Groundbreaking UC Irvine Research Reveals Significant Sex Differences in Learning Based on Brain Chemistry

In a groundbreaking study that challenges longstanding perceptions of cognitive differences between sexes, researchers at UC Irvine School of Medicine have uncovered compelling evidence that male and female brains process information distinctly due to differences in synaptic mechanisms. Led by Christine Gall, PhD, and Gary Lynch, PhD, and postdoctoral researcher Aliza Le, PhD, all from the Department of Anatomy & Neurobiology at UC Irvine School of Medicine, the new laboratory research describes startling insights into the substrates of memory and shows that these produce large male and female advantages in cognitively critical, everyday forms of learning.

The inquiry into sex differences in cognition dates back to the 19th century, sparking debates about whether observed disparities in memory and learning stem from biological or social influences. The Lynch Lab’s new study in the The Journal of Neuroscience, “Metabotropic NMDAR Signaling Contributes to Sex Differences in Synaptic Plasticity and Episodic Memory,” focused on long-term potentiation (LTP), a process essential for memory encoding where synapses — the connections between neurons — physically change to store information.

"What we have discovered is that there are surprisingly large differences in the synaptic mechanisms used by male and female rodents to encode a casual or episodic experience," said Lynch, a Psychiatry & Human Behavior professor who is a pioneer in the neurobiology of memory and has been investigating the complexities introduced by sex for nearly a decade.

The new discoveries were prompted by Le’s earlier work showing that the widely reported male advantage in spatial problems only appears after puberty; before that critical development time point, females outperformed males in remembering locations.

"The size of age-related shift in synaptic plasticity and learning was shocking but I cannot help but wonder if it’s simply part of how we change over the phases of life, though in this case with profound differences between the sexes,” said Le.

Additional studies by the group, which were published in Nature Neuroscience in 2022, explained why the female advantage in LTP and spatial memory disappears during puberty but left unanswered the complementary and critical question of why males improve over the same period.

It was then discovered that adult males use a specialized operation by the NMDA type of transmitter receptor to increase the potency of their synapses while females largely rely on estrogen for the same purpose. The transmitter receptor strategy is more efficient, which helps explain why males are faster than females at learning spatial relationships.

But are there advantages to the female strategy for generating and stabilizing memory-related changes to their brain connections? The group’s research confirmed that this is indeed the case. Female mice excel in those aspects of episodic memory that involve remembering the identities of the items and in recalling the sequence in which the items had occurred. The researchers found that females can handle longer lists than males, which gives them an advantage when processing the “what” and the “when” elements of an episode. This discovery helps to answer a fundamental mystery at the heart of what science says about sex differences in human learning.

“The overwhelming problem is you can measure differences but are these due to social variables or genuine differences in the brain,” said Lynch. “The rodent work now strongly suggests that a large part of the answer is found in the machinery used by brain cells to communicate with each other.”

The researchers can only speculate about the evolutionary pressures that could have led to male vs. female advantages in a fundamental variety of memory. Le suggested: "This adaptive mechanism could provide a species-level advantage, allowing groups to benefit from a mix of cognitive strengths.” In other words, cooperation between the sexes could combine different strengths for dealing with a complex world.

As awareness of these findings spreads, they could fundamentally alter perceptions of gender in cognitive science, highlighting a need for a nuanced approach to understanding learning differences in educational settings. Meanwhile, with further studies planned, the Lynch Lab aims to further explore the cellular mechanisms underlying these differences and to evaluate their effects on behavior.

"We are just beginning to scratch the surface of understanding how these synaptic differences manifest in cognition,” Lynch said. “This research not only challenges long-held beliefs but also prompts a reevaluation of how we think about learning and memory across genders."