Sex hormones alter the development of certain brain structures during puberty

Using advanced imaging technology, Carnegie Mellon University scientist Eric Ahrens and co-investigators have conducted the first systematic examination of developmental and sex-associated changes in adolescent and adult mouse brains to reveal fundamental differences in key brain structures, such as those important for emotions, learning, and memory.

The results, in press with NeuroImage, show that sex hormones alter the development of certain brain structures during puberty and that these effects persist into adulthood.

The findings provide a much truer representation of how circulating hormones affect brain structures than could be derived from human imaging for several reasons, according to Ahrens. The animals studied were nearly genetically identical and reared in the same environment — factors that cannot be controlled in human studies. And the imaging technology, magnetic resonance microscopy, allows high resolution, 3D imaging in the intact, tiny mouse brain.

"The finding that specific brain structures change at puberty under the influence of sex hormones should help scientists understand how levels of sex hormones alter the brain's development," said Ahrens, assistant professor of biological sciences. "Researchers could artificially manipulate sex hormones and then use MRM technology to see how the hormones affect brain structures in animal models."

"This information also may be critical for modeling human neurologic diseases such as Parkinson's and neuropsychiatric disorders such as schizophrenia so that we can develop more effective therapies," Ahrens said. "In addition, these results may reveal how structural sex-associated brain differences influence behavior and cognition."

Ahrens and Kyoko Koshibu, a graduate student, captured images of intact mouse brains using magnetic resonance microscopy (MRM), an extremely high-resolution magnetic resonance imaging (MRI) technique. Carnegie Mellon is one of few groups nationwide with the capability to perform MRM.

Koshibu, who did much of the data analysis, recently completed her doctoral work in the department of neurobiology at the University of Pittsburgh while working at the Center for the Neural Basis of Cognition, a joint University of Pittburgh-Carnegie Mellon initiative.

To date, only a limited number of quantitative 3D analyses of adult mouse brain structures have been conducted, due in part to the laborious process required to obtain such data. Using conventional histology, it would take months to section brains, measure various structures and perform a 3D reconstruction, whereas Koshibu obtained statistically relevant results in a matter of weeks with the MRM technique. Moreover, extreme manipulations of the brain needed to carry out histological investigations inevitably distort the tissue, which in turn corrupts the true brain structure, according to Ahrens.

"With MRM, we are able to use intact brains, revealing a much better image of structures in the whole brain compared to widely accepted histological techniques," Ahrens said.

MRM is based on the same principles as MRI, an imaging technology that visualizes the body's internal structures. Both MRI and MRM make use of nuclear magnetic resonance, a phenomena observed in the nuclei of atoms when they are exposed to a magnetic field and pulses of radio waves. MRM uses stronger magnets to capture images at a resolution 10-100 times finer than conventional MRI.

Using MRM, Ahrens and his colleagues imaged the brains of male and female mice, aged 1 month (adolescent) and 3 months (adult). Koshibu used a software program to digitally isolate the whole brain and specific structures from the MRM data. These include the amygdala, hippocampus, striatum, and lateral and third ventricles, structures that have been widely studied in humans because of their implications in cognition and neuropsychiatric disorders. A comparison of the 3D reconstructions of each structure revealed sex-specific and age-related structural differences in the hippocampus, amygdala and ventricles but none in the striatum.

The work was funded by the National Multiple Sclerosis Society, the National Science Foundation and the National Institutes of Health.


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