Identifying prefrontal signatures of successful and dysfunctional attention

识别成功和功能失调注意力的前额叶特征

• 批准号: 10349347
• 负责人: Brielle Ferguson
• 金额: $ 12.98万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349347
• 关键词: Address; Attention; Behavior; Biological Assay; Brain; Cells; Cognition; Complex; Cues; Data; Development; Disease; Dissection; Epilepsy; Fiber; Functional disorder; Genetic; Image; Impaired cognition; Impairment; Individual; Interneurons; Length; Life; Link; Measures; Medial; Mediating; Mental Depression; Mental disorders; Microscope; Monitor; Mus; Mutant Strains Mice; Neurons; Parvalbumins; Perception; Performance; Phase; Photometry; Physiological; Physiology; Play; Population; Prefrontal Cortex; Process; Public Health; Regulation; Research; Role; Schizophrenia; Signal Transduction; Slice; Somatostatin; Source; Specificity; Structure; Techniques; Testing; Thalamic structure; Training; Vasoactive Intestinal Peptide; Visual attention; Work; autism spectrum disorder; behavioral response; cell type; comorbidity; design; flexibility; hippocampal pyramidal neuron; in vivo; miniaturize; mouse model; neuronal cell body; novel; optogenetics; recruit; response; selective attention; sustained attention; therapeutic target; therapeutically effective

PROJECT SUMMARY Attention is comprised of several component processes, including sustained attention, selective attention, and attentional flexibility. The first phase, the initial focusing of attention, precludes engagement of other components making it an important building block of many of our more complex behaviors. Additionally, attention impairments often present as a comorbidity in conditions including but not limited to schizophrenia, autism, depression, and epilepsy, making identifying therapeutic targets a significant public health concern. Convergent data point to the medial prefrontal cortex (mPFC) as a hub for supporting attentional shifting along with other key structures, while its role in the initial engagement of attention is less clear. Somehow, mPFC pyramidal neurons integrate information from multiple sources, represent task rules, cue, and response-related information in dynamically active ensembles, and select appropriate behavioral responses. Previous physiological data suggests this astounding computational feat is made possible due to the powerful regulation of pyramidal neuron activity by cortical inhibitory interneurons, but many studies lacked the ability to monitor distinct cell-classes with specificity. Using fiber photometry of GCaMP-mediated Ca2+ signals in mPFC parvalbumin-expressing interneurons (PVINs), we have collected preliminary data demonstrating that PVINs play a novel role in cue-perception during a visual attentional engagement task (AET). Specifically, we have observed that cue-evoked population increases in PVIN activity are necessary, sufficient, and can be predictive for successful attentional engagement. We hypothesize that this may represent a universal mechanism of attention that is consistently disrupted across diseases with attentional impairments. PVINs however, do not operate in isolation, and mPFC pyramidal neurons are also regulated by long-range inputs from the mediodorsal thalamus (MD) among others, and local circuit interactions with other interneuron subtypes, such as somatostatin (SOM) and vasoactive intestinal polypeptide (VIP) expressing interneurons, all of which have also been linked to cognition and psychiatric disease dysfunction. Separate studies have identified distinct disinhibitory circuits involving VIP and SST interneurons, and SST and PV interneurons that can regulate mPFC-dependent behaviors. However, the precise circuit motifs which regulate attentional processes are largely uncharacterized. Specifically, how individual interneurons in specific classes represent information during attentional assays capturing distinct components of attention remains to be determined. Through the K99 phase, I will receive critical training in in vivo Ca2+ imaging and design and implementation of attentional tasks to test my overall hypothesis that PVINs provide broad inhibition to suppress distracting information during attentional engagement, while the R00 phase will examine how separate disinhibitory circuit motifs allow pyramidal neuron ensembles to signal cue and response information to appropriately guide separate attention functions.

项目摘要 注意由几个组件过程组成，包括持续的关注，选择性 注意和注意力灵活性。第一阶段是关注的最初关注，排除了 其他组件使其成为我们许多更复杂行为的重要组成部分。此外， 注意力障碍通常在包括但不限于精神分裂症的条件下以合并症的形式出现 自闭症，抑郁症和癫痫病，使识别治疗靶标成为一个重大的公共卫生问题。 收敛数据点指向内侧前额叶皮层（MPFC）作为支持沿着注意力转移的枢纽 对于其他关键结构，虽然其在最初的注意力参与中的作用尚不清楚。不知何故，MPFC 金字塔神经元整合来自多个来源的信息，表示任务规则，提示和与响应有关的信息 在动态活动的合奏中信息，并选择适当的行为响应。以前的 生理数据表明，由于强大的法规，使这种惊人的计算壮举成为可能 皮质抑制性中间神经元的锥体神经元活性，但许多研究缺乏监测能力 具有特异性的不同细胞类。使用MPFC中GCAMP介导的Ca2+信号的纤维光度法 表达白蛋白的中间神经元（PVIN），我们收集了初步数据，证明PVIN 在视觉注意参与任务（AET）期间，在提示感知中发挥了新作用。具体来说，我们有 观察到PVIN活性的提示诱发的人群增加是必要的，足够的，并且可以预测 成功的注意参与。我们假设这可能代表 注意力不断受到注意障碍的疾病始终受到破坏。但是，pvins不要 分别运行，MPFC锥体神经元也受到来自远程输入的调节 中腹丘脑（MD）以及与其他中间神经元亚型的局部电路相互作用，例如 作为生长抑素（SOM）和血管活性肠多肽（VIP）表达中间神经元，所有这些都有 也与认知和精神病功能障碍有关。单独的研究已经确定了不同的 涉及VIP和SST中间神经元的抑制电路，以及可以调节的SST和PV中间神经元 MPFC依赖性行为。但是，调节注意力过程的精确电路图案是 在很大程度上没有特色。具体而言，特定类中的单个中间神经元如何表示信息 在注意捕获不同注意力组成部分的注意力测定期间，尚待确定。通过 K99阶段，我将接受体内CA2+成像和设计和实施注意力的关键培训 测试我的总体假设的任务，即PVIN提供了广泛抑制以抑制分心的信息 在注意参与期间，R00阶段将检查单独的dies抑制电路图案如何允许 锥体神经元合奏以发出提示和响应信息的信号，以适当地引导单独的注意力 功能。