The cognitive searchlight: TRN circuit dissection in health and disease

 描述(申请人提供)：了解自上而下的注意控制机制是现代神经科学中最重要的努力之一。这一过程允许大脑灵活地在处理不同信息流之间切换，并从同样显著的噪声中提取相关信号。自上而下的注意力在自闭症、精神分裂症和ADHD中受到严重干扰，因此了解其潜在的机制具有重要的翻译意义。虽然灵长类动物的研究已经建立了自上而下注意的皮质底物，但我们使用老鼠的数据揭示了丘脑回路在这一过程中的一个意想不到的作用。具体地说，我们观察到了丘脑网状核(TRN)在自上而下的注意任务中的频率和时间调制，它是丘脑抑制的主要来源。扰乱这一过程会降低任务绩效，这意味着存在因果依赖。在这里，我们将测试TRN作为认知探照灯的功能的假设，将自上而下的皮质输入转化为对行为结果至关重要的丘脑处理的变化。此外，我们还将研究被干扰的探照灯是否能解释模拟人类自闭症变种的小鼠模型的注意力分散和注意力障碍。我们的工作将通过我们在老鼠身上开发的自上而下的注意任务来实现，在这种任务中，动物在逐个试验的基础上在处理两个感觉输入之间切换。在目标I中，我们将结合TRN的多电极记录和前额叶皮质的光遗传操作，询问TRN的注意调制是否依赖于前额叶自上而下的输入。使用区分速率和时间编码机制的闭环光遗传操作，我们将询问TRN神经编码如何映射到行为结果。在AIM II中，我们将研究两种可能的机制，它们将TRN活性的变化与下游电路和行为联系起来。首先，我们将开发一种纤维光度法来测量细胞内氯的动态变化，细胞内氯是突触抑制的代用品。对于第二个，我们将使用多电极方法来推断丘脑-皮质传输的动态变化。在AIM III中，我们将使用PTCHD1基因敲除进行翻译研究，这是一种被设计成模仿人类自闭症变体的小鼠。PTCHD1的表达在发育过程中对TRN具有选择性，我们将在敲除中测试TRN突发生成减少与行为分心之间的关系。我们将询问，逆转TRN功能障碍是否能挽救其行为分心。由于自上而下的注意力减少是几种大脑疾病的一个特征，我们的治疗发展将具有广泛的翻译吸引力。总而言之，通过对认知功能的电路机制提供深入的见解，我们的目标是开发新的认知障碍诊断和治疗方法。

 DESCRIPTION (provided by applicant): Understanding the mechanisms of top-down attentional control is one of the most important endeavors in modern neuroscience. This process allows the brain to flexibly switch among processing different information streams and to extract relevant signals from equally salient noise. Top-down attention is critically disrupted n autism, schizophrenia and ADHD, and understanding its underlying mechanisms is therefore of great translational importance. While primate studies have established cortical substrates for top-down attention, our data using the mouse have revealed an unsuspected role for thalamic circuitry in this process. Specifically, we have observed rate and temporal modulation of the thalamic reticular nucleus (TRN), the major source of thalamic inhibition, in a top down attentional task. Disrupting this process diminishes task performance, suggesting causal dependency. Here, we will test the hypothesis that the TRN functions as a cognitive searchlight, translating top- down cortical input to changes in thalamic processing critical for behavioral outcome. In addition, we will investigate whether a disrupted searchlight explains distractibility and attentional impairment in a mouse model engineered to mimic a human autism variant. Our work will be enabled by a top-down attentional task we developed in mice, where animals switch between processing two sensory inputs on a trial-by-trial basis. In Aim I, we will combine multi-electrode recordings in TRN and optogenetic manipulations in prefrontal cortex, asking whether TRN attentional modulation is dependent on prefrontal top-down input. Using closed-loop optogenetic manipulations that distinguish between rate and temporal coding regimes, we will ask how TRN neural codes map onto behavioral outcomes. In Aim II, we will examine two putative mechanisms that couple TRN activity changes to downstream circuitry and behavior. For the first, we will develop a fiber photometry approach to measures dynamic changes in intracellular chloride, a proxy for synaptic inhibition. For the second, we will use a multi- electrode approach to infer dynamic changes in thalamo-cortical transmission. In Aim III, we will perform translational studies using the PTCHD1 knockout, a mouse engineered to mimic a human autism variant. PTCHD1 expression is selective to TRN in development, and we will test the relationship between diminished TRN burst generation and behavioral distractibility in the knockout. We will ask whether reversing TRN dysfunction rescues its behavioral distractibility. Because diminished top-down attention is a feature of several brain disorders, our therapeutic development will be of broad translational appeal. Overall, by providing deep insights into the circuit mechanisms of cognitive function, we aim to develop novel diagnostics and therapeutics for disorders of cognition.