Date of Award
2026
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Priya Rajasethupathy
Abstract
Working memory is the ability to retain task-relevant information temporarily toward goal-direct pursuits. We use working memory constantly, in navigating environments, following instructions, and coming up with novel solutions to arising issues. Working memory is also a limited capacity system where the ability to maintain information declines over prolonged periods of time, spanning seconds to minutes, but the mechanisms that set these temporal limits are not well understood. Previously, our lab discovered that a brain orphan GPCR, Gpr12, can extend the duration of working memory through synchronizing neural activity between the prefrontal cortex (PFC) and thalamus during memory retention periods. However, the molecular mechanisms by which Gpr12 supports memory maintenance is not known. Moreover, no known endogenous ligands have been identified. In this thesis, to understand the activation mechanism of Gpr12, my collaborators and I performed single-particle cryo electron microscopy (cryo-EM)and identified two functional pockets, a canonical orthosteric site and a previously unrecognized lateral pocket that confers a potentiated, high-activityGpr12 signaling state. Through a combination of native lipidomics, functional in vivo assays, and behavior, we identify the endogenous cannabinoid lipid anandamide as a potent regulatory ligand enabling the potentiated state of Gpr12. To define the temporal basis of Gpr12 activation, we performed real-time imaging of thalamic cAMP during working memory retention and identified a persistent molecular state, the monotonic ramping of cAMP, that scales with memory duration. Anandamide extends the cAMP ramps and improves working memory duration in mice, and absence of the receptor, or a single point mutation that disrupts ligand-receptor activation, is sufficient to ablate both cAMP ramps and memory performance.These results identify a potent endogenous ligand for Gpr12, revealing a novel druggable regulatory site, and advance a model in which membrane lipids provide on-demand modulation of cognitive performance.
License and Reuse Information
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Brandt, James Newton, "Lipid Activation of an Orphan GPCR Extends the Duration of Working Memory" (2026). Student Theses and Dissertations. 855.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/855
Comments
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy