Summary: Social experience, especially interactions with females, is crucial for forming distinct, sex-specific neural populations in the ventromedial hypothalamus (VMH) and for triggering aggression in male mice, a new Caltech study shows.
Source: Caltech
Adult male mice display a narrow set of innate social behaviors: they attempt to mate with females and tend to attack other males. Because these patterns appear without training, neuroscientists long assumed the underlying brain circuits were strictly “hardwired” — genetically predetermined and largely inflexible.
New research from Caltech challenges that assumption. The team found that the neural populations linked to sex recognition and innate social actions in the ventromedial hypothalamus are shaped by social experience and show surprising plasticity.
The study, led by David Anderson (Seymour Benzer Professor of Biology; Tianqiao and Chrissy Chen Institute for Neuroscience Leadership Chair; Howard Hughes Medical Institute Investigator; director of the Tianqiao and Chrissy Chen Institute for Neuroscience), used genetically modified mice whose neurons in a VMH subregion light up when active. Researchers visualized these signals by implanting a thin glass lens into the hypothalamus and recording fluorescence with a lightweight, head-mounted miniature microscope developed by a collaborator. This approach made it possible to watch neural ensembles fire in real time while mice interacted.
In experiments using standard resident/intruder tests, socially and sexually experienced resident males were observed in their home cages as single intruders (either male or female) were introduced. The researchers discovered two distinct, minimally overlapping sets of VMH neurons activated depending on whether the intruder was male or female. Although the neurons were spatially intermixed, the male- and female-responsive ensembles were largely separate — a pattern that allowed the researchers to predict, from the activation patterns alone, whether a resident was interacting with a male or a female.
These results initially seemed to support the hardwired model. To test that idea directly, the team examined naïve males that had been isolated from weaning and had no prior social or sexual experience. If sex-specific representations were innate, these naïve animals should also show separated neural populations on first encounters with male or female intruders. Instead, the naïve mice showed overlapping neural activation for male and female intruders and displayed little mating or fighting behavior initially.
Only after repeated social exposure did the separation emerge. Following a regimen of short daily interactions (two minutes, five times per day, across three days), the naïve males began to develop distinct male- versus female-responsive ensembles in the VMH. This neural divergence coincided with the appearance of typical social behaviors: aggression toward males and mating behavior toward females.
Further tests revealed that interactions with females played a particularly important role. As little as 30 minutes of social contact with a female was sufficient to induce aggressive responses toward males 24 hours later and to promote the formation of separate male- and female-specific neural ensembles in the VMH. By contrast, naïve males exposed only to other males failed to develop these behavioral or neural distinctions.
“The mice do not have sex-specific neurons from birth,” said co-first author Ryan Remedios, a postdoctoral scholar in biology and biological engineering. “The separation forms as a consequence of social experience, specifically from social experience with a female.”
“This is an unexpected discovery,” added co-first author Ann Kennedy, a Caltech postdoctoral scholar in biology and biological engineering. “We used to think of the ventromedial hypothalamus as an evolutionarily ancient, largely fixed region. Our study shows it can perform computation and exhibit plasticity.”
Anderson emphasizes the study’s relevance to the longstanding nature-versus-nurture question. “These results reveal that even circuitry governing supposedly innate behaviors is not purely hardwired,” he said. “They raise important questions about how specific social experiences — in this case, interaction with females — reshape patterns of brain activity to promote aggression and mating behaviors.”
He also noted the broader biological significance of the close anatomical relationship between cells encoding sex and aggression. “These primitive behaviors are essential for survival,” Anderson said. He added a cautious remark on human relevance: while the findings raise provocative questions about whether aberrant coupling of sexual and aggressive circuits could underlie certain violent sexual behaviors, any clinical applications or therapies remain speculative and are far in the future.
Funding: National Institutes of Health, the Gordon and Betty Moore Foundation, the Ellison Medical Foundation, the Simons Foundation, the Harry Frank Guggenheim Foundation, the Helen Hay Whitney Foundation, the National Science Foundation, and L’Oréal USA For Women in Science.
Source and Publisher: Caltech; content organized by NeuroscienceNews.com.
Image credit: Illustrative image credited to NeuroscienceNews.com.
Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex
All animals display innate behaviors that do not require training. Whether these behaviors are supported by anatomically separate or genetically specified neural pathways has been uncertain. This study shows that neural representations in the mouse hypothalamus that guide innate social actions are shaped by social experience. Esr1-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) regulate mating and fighting in rodents. Using microendoscopic imaging of Esr1+ neuronal activity, researchers found that sexually experienced males exhibited divergent neural ensembles that encoded male versus female conspecifics. In contrast, inexperienced males responded to both sexes with overlapping populations of neurons. Ensemble divergence developed alongside social and sexual experience. Mice permitted only to investigate but not to mount or attack did not show this separation. Notably, 30 minutes of sexual experience with a female was sufficient to drive ensemble separation and to trigger attack behavior 24 hours later. These findings reveal an unexpected experience-dependent component to hypothalamic circuits that control innate social behaviors, demonstrating plasticity and dynamic coding in a deep subcortical structure traditionally viewed as hardwired.
Remedios, R., Kennedy, A., Zelikowsky, M., Grewe, B. F., Schnitzer, M. J., & Anderson, D. J. Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex. Published online October 18, 2017.