A novel method for transient and repeatable axonal tracing in developing marmosets

一种在狨猴发育过程中进行瞬时和可重复轴突追踪的新方法

• 批准号: 10526658
• 负责人: David J Schaeffer
• 金额: $ 42.78万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526658
• 关键词: Address; Adult; Age; Aging; Alzheimer' s Disease; Animal Model; Area; Autopsy; Axon; Behavioral; Biological Markers; Blood - brain barrier anatomy; Brain; Brain region; Breeding; Callithrix; Callithrix jacchus jacchus; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Distal; Dorsal; Early treatment; FDA approved; Face; Face Processing; Focused Ultrasound; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Genetic Predisposition to Disease; Histocytochemistry; Histology; Human; Impairment; Injections; Intellectual functioning disability; Laboratories; Link; Longevity; Magnetic Resonance Imaging; Manganese; Maps; Medial; Methods; Modeling; Monkeys; Neurodevelopmental Disorder; Neurons; Pattern; Pharmacology; Population; Pre-Clinical Model; Pregnancy; Primates; Screening procedure; Seeds; Social Behavior; Social Development; Symptoms; Techniques; Temporal Lobe; Testing; Tissues; Tracer; Training; Translational Research; Visual Pathways; Work; autism spectrum disorder; behavioral phenotyping; diagnostic biomarker; diagnostic criteria; diagnostic tool; efficacy evaluation; frontal lobe; gaze; indexing; insight; machine learning algorithm; manganese chloride; multimodality; neuropsychiatric disorder; novel; pre-clinical; pressure; social; social deficits; therapy outcome; translational potential; treatment strategy

PROJECT SUMMARY Preclinical animal models of neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs) and those of intellectual disabilities, have yielded insight into candidate genetic etiologies, but circuit-level hypotheses underlying behavioral alterations (particularly social impairments) have remained elusive. A significant challenge for developing biomarkers and diagnostic tools has been technological – because canonical neuronal tract-tracing techniques require histology of post-mortem tissue, longitudinal assessments of circuit development are few and far between. To address this critical unmet need, we propose to develop a novel, transient, and repeatable method that circumvents invasive histochemistry altogether and allows for longitudinal axonal-level tracing in developing marmoset monkeys. The common marmoset (Callithrix jacchus) is an ideal preclinical modeling species for studying circuit trajectories related to aberrant social development. We recently discovered that marmosets, like humans, possess socially selective face processing patches in frontal cortex. As such, marmosets can recapitulate primate-specific aspects of social behaviors that form the diagnostic criteria for many NDDs. In Aim 1, we will optimize our approach, which uses transcranial focused ultrasound (FUS) to deliver MnCl2, a magnetic resonance imaging (MRI)-visible axonal tracer to any prescribed region of the brain. In Aim 2, we seek to demonstrate that the FUS-MEMRI technique is a reliable screening tool for developmental circuit-level aberrations with test-retest reliability. We will leverage our genetically diverse breeding colony of marmosets to study the structural underpinnings of naturally occurring differences in social face processing from an early age. From two months into adulthood, we will employ the FUS-MEMRI method to track the axonal connectivity of our previously identified socially selective face patch in medial frontal cortex. This circuity is ostensibly involved in assigning social salience to faces, a classic hallmark deficit in ASDs. By employing our established fMRI paradigm – which is passive and can be used with very young marmosets – we will link axonal development to functional variability in social processing of faces. Further, we will employ trained machine- learning algorithms to isolate gaze patterns to relevant facial features, providing a behavioral index of face processing. With this noninvasive multimodal approach, we will establish parameters of healthy variability of this circuitry in our marmoset population, laying the groundwork for genetic and pharmacological models currently in development by our laboratory and others. This work will lead to the establishment of a novel noninvasive approach for longitudinal axonal tracing that is transient, targeted, and repeatable. This technique will have broad application in translational research, especially for neurodevelopmental applications, providing a means to non- invasively track the neuropathological emergence of circuit dysfunction from a young age. As a longitudinal technique, the FUS-MEMRI method is also well suited to track therapeutic outcomes aimed at determining the efficacy of early treatment strategies for NDDs.

项目摘要 神经发育障碍（NDD）的临床前动物模型，包括自闭症谱系障碍（ASDS） 以及智力残疾的人，已经深入了解候选遗传病因，但电路级别 基本的行为改变（部分社会障碍）仍然难以捉摸。一个 对于开发生物标志物和诊断工具的重大挑战是技术性的 - 因为规范 神经元路追踪技术需要验尸后组织的组织学，电路的纵向评估 开发很少，而且相距甚远。为了满足这种关键的未满足需求，我们建议开发一部小说， 瞬态且可重复的方法完全绕过侵入性组织化学并允许纵向 轴突级别的追踪在发展中，在果猴猴子发展中。普通的marmoset（callithrix jacchus）是理想的 用于研究与异常社会发展有关的电路轨迹的临床前建模物种。我们最近 发现像人类一样，果果会在额叶皮质中具有社会选择性的面部处理斑块。 因此，莫尔莫斯人可以概括构成诊断标准的社会行为的私人特定方面 对于许多NDD。在AIM 1中，我们将优化我们的方法，该方法使用专注的超声（FUS） 将MNCL2传递到大脑的任何规定区域。 在AIM 2中，我们试图证明FUS-MEMRI技术是开发的可靠筛选工具 带测试可靠性的电路级畸变。我们将利用我们一般的潜水员育种殖民地 研究摩尔果研究的结构基础是与 很小的时候。从成年后的两个月开始，我们将采用FUS-MEMRI方法来跟踪轴突 我们先前确定的社会选择性面部贴片在媒体额叶皮层中的连通性。该电路是 表面上参与将社会显着性分配给Faces，这是ASDS中经典的标志性防御。通过使用我们的 已建立的fMRI范式 - 是被动的，可以与非常年轻的果酱一起使用 - 我们将链接轴突 发展面对社会处理的功能变异性。此外，我们将采用训练有素的机器 - 学习算法将视线模式隔离到相关的面部特征，提供面部行为索引 加工。通过这种非侵入性多模式方法，我们将建立健康可变性的参数 我们的马尔莫斯特人口中的电路，为目前的遗传和药物模型奠定了基础 我们的实验室和其他人的发展。这项工作将导致建立一个新颖的无创 纵向轴突跟踪的方法是瞬态，有针对性和可重复的。这项技术将有广泛的 在翻译研究中的应用，尤其是针对神经发育应用，为非 - 从小就可以侵入性地跟踪电路功能障碍的神经病理出现。作为纵向 技术，FUS-MEMRI方法也非常适合跟踪旨在确定的治疗结果 NDD的早期治疗策略的功效。

项目成果

Noninvasive disruption of the blood-brain barrier in the marmoset monkey.

• DOI: 10.1038/s42003-023-05185-3
• 发表时间: 2023-08-02
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Parks, T. Vincenza;Szuzupak, Diego;Choi, Sang-Ho;Alikaya, Aydin;Mou, Yongshan;Silva, Afonso C. C.;Schaeffer, David J. J.
• 通讯作者: Schaeffer, David J. J.