‘Hidden’ sex differences in neurological reward pathways suggest opportunities for improved psychiatric therapies

a new study in the Journal of Neuroscience has uncovered underlying sex differences in the molecular pathways that drive reward-related behavior. In particular, the study found differences and similarities in the way men and women strengthened connections between two brain regions—the hippocampus and the nucleus accumbens—that are involved in reward signaling.

Both men and women suffer from conditions involving these mechanisms, such as depression and substance abuse. However, the presentation and prevalence of these conditions can vary by gender, and certain standard treatments are, on average, more effective in men or women. The new paper’s findings encourage further research to determine whether the molecular differences the authors discovered could underlie differences in disease progression or medication response, which could ultimately lead to more effective treatments for mental disorders.

Although this is changing, historically much more research has been done on male subjects (both in humans and in animal models), so “we just don’t know much about female brains and the differences between male and female brains,” says Tara LeGates . , assistant professor of biological sciences at the University of Maryland, Baltimore County (UMBC) and senior author of the new paper. She has seen an increase in the number of research groups working on gender differences, and is hopeful that their work will continue to yield actionable results that will lead to better outcomes for patients.

LeGates’ previous work used optogeneticswhich allows researchers to selectively stimulate certain neurons with light, to show that strengthening connections between two brain regions – the hippocampus and nucleus accumbens – is rewarding for mice. The hippocampus is best known for its role in memory and learning, but also for its emotional responses. The nucleus accumbens is a “major reward center that integrates information from different brain regions to drive goal-directed behavior,” LeGates explains.

The hippocampus-nucleus accumbens pathway also exists in humans and is involved in reward processes in the same way as in mice, LeGates said. This makes this research very applicable to human studies.

Surprising gender differences

The researchers used electrophysiology, where they observe under a microscope how living cells respond to stimulation of other brain areas. In this way, they came to conclusions about how men and women strengthen the connections between the hippocampus and the nucleus accumbens.

LeGates and lead author Ashley Copenhaver, a Ph.D. candidate in LeGates’ research group, found that mice of both sexes relied on the activation of a particular kinase protein, CAMKII, to facilitate reward-related behavior. Neither sex required dopamine activation, which was surprising, because dopamine is often involved in reward-related signaling.

The neurotransmitter receptor NMDA is also often involved in reward pathways and strengthening connections between brain regions. The researchers found that male mice used NMDA receptors to strengthen connections between the hippocampus and nucleus accumbens, but females did not. Instead, the females used a different channel for calcium ions and an estrogen receptor.

“We were really surprised to find this sex difference,” says Copenhaver. Because the NMDA receptor pathway is so widely thought to play a role, “it was just really fascinating to see that not only do men and women use different mechanisms, but one uses this NMDA receptor-dependent mechanism, while the women do not ,” says Copenhaver. “They use this different, non-canonical pathway—these alternate calcium ion channels. We didn’t expect that at all.”

Revealing these differences and similarities is an important step toward making a real difference in the medical care of patients.

“If you want to understand sensitivity and develop better treatments, you need to understand the mechanisms at these synapses,” says LeGates. “You have to understand what’s happening, and you have to understand it in every gender.”

New approaches for better results

In the early 1990s, legislation required that human studies include both men and women, but it wasn’t until 2015 that the National Institutes of Health established such a standard. policy that animal studies, which are often used to justify further human research, should include both sexes. As a result, there are still many open questions about how the physiology of men and women differs, and many opportunities to make contributions with significant biomedical impact.

LeGates became more interested in studying sex differences in brain function during her postdoctoral fellowship at the University of Maryland School of Medicine. “I think one of the problems with doing research on sex differences is that you try to use things that are optimized to work in male animals,” says LeGates, “and then when that doesn’t work in females, it’s like like, ‘Oh, it’s unreliable.’ But what if the tests were optimized in men? that is why don’t they work on women?”

“I wanted to pursue that and appreciate the differences between men and women and not try to force them into the exact same paradigms,” she adds. “Maybe we need to come up with new paradigms and a new way to study them.”