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: 10192224
• 负责人: Caroline Palavicino-Maggio
• 金额: $ 10万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192224
• 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 男性和女性会为了资源和生存而引发攻击行为。男性的攻击性已经得到了很好的研究， 许多物种。然而，人们对女性的攻击性知之甚少。最近，我的工作发现了一个小的女性- pC 1脑区（pC 1 α神经元）中的特定细胞亚群，引发雌性以极高的速度进行战斗 激活时的强度。对于K99阶段，我将在以前工作的基础上详细说明pC 1 α 神经元电路的指导下博士。克拉维茨是一位著名的攻击性和果蝇研究专家 遗传学目的1是确定pC 1 α神经元的突触前和突触后伴侣。为此 我将与我的共同导师R博士合作。威尔逊，以确定突触前和突触后的合作伙伴和设计 转基因果蝇品系来瞄准这些区域。根据我的电子显微镜描记的初步数据，我 假设a）SAG神经元向pC 1 α神经元提供输入; B）pC 1 α神经元投射树突输出， PVL04om_pct神经元在以前确定的侵略，如后外侧原大脑的区域。我 预期上游和下游的pC 1 α神经元伴侣都会诱导高强度的雌性攻击。目的2 将研究候选攻击相关基因在pC 1 α神经元中的作用。我会接受单细胞分析的训练 方法（由Kravitz实验室使用），并解决了基因在男性侵略过度表达的假设， 介导神经元在pC 1 α神经元功能中也发挥关键作用。与共同导师B de Bivort博士合作，我将 我还使用基于神经网络的身体部位跟踪软件来训练分类器， 行为。这将使我能够使用机器学习算法来捕捉 具有突变和靶向攻击回路的转基因效应物的果蝇品系之间的表型差异（例如， 激活和抑制神经元或过表达聚集蛋白）。在我的指导下获得的培训 K99阶段将有助于我过渡到研究与年龄相关的疾病和行为的独立研究。严重 据报道，攻击和激动的行为障碍在 阿尔茨海默氏症和其他相关痴呆症的进展。其原因完全未知。 此外，对于神经元变性过程中神经元的变化如何导致特定的 行为缺陷在R 00阶段，我将把重点转移到神经退行性疾病中的攻击性 模型和开始我的努力，阐明了神经元蛋白聚集体的Aβ-42攻击的贡献。 我的初步数据表明，在男性和女性中，使用a（泛神经元驱动器）过度表达人Aβ-42， （胆碱能驱动）在女性诱导高度的侵略性。基于这些发现，我假设Aβ-42 过表达诱导的攻击性是由于关键的攻击性促进神经元的兴奋性改变。我计划使用 多样化和综合系统方法（从我的指导阶段学到的）。我将领导一个多方面的研究 努力了解神经元在衰老过程中调节其正常功能的机制。 和/或神经退行性疾病状态以及这些变化如何影响电路通路并最终影响攻击性。