Ingredients of good memory

Revolutionary studies in the 70’s and 80’s drew the neural underpinnings of work memory to the brain’s prefrontal cortex. There, neurons materialize to preserve information by collectively firing for seconds to minutes, much longer than the millisecond standard for individual neurons. But this system alone doesn’t elucidate the more complicated aspects of working memory – including for example, how we can hold more than one item in mind, or face distracters and still commit to memory the thing we care about.

“It became increasingly clear that persistent activity in the prefrontal cortex, while important, can’t be the whole story,” says Rajasethupathy, Jonathan M. Nelson Family Assistant Professor.

To further investigate this, Rajasethupathy’s team partnered with Praveen Sethupathy and his lab at Cornell University to explore how working memory functions among a special population of genetically diverse mice. “Unlike standard lab mice, these mice have a level of genetic diversity mirroring that of human populations,” Sethupathy says, “This means some may be great at working memory tasks, and some not so much, and we can study what in their brain’s physiology gives rise to that variability.”

Rat can’t memorize a shopping list to show off their memory skills. But when they are put in maze, they prefer to travel around a new arm of the maze on every list. How successfully a mouse finds new territory inside the maze is therefore a measure of its working memory.

As anticipated, the scientists discovered broad variation in the mice’s performance, followed with a genetic analysis high lightened one place in the genome that could explain a considerable portion – 17 percent of that variability.

FROM GENES TO BRAIN CIRCUITS

The crew later investigated how this gene, which also exists in other humans and mammals, affects a mouse’s brain and behavior.

The gene conceals Gpr12, an “orphan receptor”, so – called because it’s blurred what molecule in the brain turns it on. To their wonder, the researchers found these receptors are on to in the prefrontal cortex, the presumed seat of working memory, but in neurons much farther away in the brain’s thalamus.

The mice which was showing high performance had about 2.5 times more than these receptors in their thalamus than mice which was showing low performance. Brain activity recording unveiled that these receptors help set up synchronous activity between the thalamus and the prefrontal cortex while working memory tasks.

“We demonstrate that mice that perform better, have more of these receptors and are therefore able to establish more synchrony,” Rajasethupathy said.

“The findings expand classical models by revealing the crucial role of the dialogue between the prefrontal cortex and thalamus, suggesting new ways for researchers to think about working memory. Rajasethupathy and her colleagues plan to continue investigating the details of the role played by Gpr12 receptors — work which may lead to potential therapeutic targets for treating deficits in working memory.”

“It’s rare to find a single gene with a strong influence on a complex cognitive function like working memory,” she says. “But it happened to be true in this case, and it led us to unexpected mechanisms involved in working memory.”