The cognitive searchlight: TRN circuit dissection in health and disease

 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切换，并从同样突出的噪声中提取相关信号。自上而下的注意力在自闭症、精神分裂症和多动症中受到严重破坏，因此了解其潜在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的注意力的皮质基底，但我们使用小鼠的数据揭示了丘脑回路在这一过程中的未知作用。具体来说，我们已经观察到率和时间调制的丘脑网状核（TRN），丘脑抑制的主要来源，在一个自上而下的注意任务。破坏这一过程会降低任务绩效，表明因果依赖性。在这里，我们将测试这一假设，即TRN功能作为一个认知探照灯，翻译自上而下的皮层输入的变化，在丘脑处理的行为结果至关重要。此外，我们还将研究一个被破坏的探照灯是否能解释一个被设计成模仿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老鼠身上开发的自上而下的注意力任务来实现，在这种任务中，动物在逐个试验的基础上在处理两种感官输入之间切换。在目的I中，我们将结合联合收割机在TRN的多电极记录和前额叶皮层的光遗传学操作，询问TRN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学操作，我们将询问TRN神经代码如何映射到行为结果。在目标II中，我们将研究两个假定的机制，耦合TRN活动的变化，下游电路和行为。首先，我们将开发一种纤维光度法来测量细胞内氯化物的动态变化，这是突触抑制的代理。第二，我们将使用多电极方法来推断丘脑-皮层传输的动态变化。在Aim III中，我们将使用PTCHD 1敲除进行翻译研究，PTCHD 1敲除是一种模拟人类自闭症变体的小鼠。PTCHD 1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爆发产生减少与行为注意力分散之间的关系。我们将询问逆转TRN功能障碍是否可以挽救其行为注意力分散。由于自上而下的注意力减弱是几种大脑疾病的特征，我们的治疗发展将具有广泛的转化吸引力。总的来说，通过深入了解认知功能的电路机制，我们的目标是开发新的诊断和治疗认知障碍。

 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.