SIGNALING OF SALIENCE AND PREDICTION ERRORS BY THE INSULA

概况.人类fMRI和LFP记录研究表明，前额叶编码的显着性， 刺激和偏离预期。然而，BOLD信号和LFP的分辨率不足以评估 这些代码是如何在孤立细胞中分布的此外，岛屿的起源和功能相关性 代码不清楚。我们将通过多部位单个装置和LFP记录以及 光遗传学方法。重要的是，我们的试点数据表明，呈现突出刺激elands相同 大鼠和人类的LFP反应：高振幅β（13-30 Hz）振荡的爆发。 意义和方法。因为它的体积在大多数精神疾病中减少，所以它是一个 经颅或深部脑刺激的有前途的治疗靶点。然而，这一领域的进展一直是 由于缺乏关于蓝牙信号的高分辨率数据而受阻。因此，这项建议可能有助于 开发新的治疗方法。为了研究大鼠的大脑皮层，我们开发了一种新的强化学习任务， 其特点是对老鼠的期望（以及它们的违规行为）进行行为读出。这项任务将使我们能够评估 前额叶神经元和它们的突触伙伴如何编码多个变量，并探索它们在学习中的作用。 目的#1描述前额叶神经元及其突触伙伴的编码特性。 我们将在前额叶及其突触伙伴中进行多位点单位和LFP记录。这将允许 我们：（1）测试这些不同部位的细胞是否编码结果效价、幅度、显著性和偏差 （2）测试效价刺激是否引起前额叶的β振荡爆发，如图所示。 （3）通过不同频率的振荡比较这些不同部位的神经元的夹带; (4)测试岛叶β爆发的幅度是否跟踪刺激的显著性和与预期的偏差。 目标2：确定哪些输入驱动前额叶神经元中不同变量的编码。数据 在目标1中得到的结果将表明哪些输入将关于不同变量的信息传递给神经元。类似 关于岛状β爆发的起源和传播将出现假设。为了验证这些假设，我们 将注入驱动抑制性视蛋白在投射限定的细胞类型中表达的AAV。然后，我们将抑制 候选细胞类型，并评估这些操作如何影响神经元的编码特性， 以及岛叶β爆发的发生和传播。 目的#3测试减少或增强岛叶β爆发是否会损害或促进学习。我们将 通过将光遗传学与可编程多通道相结合，实现对岛叶β爆发的实时控制 信号处理器，给我们前所未有的控制快速神经元事件。我们将增强或抑制 通过传递低强度的光刺激来产生孤立的β爆发， β振荡，而不改变发射率。如果岛叶β爆发促进学习，上调或下调它们 应该分别加速或减慢任务中的学习。

Overview. Human fMRI and LFP recording studies suggest that the anterior insula encodes the salience of stimuli and deviations from expectations. However, BOLD signals and LFPs have insufficient resolution to assess how these codes are distributed across insular cells. Moreover, the origin and functional relevance of insular codes is unclear. We will address these questions with multi-site single unit and LFP recordings as well as optogenetic methods in rats. Critically, our pilot data indicates that presentation of salient stimuli elicits identical LFP responses in rats and humans: bursts of high amplitude beta (13-30 Hz) oscillations. Significance and approach. Because its volume is reduced in most psychiatric disorders, the insula is a promising therapeutic target for transcranial or deep brain stimulation. However, progress in this field has been hindered by a lack of high-resolution data about insula signaling. Thus, this proposal may facilitate the development of novel therapies. To study the insula in rats, we developed a novel reinforcement learning task that features a behavioral readout of the rats’ expectations (and their violations). This task will allow us to assess how anterior insula neurons and their synaptic partners encode multiple variables and probe their role in learning. Aim #1 Characterize the coding properties of neurons in the anterior insula and its synaptic partners. We will perform multi-site unit and LFP recordings in the anterior insula and its synaptic partners. This will allow us to: (1) test whether cells at these various sites encode outcome valence, magnitude, salience, and deviations from expectations; (2) test whether valenced stimuli elicit bursts of beta oscillations in the anterior insula, as seen in humans; (3) compare the entrainment of neurons at these various sites by oscillations of different frequencies; (4) test whether the amplitude of insular beta bursts tracks stimulus salience and deviations from expectations. Aim #2: Determine which inputs drive coding of different variables in anterior insula neurons. The data obtained in Aim 1 will suggest which inputs convey information about different variables to insula neurons. Similar hypotheses will arise regarding the origin and propagation of insular beta bursts. To test these hypotheses, we will infuse AAVs driving the expression of an inhibitory opsin in projection-defined cell types. Then, we will inhibit the candidate cell types and assess how these manipulations affect the coding properties of insula neurons as well as the genesis and propagation of insular beta bursts. Aim #3 Test whether reducing or enhancing insular beta bursts impairs or facilitates learning. We will achieve real-time control over insular beta bursts by combining optogenetics with programmable multi-channel signal processors, giving us unprecedented control over fast neuronal events. We will enhance or dampen insular beta bursts by delivering low-intensity light stimuli that bias spike times in or out-of-phase with respect to beta oscillations, without altering firing rates. If insular beta bursts facilitate learning, up- or down-regulating them should respectively accelerate or slow down learning in the task.