Identify the neuronal link between gut bacteria and social behavior in mice

Could the germs that live inside our bodies affect our ability to socialize and make friends? Research over the past few decades suggests that the answer – for mice – is yes.

Research has shown that the communities of bacteria that live in a mouse’s gut are essential for animals to exhibit normal social behavior with other mice. Mice that have been bred to be germ-free, without a gut microbiome, display significant antisocial behaviors, such as avoiding a foreign mouse rather than interacting with it. How do microbes influence an animal’s behavior? In other words, what is the chain of events that unfold at the molecular and cellular levels, from gut bacteria to the brain to behavioral changes?

Now, a new study has identified a specific circuit of neurons that is directly influenced by the gut microbiome and is subsequently responsible for antisocial behavior in mice lacking a gut microbiome. The transplants of feces from mice with healthy gut microbiomes into these germ-free mice were sufficient to modify the activity of these neurons and thus improve their social behavior. Researchers have also identified a specific bacterial species that can increase sociability.

Identifying the interactions between gut microbes, neurons, and body-wide health effects (such as changes in behavior) may be an important avenue of research on how one day to help improve social deficits, such as those associated with depression and autism. Current practices for dealing with these types of problems include the prescription of pharmaceuticals, such as antidepressants and anxiolytics. However, it is difficult to get these drugs to get to the right areas of the brain at the right concentrations, and much of the drug is found throughout the body. Understanding the gut-brain connections adds to the evidence that neuropsychiatric disorders can be indirectly ameliorated by processing the gut microbiome, which is much easier to access pharmaceutically than the brain.

The research was carried out mainly in the laboratory of Sarkis Mazmanian, Luis B. and Nelly Soux Professor of microbiology and researcher at the Heritage Medical Research Institute. An article describing the study appears in the journal Nature June 30.

It had previously been shown that, chemically, germ-free mice have significantly higher levels of the hormone corticosterone (the analogue of the so-called stress hormone, cortisol, in humans) than mice. mice with healthy microbiomes. The team of researchers, led by former Mazmanian lab postdoctoral researcher Wei-Li Wu, aimed to identify neurons that were both affected by corticosterone and played a role in social behavior.

“By changing the microbiome of the mouse, we were able to change corticosterone levels: less microbiome means more stress hormone,” explains Mazmanian. “There are a lot of neurons in the body that respond to corticosterone – called glucocorticoid receptor positive neurons – and we wanted to know which cell populations and brain regions were then responsible for the altered social behaviors in germless mice?”

After identifying several subsets of neurons in the brain involving stress control, the team used chemical and genetic tools to artificially prevent corticosterone from activating these neurons in mice without a microbiome. These mice, despite the lack of a gut microbiome, were able to exhibit more normal social behavior because their neurons did not respond to the stress hormone.

So what was in the gut bacteria – or the lack of it – that caused corticosterone levels to spike in the first place? To address this problem, the team performed fecal transplants from wild-type mice with normal gut microbiota into germ-free mice. These mice then showed decreased corticosterone levels and more normal social behavior. The team then systematically identified a species of bacteria responsible for this improvement, namely Enterococcus faecalis. Germless mice that were colonized by E. faecalis showed improved social behavior and lower corticosterone levels. The mechanisms by which E. faecalis is able to arbitrate this improvement will be the subject of future research.

“A number of studies have shown that the gut microbiome impacts complex behaviors in mice, such as sociability. The underlying neural circuits that mediate the influence of the microbiome on behavior had not been discovered previously. gut-brain connection, ”says Mazmanian. Conceptually, the results lay the groundwork for exploring similar effects in humans.

Wu is now a faculty member at National Cheng Kung University of Taiwan. Future directions for this research include a closer look at the host-bacteria relationship, identifying the molecular signals produced by gut microbes and how these signals influence the host. Mazmanian and Wu plan to continue their collaboration.

“Our study benefited enormously from a number of collaborations, including critical contributions from the laboratories of Viviana Gradinaru and Rustem Ismagilov at Caltech,” Mazmanian said.

The article is titled “The microbiota regulates social behavior via stress response neurons in the brain.” Wei-Li Wu is the first author of the study. In addition to Mazmanian, Caltech’s co-authors are former assistant research technician Mark Adame; graduate student Jacob Barlow; former Mazmanian laboratory postdoctoral researcher Gil Sharon; former graduate student Catherine Schretter (PhD ’19); postdoctoral researcher Brittany Needham, former undergraduate Madelyn Wang (BS ’19); graduate students Weiyi Tang, James Ousey and Reem Abdel-Haq; former research associate Keith Beadle; Viviana Gradinaru (BS ’05), professor of neuroscience and biological engineering, researcher at the Heritage Medical Research Institute and director of the Center for Molecular and Cellular Neuroscience at the T&C Chen Institute for Neuroscience; and Roustem Ismagilov, Ethel Wilson Bowles and Robert Bowles professor of chemistry and chemical engineering and director of the Jacobs Institute for Molecular Engineering for Medicine. Additional co-authors are Chia-Wei Liou, Tzu-Ting Lai, Yuan-Yuan Lin, and Tzu-Hsuan Yao from National Cheng Kung University of Taiwan. Funding was provided by Taiwan Ministry of Science and Technology, Higher Education Sprout Project, Ministry of Education at the headquarters of academic advancement; a National Institutes of Health (NIH) Undergraduate Biotechnology Training Scholarship; the National Science Foundation Graduate Research Fellowship Program; the Jacobs Institute for Molecular Engineering for Medicine, the Kenneth Rainin Foundation Innovator Award; and Lynda and Blaine Fetter, Charlie Trimble (BS ’63, MS ’64), the Heritage Medical Research Institute and the NIH. Sarkis Mazmanian is a faculty member affiliated with the Tianqiao and Chrissy Chen Neuroscience Institute at Caltech.