Journal Club

Our Journal Club highlights high-profile work from our young scientists-in-training and discusses the impact of the Neuroscience Institute's research on the field, our understanding of the brain, and potential breakthroughs that may translate into improved patient care.

The circuitry of sex and aggression

by Koichi Hashikawa, PhD

Aggression is essential for competing over 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 took almost a century before Lin and Anderson identified a specific nucleus, ventromedial hypothalamus, ventrolateral part (VMHvl) as the aggression locus in 2011. They utilized optogenetic and pharmacogenetics to show that this small nucleus, consisting only ~10000 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, concluding that VMHvl’s role in aggression is sexually dimorphic, 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 (table1). In addition, we observed that aggression related activity in VMHvlEsr1+ cells.

Historically, female VMHvl has been considered for regulating female mating behaviors for the last 40 years. That elicited an obvious question, “how could the female VMHvl regulate distinct social behaviors, aggression and mating?” We utilized a variety of methodologies, c-Fos mapping, single unit recording, neural tracing and RNAseq and demonstrated that female VMHvl consisted of two anatomically/molecularly distinct subnuclei where aggression and mating relevant populations reside. (Figure 1)

Note from the first author

Our work has received some media attention after publication and a relatively naïve 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. I would like to emphasize that: 1) this is not our main conclusion of the paper. Only the “not in females” aspect is supported by our data set,   2) 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 conclude that male aggression/mating are governed by the same/overlapped circuitry, 3) Our study has consistently observed that the aggression related subnucleus (VMHpvlm) is activated during aggression, independent of different female reproductive states and different aggression targets. However, previous studies reporting higher overlap did not systematically test this region as in our study, and4) 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 much 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, Yoshiko Hashikawa, Robin Tremblay, Jiaxing Zhang, James E Feng, Alexander Sabol, Walter T Piper, Hyosang Lee, Bernardo Rudy & Dayu Lin. Esr1+ cells in the ventromedial hypothalamus control female aggression. Nature Neuroscience, Published online 9/18/2017.

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