Aggression is essential to competing for limited resources and is observed in a wide range of animals. It is typically observed more frequently in males than in females, with some differences in aggressive behaviors between sexes, such as intensity, frequency, and pattern of motor actions. Given that aggression is more prevalent in males, our understanding of the neural basis for aggression has been more advanced in males by previous studies with relatively much less knowledge on female aggression.

Although the hypothalamus has been implicated in controlling aggression since the initial work of Walter Hess, a Nobel Prize winner, who evoked aggression by hypothalamic electric stimulation in 1930s, it was almost a century before Dayu Lin, MD, and David J. Anderson identified a specific nucleus, the ventromedial hypothalamus, ventrolateral part (VMHvl), as the aggression locus in 2011. They utilized optogenetics and pharmacogenetics to show that this small nucleus, consisting of only approximately 10,000 neurons in the mouse brain, is necessary and sufficient for male aggression. Moreover, the authors characterized natural neural activity in freely behaving animals and found a subset of cells encoding various phases of aggression (Lin et al., 2011).

Follow-up studies have further identified a subpopulation of neurons in the VMHvl expressing Esr1/PR as male aggression substrate (Yang et al., 2013; Lee et al., 2014). In contrast, the same functional manipulation experiments in those studies did not observe significant behavioral effects on female aggression, leading to the conclusion that VMHvl’s role in aggression is sexually dimorphic, and crucial for males but not for females. However, given that females’ aggression level is generally lower and more unstable than males’ aggression in previous studies, there remained a possibility that VMHvl’s engagement in female aggression was overlooked.

We explored and identified experimental conditions in which female aggression was reliably observed. Using those conditions, we demonstrated clearly that VMHvlEsr1+ cells are necessary and sufficient for female aggression. In addition, we observed aggression-related activity in VMHvlEsr1+ cells.

For 40 years, female VMHvl has been considered necessary for regulating female mating behaviors. That elicited an obvious question, “how could the female VMHvl regulate distinct social behaviors, aggression, and mating?” We utilized a variety of methodologies including c-Fos mapping, single-unit recording, neural tracing, and RNA-seq, and demonstrated that female VMHvl consisted of two anatomically/molecularly distinct subnuclei where aggression- and mating-relevant populations reside.

Note from the First Author

Our work received some media attention after publication, and a relatively naive and simplistic conclusion, namely that “aggression and sex overlap in males, but not in females,” is spreading more widely than the content of the paper. First, I would like to emphasize that this is not the main conclusion of our paper. Only the “not in females” aspect is supported by our data set.

Second, while it is clear from our study that aggression and mating populations in the female, but not male, VMHvl are topographically segregated, this does not mean that male aggression and mating are governed by the same or overlapping circuitry.

Third, our study has consistently observed that the aggression-related subnucleus, VMHpvlm, is activated during aggression independent of different female reproductive states and aggression targets. However, previous studies reporting higher overlap did not systematically test this region as in our study.

Fourth, while motor actions of male aggression and mating (e.g., mounting) have more similarities (e.g., approach, rush), motor actions of female aggression and mating (e.g., lordosis) have fewer similarities. Thus, in terminology, the same word “mate” is often used for both sexes, but it may differ in the brain. Therefore, it is possible that a higher overlap of aggression and mating populations in male VMHvl may reflect an aggressive component in male mating behaviors (e.g., mounting).

—Koichi Hashikawa, PhD

Read the paper “Esr1+ cells in the ventromedial hypothalamus control female aggression” in Nature Neuroscience, published September 18, 2017.