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Spatial transcriptomics mapping of basal ganglia to understand critical periods for sensorimotor learning

基底神经节的空间转录组学绘图，以了解感觉运动学习的关键时期

基本信息

批准号：
10378230
负责人：
STEPHANIE ANN WHITE
金额：
$ 42.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378230
关键词：
Acute Adolescent Adult Age Anatomy Animals Area Basal Ganglia Behavior Behavior Therapy Behavioral Blood specimen Brain Brain Diseases Brain region Cells Cerebral Palsy Child Complex Development Effectiveness Experimental Designs Female Fingerprint Fluorescent in Situ Hybridization Future Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Glean Goals Hearing Human Immediate-Early Genes Impairment Individual Intervention Knowledge Learning Link Maps Modeling Molecular Motor Movement Neurodevelopmental Disorder Neurons Noise Organism Pathway Analysis Pathway interactions Pattern Phenotype Physical therapy Play Process Production Role Sampling Signal Pathway Signal Transduction Stroke Structure Testing Tissue Sample Tissues Transcript Transcriptional Activation Treatment Efficacy Update Work autism spectrum disorder base brain tissue cDNA Arrays cell type critical developmental period critical period differential expression droplet sequencing improved learned behavior learning ability male neurogenesis programs sex sexual dimorphism skills spatiotemporal therapeutic target transcriptome sequencing transcriptomics tutoring vocalization zebra finch

项目摘要

Summary The basal ganglia comprise key brain structures for generating and refining motor sequences necessary for a variety of complex behaviors that are acquired through procedural learning. These skills are often best learned during early developmental critical periods. Prior work has shown that practicing these skills drives acute changes in gene expression within the underlying basal ganglia microcircuit. This behavior-linked transcriptional activation is observed in juveniles during the sensorimotor critical period but also occurs in adults after the critical period has closed, suggesting that it is not specific to learning. Remarkably, a separate transcriptional profile is only found in juveniles and correlates with the quality of the learned skill. These observations suggest that the spatiotemporal overlap of the behavior-linked and learning-related changes in juveniles constitute a transcriptional program that is permissive for learning. To test this idea, the individual basal ganglia cell types in which these programs occur, currently unknown, must be resolved. Understanding these ‘transcriptional fingerprints’ will be key to deciphering molecular signaling pathways that support sensorimotor learning. This project leverages a well-characterized vertebrate model, the zebra finch, in which basal ganglia transcriptional changes linked to both practice and learning have been demonstrated via bulk sequencing of the entire region, but have not yet been traced to distinct basal ganglia cell types. Thus, one major aim is to identify and compare single-cell gene transcripts from behaviorally activated and non-activated basal ganglia, during and after the critical period, in order to identify specific cell types and cell signaling pathways undergoing behaviorally regulated changes, including those that support learning. In this species, only males undergo sensorimotor learning so comparison to the analogous regions in female brains will highlight the most relevant changes. The second goal is to select key cell type identifiers as well as molecules implicated in the sensorimotor learning process and develop probes to map their spatial expression in samples of the intact microcircuit using multiplexed error-robust fluorescence in situ hybridization (MERFISH). Together, these two integrated aims will illuminate how the basal ganglia changes over the course of repeated behavioral refinement to enable optimal sensorimotor learning. This work has direct implications for better understanding of the mechanisms that underlie the effectiveness of human behavioral therapies and may highlight pharmaco-therapeutic targets to improve treatment efficacy in brain disorders ranging from autism to stroke to cerebral palsy.

总结