A molecular timer that counts out the seconds a thought is held has turned up in the thalamus. Working memory is a mental notepad that keeps information for a few seconds while we read, do arithmetic, or plan. Its capacity is limited, and over time the trace fades. But what exactly sets that time limit long remained a mystery.
The answer came from the thalamus, a subcortical hub that relays signals to the cortex. There, a receptor called Gpr12 does its work, long considered an "orphan": no one knew what activated it. Researchers obtained its structure and saw two binding pockets. One is classic, the other an unusual lateral pocket embedded in the membrane. It turned out that the natural key to this receptor is anandamide, a lipid from the endocannabinoid family.
Anandamide binds to Gpr12 through the lateral pocket and triggers a slow suppression of cAMP, an intracellular signaling molecule, in thalamic neurons. This suppression works like an hourglass: it lasts exactly as long as the animal holds information in a task. In mice with elevated Gpr12 expression, the suppression persisted at delays of 30 and 60 seconds, whereas in control mice it vanished after just 15 seconds.
A point mutation in the lateral pocket abolished both the cAMP suppression and the memory improvement, even though the receptor's basal activity was preserved. After a cognitive challenge, anandamide levels in the thalamus rose, while the levels of other lipids stayed the same. Administering anandamide to mice improved memory, but had no effect in mice lacking Gpr12. In macaques, blocking the breakdown of anandamide also improved working memory, and the effect was dose-dependent.
This is the first case in which a molecular mechanism has been tied directly to behavior on timescales of up to a minute. The discovery explains why the thalamus sustains cortical representations longer than the cortex itself does: local production of anandamide sets off a slow suppression of cAMP that acts as a timer. The lateral pocket of Gpr12 is a ready-made target for drugs that could improve working memory in schizophrenia, ADHD, and age-related impairments.
Anandamide got its name from the Sanskrit word "ananda," meaning bliss or joy. It is the same lipid that activates CB1 cannabinoid receptors, but in the thalamus it acts on a completely different receptor, Gpr12, and instead of impairing memory it improves it.
The idea of a molecular timer that counts out the seconds of information retention echoes the concept of the "mental chronometer" from Ted Chiang's "Story of Your Life," where the perception of time and memory plays a key role. More broadly, controlling the duration of working memory resembles the technologies in Philip K. Dick's "We Can Remember It for You Wholesale," except that instead of implants, it is an endogenous lipid.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.