Multilevel Characterization of Approach and Avoidance Biases Linked to Social Stress

与社会压力相关的接近和回避偏差的多层次表征

• 批准号: 10650154
• 负责人: Angelica Minier-Toribio
• 金额: $ 4.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10650154
• 关键词: 3-Dimensional; Academia; Affect; Amygdaloid structure; Applications Grants; Area; Automobile Driving; Aversive Stimulus; Behavior; Behavioral; Brain; Brain Mapping; Brain region; CREB1 gene; Calcium; Chronic; Complement; Complex; Computer Models; Corpus striatum structure; Cues; Data; Data Analyses; Decision Making; Equilibrium; Event; Exposure to; Extinction; FOSB gene; Face; Fellowship; Fiber; Freezing; Future; Gene Expression Profile; Genetic; Genetic Transcription; Goals; Grant; Image; Immunohistochemistry; Impairment; Laboratories; Learning; Limbic System; Link; Major Depressive Disorder; Mediating; Mental Depression; Modeling; Molecular; Molecular Profiling; Motivation; Mus; Neurobiology; Neurons; Neurosciences; Nucleus Accumbens; Pathology; Patients; Pattern; Persons; Phase; Phenotype; Photometry; Population; Postdoctoral Fellow; Predisposition; Prefrontal Cortex; Prevalence; Process; Proxy; Psychopathology; Rattus; Research; Rewards; Role; Saccharin; Scientist; Shapes; Shock; Signal Transduction; Social Interaction; Stress; Testing; Training; Training Support; Water; Woman; Women' s Role; adverse outcome; behavior test; biological adaptation to stress; cell type; cost; depressed patient; experience; experimental study; in vivo; in vivo calcium imaging; insight; learning extinction; male; mouse model; neural; neurotransmission; novel; resilience; role model; social; social defeat; social stress; stress related disorder; therapeutic target; transcriptome sequencing; transcriptomics; translational model

PROJECT SUMMARY People experiencing major depression often decline their approach to rewards, to instead avoid threats (including irrelevant ones). Despite the prevalence of these costly behaviors featuring decision-making impairments, their underlying neurobiology is poorly defined. Here, I combine powerful mouse models to provide a multilevel characterization of approach and avoidance decisions linked to depression. Previous studies highlight specific areas within the corticostriatal-limbic system as signaling approach and avoidance expression. However, I propose to go beyond this limited approach by unbiasedly profiling neuronal activity in the whole brain of mice showing approach and avoidance decisional biases linked to depression-related phenotypes. Further, I propose to unbiasedly profile transcriptional patterns in key areas and to chemogenetically test the role of key cell types. I hypothesize that, in addition to proven areas, our results will reveal overlooked areas and cell types whose activity might be crucial in driving approach and avoidance biases linked to depression. Moreover, our transcriptional analyses will identify proven (i.e., ∆FOSB & CREB) and novel transcriptional regulators driving these biases. In Aim 1, I adapted a platform-mediated avoidance task, to profile approach and avoidance biases in mice exposed to chronic social defeat stress (CSDS), a model used to study depression-related pathology. I first demonstrated that mice susceptible to the CSDS, similar to depressed patients, show persistent avoidance to a cue previously announcing a shock threat, at the cost of missing rewards. In contrast, mice resilient to the CSDS quickly decrease their avoidance to maximize gaining rewards. To further characterize these behavioral biases, in Experiment 1.1, I use brain-wide immunostaining of cFOS as a proxy for correlated neuronal activity. Next, to leverage neuronal activity and gene expression patterns, in Experiment 1.2, I will use RNA-sequencing to transcriptionally profile areas whose activity most strongly correlated with approach and avoidance biases. Simultaneously, I will profile the nucleus accumbens, amygdala, and prefrontal cortex within the corticostriatal- limbic system, which have been proven to signal approach and avoidance and to be sensitive to the adverse consequences of stress. Next, in Experiment 1.3, I will perform chemogenetics, to test the causal role of key areas and cell types in biasing approach or avoidance decisions after CSDS. Capitalizing on this training, in the K00 phase, I will study in vivo temporospatial dynamics of decision-making circuits sensitive to stress, by combining behavior with calcium-imaging and computational modeling. The overall training and research plans outlined here will reveal novel insights into decision-making processes impacted by stress, and will greatly support my successful transition to a postdoctoral fellowship and subsequent scientific independence.

项目总结 经历严重抑郁的人通常会拒绝获得回报，而是避免威胁(包括 不相关的问题)。尽管这些以决策障碍为特征的代价高昂的行为很普遍，但他们的 潜在的神经生物学的定义并不明确。在这里，我结合了强大的鼠标模型来提供多层次的 与抑郁有关的接近和回避决定的特征。之前的研究强调了具体的 皮质纹状体-边缘系统内的区域作为信号途径和回避表达。然而，我 建议超越这种有限的方法，无偏见地描绘小鼠整个大脑中的神经元活动 表现出与抑郁相关的表型相关的接近和回避决策偏差。此外，我建议 不偏不倚地描述关键区域的转录模式，并从化学遗传学角度测试关键细胞类型的作用。 我假设，除了已证实的区域外，我们的结果将揭示被忽视的区域和细胞类型 活动可能对驾驶方法和与抑郁有关的回避偏见至关重要。而且，我们的 转录分析将确定已证实的(即∆FosB和CREB)和新的转录调控因子驱动 这些偏见。在目标1中，我采用了一种平台中介的回避任务，以描述接近和回避偏见 在暴露于慢性社会失败压力(CSDS)的小鼠中，这是一种用于研究抑郁症相关病理的模型。我 首次证明易受CSDS影响的小鼠，与抑郁症患者相似，表现出持续的回避。 之前宣布了一个令人震惊的威胁，但代价是错过了奖励。相比之下，小鼠对 CSD迅速减少他们的回避，以最大限度地获得奖励。为了进一步描述这些行为 偏倚，在实验1.1中，我使用CFO的全脑免疫染色作为相关神经元活动的替代。 接下来，为了利用神经元活动和基因表达模式，在实验1.2中，我将使用RNA测序 从转录水平描述其活动与接近和回避偏见最密切相关的区域。 同时，我将描绘伏隔核，杏仁核，以及皮质纹状体内的前额叶皮质- 边缘系统，已被证明是接近和回避的信号，并对不利因素敏感 压力的后果。接下来，在实验1.3中，我将执行化学遗传学，以测试键的因果作用 CSDS后偏向接近或回避决策中的区域和细胞类型。利用这次培训，在 K00阶段，我将在活体内研究时空动力学中对应激敏感的决策回路，通过 将行为与钙成像和计算建模相结合。总体培训和研究计划 这里概述的将揭示受压力影响的决策过程的新见解，并将极大地 支持我成功地过渡到博士后奖学金和随后的科学独立。