BRC-BIO: Adult hippocampal neurogenesis: GPR37 mediated regulation of granule cell maturation

Adult neurogenesis, the process of producing new neurons in the adult brain, can change the function of established neural circuits and the behavior of an animal. Neurogenesis occurs continuously throughout adulthood in a region of the brain called the hippocampus, a structure important for consolidation of memory and for spatial memory used in navigation.

The integration of these new neurons into the normal functional circuitry of the hippocampus occurs in several stages. One of the later stages, called maturation, is when the new cells ‘mature’ into neurons. Th process of maturation is regulated by molecules that integrate information from many sources through many molecular pathways inside the cells.

These signaling pathways are important for controlling the integration of the cells into established circuits, memory formation, and emotional processing. Currently, many of the signaling pathways remain unknown. This project will focus on understanding novel signaling pathways capable of regulating late-stage maturation, with a particular focus on the ability of specific G protein-coupled receptors (GPCRs), to enhance neuronal maturation, and facilitate emotional processing.

Understanding the signals which regulate these processes will allow researchers to better predict how changes in these signals can affect brain networks and behavior. This project will provide research experiences for students at Smith College (a women’s college), in the form of assistantships, and facilitate a course-based undergraduate research experience (CURE).

In addition, this project will provide research experiences for freshman and AP biology high school students from Springfield Central High School (SCHS), a high school with a total minority enrollment of 90%. To improve the quality of these research experiences this project will prioritize developing an environment founded on the power of seeing ‘self’ by intentionally increasing the representation of diverse individuals as lab leaders.

Neurogenesis occurs through a complex multistep process which involves the proliferation, differentiation, and maturation of neural precursor cells into mature neurons. These stages are highly regulated by environmental cues composed of numerous intrinsic and extrinsic signaling molecules. The canonical Wnt/β-catenin signaling pathway is one such network which has been shown to control both early and late stages of hippocampal neurogenesis.

Although numerous targeted screens have been performed to identify core pathway components of the Wnt/β-catenin pathway, a complete understanding of the formation, composition, and relevance of interacting partners capable of modulating Wnt signaling is lacking. The G protein-coupled receptor (GPCR), GPR37, has recently been identified as a novel interacting partner for this pathway where it has been proposed to potentiate Wnt signaling by functioning as an endoplasmic reticulum chaperone for the Wnt co-receptor, LRP6.

The foundation of this project is built on preliminary findings which support a more direct role for GPR37 mediated potentiation of Wnt signaling, and the observation that the loss of GPR37 appears to reduce the number of mature neurons within the hippocampus. This project aims to build upon these findings by testing the central hypothesis that the GPR37/LRP6/Wnt β-catenin pathway constitutes a novel signaling network which positively regulates granule cell maturation during late-stage neurogenesis.

This hypothesis will be tested by performing morphological analysis of mature and immature neurons within the hippocampus of wild type, Gpr37+/-, and Gpr37-/- mice, analysis of newborn neurons through retroviral tracing, and the assessment of emotional/affective behaviors in this model using deep neural networks for behavioral analysis.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.