有截然不同的响应特性的亚域。CBF的预测 尾神经元(CBFt)集中在两个区域：听觉皮质(ACTx)和丘脑网状结构 核(TRN)。我们发布的被动听音小鼠CBFt神经元的初步记录显示 对一大类听觉刺激的惊人强烈、短潜伏期、低阈值反应 明确的行为关联。对于其他形式的刺激或来自 更多的嘴部CBF神经元。CBFt的声音响应并不稳定，而是快速和选择性的 在巴甫洛夫学习范例和工具性学习范例中增强了威胁预测声音。因此，我们的 对尾部区域的研究表明，大脑皮层声音处理的胆碱能调制模式不同 ACTx被声音触发的乙酰胆碱(ACh)浪涌持续轰炸， 在学习过程中，强调相关的声音，并引导大脑皮层接受野的可塑性。在这里，我们描述三个 未来项目期的具体目标，将阐明CBFt如何调节丘脑皮质声音 听觉学习过程中的加工、声音知觉和联想可塑性。AIM中的研究 1将测试对声音处理的胆碱能调制的倒U型假说，该假说支持这种感觉 在瞬时波峰和波谷期间，初级ACTx(A1)和TRN中的调谐变得不精确和不可靠 局部内源性ACh的释放。此外，我们预测，这些影响可以部分地解释为 CBFt介导的ACh释放对A1层6层皮质丘脑神经元的影响尤其强烈 完整和急性丘脑皮质脑片制备的研究。目标2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 靶音(即未命中试验)可归因于CBFt介导的ACh水平的随机波峰和波谷 紧接在目标声响开始之前。目标3将检验以下假设：增强的CBFt反应 与厌恶--但不是食欲--强化有关的声音足以转移A1音 从网络稳定的模式到支持联想听觉学习的高度可塑性。 这些假设将通过基因编码的ACH传感器成像的组合应用来检验， 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 在自愿和非自愿的声音感知行为报告过程中唤醒转基因小鼠。

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.