Investigating the Asymmetrical Development of Ebf1+ Cells in the Central Amygdala and Its Functional Consequences

About This Grant

Project Summary Brain asymmetry, a conserved feature of the vertebrate nervous system, is thought to be an advantageous mechanism for efficient information processing. This asymmetry manifests in anatomical and molecular left-right (L-R) differences that correlate with specialized functions in specific cognitive processes. Disruption of asymmetry in multiple brain regions including the prefrontal lobe and the amygdala has been implicated in the pathogenesis of several neurodevelopmental disorders, such as autism spectrum disorders. In mammals, brain asymmetry has been demonstrated in multiple brain regions involved in regulating emotion processing and memory, including the habenula, the hippocampus, the prefrontal cortex, and the amygdala. Our preliminary single-cell RNA sequencing (scRNAseq) and in situ hybridization (ISH) analyses revealed a distinct, left-to-right biphasic expression pattern of the early B cell factor gene, Ebf1, in the lateral ganglionic eminence (LGE)/striatum and central amygdalar nucleus (CeA). Ebf1 expression displayed a predominant L-sided dominance in the LGE/striatum and CeA before embryonic day 14 (E14), switching to R-sided dominance after E16 and persisting into adulthood. Furthermore, our ISH data showed that Ebf1 primarily colocalizes with Drd1 in striatal and CeA cells, suggesting a role for Ebf1+ cells in regulating the acquisition of contextual fear, Pavlovian conditioned fear responses, and appetitive behaviors. In this proposed study, I aim to investigate the cellular and molecular signatures of Ebf1 cells in the amygdala and determine whether these lateralized expression patterns have functional consequences in regulating emotion-related behaviors. By forging a new path in this area of research, our findings have the potential to significantly advance our understanding of neurodevelopmental disorders. To achieve this goal, we have outlined three specific aims: 1) To trace the developmental origin of asymmetrical Ebf1+ cells and their progenies in the L-R CeA. 2) To identify the cellular and molecular signatures of asymmetrically distributed Ebf1+ cells and Ebf1 lineages in adult CeA. 3) To investigate how asymmetrical Ebf1+ cells contribute to CeA-dependent emotion behaviors. This study will address the following key questions: When do the asymmetric L-R Ebf1 cells develop in the CeA? What are the functional properties of CeA-Ebf1 cells? How do these unilaterally distributed Ebf1 cells contribute to behavioral asymmetry? By elucidating these questions, this study will serve as a proof-of-principle, paving the way for a deeper understanding of brain asymmetry and its potential role in neurodevelopmental disorders.