Lipid Activation of a Thalamic GPCR Extends Working Memory Time-scales
- 1Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA
Abstract
Working memory capacity is poorly understood. The ability to control and extend working memory time-scales provides the potential to alleviate cognitive decline in disease and aging. Through an unbiased genetic search, we previously identified a thalamic orphan receptor Gpr12 as a potent enhancer of working memory, however its activation mechanism remains poorly understood. Here, we describe the CryoEM structure of Gpr12, revealing a lipidic regulatory site enabling an activated signaling state. By surveying the native lipidic environment in mouse thalamus we identified a class of 20 carbon:4 double bond fatty acid eicosanoids as potential ligands. Cell-based assays confirmed that the endogenous cannabinoid anandamide (AEA), but not other closely related family members or derivatives, robustly activates Gpr12. In vivo imaging during behavior revealed that Gpr12 activation produces a striking molecular state - the persistent suppression of cAMP in thalamus that tracks the duration of memory maintenance. Notably, genetic or pharmacological manipulations that enhance the AEA-Gpr12 signaling axis are sufficient to prolong cAMP suppression and extend the temporal window of memory maintenance. Furthermore, AEA-mediated cAMP suppressions in thalamus support sustained neural activity in PFC, specifically during memory maintenance. Thus, while cannabinoids often impair memory, here we identify an AEA-Gpr12 signaling axis in thalamus that enhances memory, including in primates. These findings identify a lipidic signaling mechanism in thalamus that is sufficient to control and extend working memory duration.
Related
- Transcranial Random Aperiodic Stimulation Improves Working Memory Precision
- Neural signatures of serial order access in verbal working memory
- Rightward Saccades Distort the Scaffold of Spatial Working Memory in ADHD
- Emotional Modulation of Face Working Memory Precision in Specific Learning Disorders: Valence Flattening and Mnemonic Distortions
- Frontoparietal effective connectivity supports working memory in early childhood
BibTeX
@misc{brandt2026lipid,
title = {{Lipid Activation of a Thalamic GPCR Extends Working Memory Time-scales}},
author = {J. N. Brandt and A. Bonito-Oliva and N. Paknejad and C. Chen and J. J. Fak and A. Luskin and G. Rankin and M. Kirylo and L. J. Sibener and A. Arnsten and V. Ruta and P. Rajasethupathy},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749183},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749183v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Lipid Activation of a Thalamic GPCR Extends Working Memory Time-scales
AU - J. N. Brandt
AU - A. Bonito-Oliva
AU - N. Paknejad
AU - C. Chen
AU - J. J. Fak
AU - A. Luskin
AU - G. Rankin
AU - M. Kirylo
AU - L. J. Sibener
AU - A. Arnsten
AU - V. Ruta
AU - P. Rajasethupathy
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749183
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749183v1
AB - Working memory capacity is poorly understood. The ability to control and extend working memory time-scales provides the potential to alleviate cognitive decline in disease and aging. Through an unbiased genetic search, we previously identified a thalamic orphan receptor Gpr12 as a potent enhancer of working memory, however its activation mechanism remains poorly understood. Here, we describe the CryoEM structure of Gpr12, revealing a lipidic regulatory site enabling an activated signaling state. By surveying the native lipidic environment in mouse thalamus we identified a class of 20 carbon:4 double bond fatty acid eicosanoids as potential ligands. Cell-based assays confirmed that the endogenous cannabinoid anandamide (AEA), but not other closely related family members or derivatives, robustly activates Gpr12. In vivo imaging during behavior revealed that Gpr12 activation produces a striking molecular state - the persistent suppression of cAMP in thalamus that tracks the duration of memory maintenance. Notably, genetic or pharmacological manipulations that enhance the AEA-Gpr12 signaling axis are sufficient to prolong cAMP suppression and extend the temporal window of memory maintenance. Furthermore, AEA-mediated cAMP suppressions in thalamus support sustained neural activity in PFC, specifically during memory maintenance. Thus, while cannabinoids often impair memory, here we identify an AEA-Gpr12 signaling axis in thalamus that enhances memory, including in primates. These findings identify a lipidic signaling mechanism in thalamus that is sufficient to control and extend working memory duration.
ER -