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: 10754984
• 负责人: Brielle Ferguson
• 金额: $ 24.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754984
• 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 注意力是由几个过程组成的，包括持续的注意力、选择性注意力和选择性注意力。 注意力和注意力灵活性。第一个阶段，即最初集中注意力，排除了 其他成分使它成为我们许多更复杂行为的重要组成部分。此外，本发明还 注意力损伤通常作为包括但不限于精神分裂症的病症的合并症出现， 孤独症、抑郁症和癫痫症，使得确定治疗目标成为一个重大的公共卫生问题。 聚合数据指出，内侧前额叶皮层（mPFC）是支持注意力转移的中心，沿着 它与其他主要机构的合作，而它在最初引起注意方面的作用则不那么明确。不知何故，mPFC 锥体神经元整合来自多个来源的信息，代表任务规则，线索和反应相关 信息在动态活动的合奏，并选择适当的行为反应。先前 生理学数据表明，这一令人震惊的计算壮举之所以成为可能，是因为强大的调节机制， 皮质抑制性中间神经元的锥体神经元活动，但许多研究缺乏监测能力， 具有特异性的不同细胞类别。用纤维光度法检测mPFC中GCaMP介导的Ca ~（2+）信号 表达小清蛋白的中间神经元（PVIN），我们收集了初步数据，表明PVIN 在视觉注意参与任务（AET）中的线索感知中发挥新的作用。具体来说，我们有 观察到提示诱发的PVIN活动的群体增加是必要的，足够的，并且可以预测 成功的注意力投入。我们假设这可能代表了一种普遍的机制， 注意力在患有注意力障碍的疾病中一直受到干扰。但是，PVIN不会 mPFC锥体神经元也受到来自大脑皮层的长距离输入的调节。 中间背丘脑（MD）等，以及与其他中间神经元亚型的局部回路相互作用， 作为生长抑素（SOM）和血管活性肠多肽（VIP）表达的中间神经元，它们都具有 也与认知和精神疾病功能障碍有关。独立的研究已经确定了不同的 涉及VIP和SST中间神经元的去抑制回路，以及SST和PV中间神经元可以调节 mPFC依赖性行为。然而，调节注意力过程的精确电路图案是 基本上没有特征。具体来说，特定类别中的单个中间神经元如何表示信息 在注意力测定期间，捕获注意力的不同成分仍有待确定。通过 K99阶段，我将接受体内Ca 2+成像以及注意力设计和实施方面的关键培训 任务来测试我的总体假设，即PVIN提供广泛的抑制来抑制分散注意力的信息 在注意力参与期间，而R 00阶段将检查单独的去抑制回路基序如何允许 锥体神经元集合以信号提示和响应信息来适当地引导分开的注意 功能协调发展的