Serotonin shapes social reminiscence indicators | Spectrum
Activation of serotonin receptors in the medial septum, a region along the midline of the brain, reverses social memory deficits in a mouse model of autism, according to new research.
The results show a new mechanism by which serotonin shapes social function and suggest that the effects of the chemical messenger can vary depending on the region of the brain.
“It’s a tour-de-force study,” says Weizhe Hong, an adjunct professor of neurobiology and biological chemistry at the University of California at Los Angeles, who was not involved in the work.
Social memory – a person’s ability to remember who they know and how – is an integral part of social behavior and can be impaired in people with autism. A region of the hippocampus called dorsal CA2 is linked to social memory, but it was previously unclear how cells in the region receive information about social stimuli at all.
The new research traces the source to the medial septum, which carries nerve signals to the hippocampus, and identifies serotonin as a modulator of those signals. The release of serotonin improves sociability in mice and is dysfunctional in a mouse model of autism, previous studies have shown.
With serotonin now linked to several aspects of social function, “it seems to me that if you have an interest in autism this should be a focus,” says lead researcher Robert Malenka, professor of psychiatry and behavioral science at Stanford University California.
Malenka and his colleagues have genetically modified mice so that activated neurons fluoresce red after an active ingredient has been injected into brain slices that are viewed under a microscope. Then they put the animals in an empty cage or one with a novel mouse or object and, after each situation, counted the number of marked cells in regions of the brain known to send signals to CA2.
Courtesy Ting Wu / Stanford University
Neurons in the medial septum in particular showed an increase in red fluorescent cells after a genetically engineered mouse interacted with a novel mouse, suggesting that social memory had formed, the team found.
They then used a strategy called chemogenetics to modulate the activity of these neurons. They constructed a second group of mice so that these neurons produce designer receptors that only bind to a specific drug. Injection of the drug into the medial septum of mice inhibited the activity of the neurons and caused the animals to lose their usual fondness for interacting with a new mouse over a familiar one.
Using the same chemogenetic strategy, the researchers equipped mice with drug-sensitive receptors that activate the same neurons instead of inhibiting them. Control mice retained social memories for at least 10 minutes after being separated from another animal, but not after two hours. However, mice treated with the activating drug preferred the new mice for at least 24 hours – suggesting that the treatment extended their social memory.
Neurons in the medial septum have receptors for both serotonin and the hormone oxytocin. The researchers found that infusing a drug into a mouse’s medial septum that blocks a certain type of serotonin receptor decreased the activity of neurons in the area and affected the animal’s performance in a social memory task. Alternatively, infusing a drug that activates serotonin receptors improves social memory. On the other hand, drugs that block oxytocin receptors had no effect.
“Everything fits together perfectly,” says Malenka.
The team then injected the serotonin activator called CP93129 into the medial septum of mice that lack copies of the genes coding for NLGN 1, 2, and 3 that have been linked to autism. The treatment improved the animals’ social memory, but did not affect their sociability or object memory deficits, the team found. The results were published in Nature this month.
Conclusions on the collateral:
Some researchers are not convinced that the newly identified circuit has direct links to autism.
“The lack of effects of serotonergic manipulation of the medial septum on baseline sociability appears to reduce the relevance of the medial septum-dorsal CA2 pathway to autism,” said George Anderson, senior researcher in child psychiatry at Yale University. “An important side conclusion of the study is that the role of serotonin in social behavior and in other behaviors relevant to autism is very complex.”
Malenka and his colleagues agree that the work paints a more complicated picture of the role of serotonin in the brain. For example, previous research by the group showed that releasing serotonin to another region of the brain, called the nucleus accumbens, can increase a mouse’s social motivation.
It shows “that there is no clear-cut conclusion about what serotonin does,” says study researcher Xiaoting Wu, a postdoctoral fellow in Malenka’s laboratory. Instead, the neurotransmitter appears to be “very tightly coupled to the region of the brain into which it is being released,” she says. “If the serotonin system is dysregulated, it can have an impact not only on social deficits in motivation, but also on deficits in social memory.”
Going forward, the team plans to measure gene expression levels in the medial septal neurons that project onto CA2 in order to identify other neuromodulators that may affect social behavior.
Quote this article: https://doi.org/10.53053/IJIG7693