The cognitive searchlight: TRN circuit dissection in health and disease

认知探照灯：健康和疾病中的 TRN 电路剖析

基本信息

批准号：
9263001
负责人：
Michael M Halassa
金额：
$ 52.39万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2018-01-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263001
关键词：
Animals Area Attention Attention deficit hyperactivity disorder Attentional deficit Autistic Disorder Behavior Behavioral Brain Brain Diseases Cell Nucleus Characteristics Chlorides Code Cognition Cognition Disorders Cognitive Coupling Data Dependency Development Diagnostic Disease Dissection Electrodes Electrophysiology (science)Engineering Etiology Fiber Fluorescence Foundations Functional disorder Generations Genetic Health Human Impairment Income Intervention Knock-out Knockout Mice Knowledge Lesion Maps Measures Modality Modeling Modernization Mus Neurons Neurosciences Noise Pattern Performance Periodicity Pharmacology Photometry Play Positioning Attribute Prefrontal Cortex Primates Process Proxy Psychophysics Publishing Research Role Schizophrenia Sensory Signal Transduction Site Source Speed Stream Structure Task Performances Testing Thalamic Nuclei Thalamic structure Training Translating Update Variant Work attentional control attentional modulation base behavioral outcome cognitive function experimental study extracellular flexibility insight mouse model novel novel diagnostics novel strategies novel therapeutics optogenetics public health relevance relating to nervous system sensory input synaptic inhibition therapeutic development translational impact translational study transmission process

项目摘要

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.

描述（由申请人提供）：理解自上而下的注意力控制机制是现代神经科学中最重要的努力之一，这个过程允许大脑在处理不同的信息流之间灵活地切换，并从同样显着的噪声中提取相关信号。自上而下的注意力受到自闭症、精神分裂症和多动症的严重破坏，因此了解其潜在机制具有重要的转化意义。具体来说，我们观察到丘脑网状核（TRN）的速率和时间调节，丘脑抑制的主要来源，在自上而下的注意力任务中，揭示了丘脑回路的作用。在这里，我们将测试 TRN 作为认知探照灯的假设，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。将研究被破坏的探照灯是否可以解释模拟人类自闭症变体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小鼠中开发的自上而下的注意力任务来实现，其中动物在处理两个感官输入之间进行切换。在逐个试验的基础上，我们将结合 TRN 中的多电极记录和前额叶皮层的光遗传学操作，询问 TRN 注意力调节是否依赖于前额叶自上而下的输入。区分速率和时间编码机制的光遗传学操作，我们将询问 TRN 神经编码如何映射到行为结果，我们将研究将 TRN 活动变化与下游电路和行为耦合的两种假定机制。开发一种纤维光度测定方法来测量细胞内氯的动态变化，这是突触抑制的代表。第二，我们将使用多电极方法来推断丘脑皮质传输的动态变化。使用 PTCHD1 敲除的转化研究，模拟人类 PTCHD1 表达的小鼠在发育过程中对 TRN 具有选择性，我们将测试敲除后 TRN 爆发减少与行为分散之间的关系。由于自上而下的注意力减弱是几种大脑疾病的一个特征，因此我们的治疗开发将具有广泛的转化吸引力，总体而言，通过深入了解认知功能的循环机制，我们的目标是：开发针对认知障碍的新诊断和治疗方法。