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。

基本信息

批准号：
10633263
负责人：
Caroline Palavicino-Maggio
金额：
$ 24.9万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633263
关键词：
Abdomen Address Affect Age Aggressive behavior Aging Agitation Alzheimer&apos 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 Dimensions 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 Learning Libraries Link Longevity Mammals Mediating Mediator Mentors Mentorship Methods Mutation N-Methylaspartate Nerve Degeneration Nervous System 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 Subgroup Symptoms Synapses System Systems Biology Testing Training Transcript Transgenes Transgenic Organisms Work age related behavior change behavior test bullying candidate identification cholinergic cholinergic neuron common symptom connectome design extracellular fighting fly gene conservation genetic manipulation instrumentation machine learning algorithm male neglect neural neural circuit neural network neuronal circuitry neuronal excitability novel overexpression postsynaptic presynaptic prevent programs protein aggregation research study response sex single-cell RNA sequencing skills therapeutic target

项目摘要

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.

项目概要雄性和雌性会为了资源和生存而引发攻击性行为，这一点在很多研究中都得到了充分的研究。然而，我们对雌性的攻击性知之甚少。最近，我的工作发现了一种小型雌性。 PC1 大脑区域（PC1α 神经元）中的特定细胞亚群，触发雌性以极高的速度进行战斗对于 K99 阶段，我将在之前的工作基础上详细阐述 pC1α。在攻击性和果蝇方面的著名专家 E. Kravitz 博士的指导下研究神经元回路目标 1 涉及确定 pC1α 神经元的突触前和突触后伙伴。目标，我将与我的共同导师 R. Wilson 博士合作，确定突触前和突触后的合作伙伴和设计根据我的电子显微镜追踪的初步数据，我找到了针对这些区域的转基因蝇系。研究发现，a)SAG 神经元向 pC1α 神经元提供输入；b) pC1α 神经元将树突输出投射到 PVL04om_pct 神经元位于先前识别的攻击性区域，例如后外侧原脑 I。预计上游和下游 pC1α 神经元伙伴都会诱发高强度的女性攻击性目标 2。将研究候选攻击相关基因在 pC1α 神经元中的作用，我将进行单细胞分析训练。方法（克拉维茨实验室使用）并解决了男性攻击性中基因过度表达的假设介导神经元在 pC1α 神经元功能中也发挥着关键作用。我将与共同导师 B de Bivort 博士合作。还使用基于神经网络的身体部位跟踪软件来训练分类器自动标记攻击性这将使我能够使用机器学习算法来捕获行为的多维表示。具有针对攻击回路的突变和转基因效应子的果蝇品系之间的表型差异（例如激活和抑制神经元或过度表达聚集蛋白）。 K99 阶段将有助于我过渡到研究年龄相关疾病和行为的独立研究。据报道，攻击性和激动等行为障碍在儿童时期越来越普遍。阿尔茨海默病和其他相关痴呆症的进展。其原因完全未知。此外，人们对神经变性过程中神经元的变化如何导致特定的神经元变化缺乏了解。对于 R00 阶段，我将把重点转向研究神经退行性疾病中的攻击行为。我的工作首先是阐明 Aβ-42 神经元蛋白聚集体对攻击行为的贡献。我的初步数据表明，在男性和女性中使用（泛神经元驱动器）时人类 Aβ-42 过度表达（胆碱能驱动剂）在女性中会引起高水平的攻击性。基于这些发现，我勇敢地勇敢地接受了 Aβ-42。过度表达诱导攻击是由于我计划使用的关键攻击促进神经元的兴奋性改变所致。多样化和综合的系统方法（从我的指导阶段学到）我将领导一项多管齐下的研究。努力了解神经元在衰老时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回路通路并最终影响攻击性。