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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

基本信息

批准号：
10541681
负责人：
Angelica Minier-Toribio
金额：
$ 4.62万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541681
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 Cues Data Data Analyses Decision Making Equilibrium Event Exposure to Extinction (Psychology)FOSB gene Face Fellowship Fiber Freezing Future Gene Expression Profile Genetic Transcription Goals Grant Image Immunohistochemistry Impairment Laboratories Learning Limbic System Link Major Depressive Disorder Maps Mediating Mental Depression Modeling Molecular Molecular Profiling Motivation Mus Neurobiology Neurons Neurosciences Nucleus Accumbens Pathology Patients Pattern Persons Phase Phenotype Photometry Population Predisposition Prefrontal Cortex Prevalence Process Proxy Psychopathology Research Rewards Role Saccharin Scientist Shapes Shock Signal Transduction Social Interaction Stress Testing Training Training Support Water Woman Women&apos s Role adverse outcome base 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 neurotransmission novel relating to nervous system role model social social defeat social stress stress related disorder therapeutic target transcriptome sequencing transcriptomics translational model

项目摘要

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