Using advanced deep brain imaging techniques and optogenetics, the UNC scientists found that a small cluster of sex–hormone–sensitive neurons in the mouse hypothalamus are specialized for inducing mice to “notice” the opposite sex and trigger attraction.

This study, led by Garret D. Stuber, PhD, associate professor of psychiatry and cell biology & physiology, and Jenna A. McHenry, PhD, a postdoctoral research associate in Stuber’s lab, identified a hormone–sensitive circuit in the brain that controls social motivation in female mice.

The findings, reported in the journal Nature Neuroscience, illuminate the neural roots of opposite–sex social behavior in mammals, and may also be relevant to certain psychiatric illnesses.

In the study, Stuber and colleagues examined the medial preoptic area (mPOA) of the brain. This clump of neurons sits within the hypothalamus, an evolutionarily ancient structure at the bottom–center of the brain. Prior research showed that the mPOA is important for social and reproductive behavior in all vertebrate species studied from fish to human, but it has been unclear whether this area drives social motivation through circuit connections with reward systems in the brain.

The researchers focused on one of the mPOA’s major connections, through which it sends neural signals to another brain structure called the ventral tegmental area (VTA) – known to be a powerful contributor in motivating behavior and the release of the neurotransmitter dopamine.

The researchers injected the VTAs of female mice with special fluorescent beacon molecules that, like some viruses, tend to move “upstream” along nerve connections. When these tiny beacons reached the mPOA, they ended up highlighting VTA–projecting neurons that express a gene called neurotensin. Analyses of these VTA–projecting neurons showed that most of them also express estrogen receptors and are therefore likely to be sensitive to rises and falls of ovarian hormones in the mouse fertility cycle, also known as the estrus cycle.

The researchers next studied this specific set of mPOA neurons in living mice, which was a considerable challenge. The microscopy techniques that permit imaging of brain cells in awake mice generally can’t visualize anything deeper than a fraction of a millimeter below the brain‘s surface, whereas the mPOA is several millimeters deep. To get around this problem, Stuber’s team used tiny tubular lenses connected from their microscope, in effect, to the mPOA. With a technique known as two–photon calcium imaging, the scientists were then able to visualize the activity of mPOA neurons in awake, behaving female mice. To enhance the accuracy of the technique, the researchers used mice that had been genetically engineered so that only their mPOA neurotensin neurons could be imaged.

The team found that when the female mice were exposed to the odor of male mouse urine – but not the odor of female mouse urine or other attractive odors, like appetizing food – a large subset of the mPOA neurotensin neurons was excited into greater activity. The researchers also found that these neurons responded more robustly to male mouse urine when females had high circulating levels of estrogen or a combination of estrogen/progesterone, which surges before the mice become fertile.

“On the whole, the data suggest that these mPOA neurons help drive social attraction toward a potential mate,” Stuber said.

“While hormone–related changes in motivation are important for mating or maternal behavior in female mice, some atypical hormonal changes in women appear to underlie reproductive mood disorders, such as postpartum depression,” said McHenry, who is also a Fellow on the Postdoctoral Reproductive Mood Disorders Training Fellowship at UNC.

Stuber added, “The study of hormone–sensitive circuits that control motivational st