Summary: A new mouse study reveals females have a three fold higher abundance of EP3, in addition to elevated levels of genes associated with major depressive disorder in the locus coeruleus.
Source: Cell Press.
Using male individuals has long been a tradition in scientific mice studies. But new research enforces the importance of using a balanced population of male and female mice.
In a paper published May 22 in the journal Cell Reports, scientists studying the locus coeruleus brain structure in mice unexpectedly found substantial differences in the molecular structures of this part of the brain between male and female mice. They found that female mice had a three-fold higher abundance of the prostaglandin receptor EP3 (PTGER3), as well as elevated levels of Slc6a15 and Lin28b, both genes in regions associated with major depressive disorder (MDD).
“This is particularly interesting because many of the same diseases that are targeted by drugs that work on this structure, such as ADHD or depression, also really have differences in prevalence between men and women in the general population,” says senior author Joseph Dougherty of the Department of Genetics at Washington University School of Medicine in St. Louis.
Women are usually two to four times more likely to suffer from depression or anxiety, and ADHD is more commonly found in males. “We thought it really striking that there was this structure in the brain that is the target of these drugs that also has this very profound molecular-level difference between males and females,” he says.
The researchers initially set out to study gene expression in the mouse locus coeruleus, a small nucleus of neurons in the brain that is the primary source for the neurotransmitter norepinephrine. Norepinephrine is a major target of many drugs to treat disorders like ADHD and depression.
“We are the first to take a genome-wide view of all of the genes utilized in this small structure,” adds Dougherty. In this study, he and his team studied mouse noradrenergic neurons found in the locus coeruleus in vivo and identified over 3,000 transcripts it expressed.
Because Dougherty follows current practices mandated by the National Institutes of Health since 2016, his experiments included a balanced population of both male and female mice in the experiment. When they studied the gene expression of the mice, they unexpectedly found these differences in the transcriptome between the male and female mice in this part of the brain structure.
This finding prodded the researchers to test whether this molecular difference had any functional consequences. They next delivered sulprostone, a drug targeting PTGER3, to see if they could influence its activity. When both male and female mice received sulprostone directly to the locus coeruleus via cannula after a simulated stress event, only the females responded. “We could turn off a stress-induced anxiety like behavior, specifically in the female mice, but not in the males,” says Dougherty, who believes that this sex-based difference may help inform how to conduct experimentation around mood disorders and development of therapeutics.
Going forward, Dougherty plans on researching whether these molecular and functional differences in the locus coeruleus of mice are duplicated in the human brain.
Funding: This work was supported by grants from the National Institutes of Health, the Simons Foundation, the Brain and Behavior Research Foundation, the Ludwig Cancer Research, the Biotechnology and Biological Sciences Research Council, and a CDI Microgrant from the Washington University Center for Cellular Imaging.
Source: Joseph Caputo – Cell Press
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Bernard Mulvey.
Original Research: Open access research for “Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus” by Bernard Mulvey, Dionnet L. Bhatti, Sandeep Gyawali, Allison M. Lake, Skirmantas Kriaucionis, Christopher P. Ford, Michael R. Bruchas, Nathaniel Heintz, and Joseph D. Dougherty in Cell Reports. Published May 22 2018.
Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus
• More than 3,000 genes highly expressed in adult mouse locus coeruleus (LC) are identified
•Norepinephrine neurons of LC sex-differentially express >100 genes
•PGE2 receptor Ptger3 is more highly expressed in female LC
•PTGER3 agonism inhibits LC firing and LC-driven anxiety behavior only in female mice
Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females—which we leverage to illustrate the behavioral and pharmacologic relevance of these findings—and of Slc6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease.