Unraveling the neural basis of female aggression and dementia-related aggression: a systems biology approach.

揭示女性攻击性和痴呆相关攻击性的神经基础：系统生物学方法。

• 批准号: 10361486
• 负责人: Caroline Palavicino-Maggio
• 金额: $ 0.83万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361486
• 关键词: Abdomen; Address; Affect; Age; Aggressive behavior; Aging; Agitation; Alzheimer' s Disease; Amyloid beta-42; Amyloid beta-Protein; Animals; Area; Behavior; Behavioral; Biological; Body part; Brain region; Candidate Disease Gene; Cells; Cognitive; Collaborations; Complex; Computer software; Data; Defect; Dementia; Development; Disease; Disease model; Drosophila genus; Drosophila melanogaster; Electron Microscopy; Female; Ganglia; Gene Cluster; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Human; Instinct; Label; Lateral; Lead; Libraries; Link; Longevity; Mammals; Mediating; Mediator of activation protein; Mentors; Mentorship; Methods; Mutation; Nerve Degeneration; Nervous system structure; Network-based; Neurodegenerative Disorders; Neurons; Output; PC3 cell line; Pathology; Pathway interactions; Patients; Phase; Phenotype; Physical aggression; Play; Population; RNA Interference; Reporter; Reporting; Research; Resources; Role; Senile Plaques; Social Behavior; Stream; Subgroup; Symptoms; Synapses; System; Systems Biology; Testing; Training; Transcript; Transgenes; Transgenic Organisms; Work; age related; base; behavior change; behavior test; bullying; cholinergic; cholinergic neuron; common symptom; connectome; design; extracellular; fighting; fly; genetic manipulation; instrumentation; machine learning algorithm; male; neglect; neural circuit; neural network; neuronal excitability; novel; overexpression; prevent; programs; protein aggregation; relating to nervous system; research study; response; sex; single-cell RNA sequencing; skills; therapeutic target

Project Summary Males and females elicit aggressive behavior for resources and survival. Male aggression has been well studied in many species. However, not much is known about female aggression. Recently, my work identified a small female- specific subgroup of cells in the pC1 brain region (pC1α neurons), that triggered females to fight at extremely high intensity levels when activated. For the K99 phase, I will build on my previous work and elaborate on the pC1α neurons circuitry under the mentorship of Dr. E. Kravitz, a well-renowned expert in aggression and Drosophila genetics. Aim 1 is concerned with determining the pre- and post-synaptic partners of the pC1α neurons. For this aim, I will work with my co-mentor, Dr. R. Wilson, to determine pre- and post- synaptic partners and design transgenic fly lines to target these areas. Based on my preliminary data of electron microscopy tracings, I hypothesize that, a)SAG neurons provide inputs to pC1α neurons; and b) pC1α neurons project dendritic outputs to PVL04om_pct neurons in areas previously identified in aggression such as Posterior Lateral Protocerebrum. I anticipate that both up- and down-stream pC1α neurons partners will induce high intensity female aggression. Aim 2 will investigate the role of candidate aggression-associated genes in pC1α neurons. I will train in single-cell profiling methods (used by the Kravitz lab) and address the hypothesis that genes overexpressed in male aggression mediating neurons also play key role in pC1α neuron function. In collaboration with co-mentor Dr. B de Bivort, I will also use neural network-based body part tracking software to train a classifier to automatically label aggressive behaviors. This will allow me to use machine-learning algorithms to capture multi-dimensional representations of the phenotypic differences among fly lines with mutations and transgenic effectors that target aggression circuits (e.g, activating and inhibiting a neuron or overexpressing aggregating proteins). The trainings acquired in my mentored K99 phase will facilitate my transition to independent research studying age-related diseases and behavior. Severe behavioral disturbances of aggression and agitation have been reported to be increasingly common during the progression of Alzheimer's disease and other related dementias.The reasons for this are completely unknown. Moreover, there is a dearth of understanding of how changes in neurons, during neurodegeneration, lead to specific behavioral defects. For the R00 phase, I will shift my focus to looking at aggression in neurodegenerative disease models and begin my efforts by elucidating the contribution of neuronal protein aggregates of Aβ-42 to aggression. My preliminary data indicates that overexpression of human Aβ-42 in using a (pan-neuronal driver) in males and (cholinergic driver) in females induces heightend levels of aggression. Based on these findings, I hypothesize Aβ-42 overexpression induced aggression is due to altered excitability of key aggression promoting neurons. I plan to use diverse and integrative systems approaches (learned from my mentored phase). I will lead a multi-pronged research effort to understand the mechanisms by which neurons regulate their normal function in the presence of an aging and or neurodegenerative disease state and how these changes affect circuit pathways and ultimately aggression.

项目摘要 男性和女性为资源和生存带来了侵略行为。男性侵略性一直很好地研究 许多物种。但是，关于女性侵略性并不了解。最近，我的工作确定了一个小女性 PC1脑区域（PC1α神经元）中细胞的特定亚组，触发女性在极高的 激活时强度水平。对于K99阶段，我将以我以前的工作为基础，并详细介绍PC1α 在E. Kravitz博士的心态下，神经元电路是一位著名的侵略性和果蝇专家 遗传学。 AIM 1关注的是确定PC1α神经元的突触前和突触后伴侣。为了这 AIM，我将与我的联合学家R. Wilson博士一起确定突触前和后的设计前和设计 转基因飞行线以这些区域为目标。根据我的电子显微镜示踪数据的初步数据 假设，a）SAG神经元为PC1α神经元提供了输入； b）PC1α神经元项目树突输出为 先前在侵略性鉴定的区域（如后侧杂脑）中的PVL04OM_PCT神经元。我 预计上游和下游PC1α神经元伴侣都会引起高强度的女性侵略性。目标2 将研究候选侵袭性相关基因在PC1α神经元中的作用。我将训练单细胞分析 方法（Kravitz Lab使用），并解决了以下假设：雄性侵略性过表达的基因 介导神经元在PC1α神经元功能中也起关键作用。在与Co-Encormor B. B de Bivort博士合作的情况下，我将 还使用基于神经网络的身体部位跟踪软件来训练分类器以自动标记侵略性 行为。这将使我可以使用机器学习算法来捕获该算法 具有突变和转基因作用的飞行线之间的表型差异，以攻击性电路（例如，，例如， 激活和抑制神经元或过表达聚集蛋白）。在我的指导中获得的培训 K99阶段将促进我向独立研究的过渡，以研究与年龄相关的疾病和行为。严重 据报道，侵略和躁动的行为干扰在此期间越来越普遍 阿尔茨海默氏病和其他相关痴呆的进展。原因是完全未知的。 此外，了解神经变化如何导致特定的神经元的变化如何导致 行为缺陷。对于R00阶段，我将把重点转移到神经退行性疾病中的侵略性 模型并通过阐明Aβ-42对侵略性的神经元蛋白聚集体的贡献开始了我的努力。 我的初步数据表明，在男性中使用（泛神经元驱动器）和人类Aβ-42的过表达 （胆碱能驱动器）女性诱导侵略性水平。根据这些发现，我假设Aβ-42 过表达引起的侵略性是由于关键侵袭性促进神经元的兴奋性改变。我打算使用 多样化和集成的系统方法（从我的指导阶段学习）。我将领导一项多管齐下的研究 努力了解神经元在衰老的存在下调节其正常功能的机制 或神经退行性疾病状态以及这些变化如何影响电路途径并最终侵略性。

项目成果

Cohort profile: the COVID-19 Coping Study, a longitudinal mixed-methods study of middle-aged and older adults' mental health and well-being during the COVID-19 pandemic in the USA.

• DOI: 10.1136/bmjopen-2020-044965
• 发表时间: 2021-02-10
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Kobayashi LC;O'Shea BQ;Kler JS;Nishimura R;Palavicino-Maggio CB;Eastman MR;Vinson YR;Finlay JM
• 通讯作者: Finlay JM