Exciting new work published in Nature Neuroscience by Minakuchi and colleagues from the Falkner lab shows how separate inputs into a single brain region can independently affect aggression. Specifically, it explores the role of inputs into a part of the mouse hypothalamus (the ventromedial hypothalamus ventrolateral area, which we will refer to as VMHvl). Previous research has shown that VMHvI activity is correlated with aggressive behaviors. For example, there is increased activity in VMHvI when an animal investigates or engages in aggression towards a fellow animal. Stimulation of VMHvI also promotes attacks in both males and females. However, it remained unclear whether VHMvl activity was correlated specifically with aggressive actions, or with aggressive motivation more broadly.

The structure of the VHMvl also raises interesting questions about its functionality which, before now, had not been addressed. First, the internal structure of the VHMvl core is arranged in such a way that local populations of neurons may perform distinct functions. Second, VHMvl can be thought of as receiving two channels of inputs from different regions: long-range inputs from the medial preoptic area (MPO) and short-range inputs from a peri-VMHvl zone, which the authors term the ‘VMHvl shell’. Together, these anatomical configurations (separable populations inside VMHvI and distinct inputs) leave open the possibility of separate aggression mechanisms co-occurring within the VHMvl.

To explore the role of VHMvl in aggressive motivation and action, the experimenters investigated the temporal dynamics of VHMvl neurons during aggressive states. They used two paradigms to explore aggression in male mice. In one case, called “free aggression,” the mouse of interest could freely attack another male mouse moving about the cage. In another case, which we can call “constrained aggression,” the mouse of interest had to activate a trigger (“nosepoke”) in order to gain access to part of the cage containing a second, tethered mouse.  The mouse of interest could then attack the tethered mouse for a brief duration of time. 

VMHvl neurons encode an aggressive motivation-to-action sequence. When separating the time surrounding aggressive behavior into behaviorally relevant periods (attack onset, nose-poke, male-in and male-out time), researchers found that distinct populations of VHMvl neurons had peak activity during different periods of the motivation-to-action sequence. Compellingly, these neurons showed the same temporally selective activity in both the free aggression and constrained aggression paradigms.

Local and long-range inhibitory inputs target heterogeneous VMHvl neurons. The researchers did not find evidence to support the notion that specific inputs (long-range and short-range) targeted specific subsets of VMHvI neurons. However, they found that long-range inputs had the strongest impact on neurons in anterior VMHvI, and that VHMvl core neurons can be considered as two groups based on their anterior-posterior location. 

Neurons modulated by local and long-range inputs have distinct temporal profiles. Temporally, the researchers found that some neurons are activated earlier in the motivation-action sequence than others. Specifically, MPO-modulated neurons are active first in the sequence, and VHMvl-shell-modulated neurons are activated last.

Local and long-range inputs to the VMHvl have distinct activity profiles. Comparing the temporal activity of different neurons with respect to the timecourse of aggressive behaviors, the researchers found that VHMvl-shell-modulated neurons were most active at the onset of an attack, whereas MPO-modulated neurons were most active as an attack was ending.  

Closed-loop optogenetic activation of local and long-range inhibitory inputs. Finally, the researchers found a dissociation between aggressive motivation and aggressive action, insofar as long-range inhibition decreased aggressive motivation but not aggressive action, whereas short-range inhibitory inputs decreased aggressive action without generally changing aggressive motivational states.

In conclusion, this work demonstrates a fascinating variety of ways in which different inhibitory inputs to the hypothalamus separably impact aggressive motivation and aggressive actions.

Minakuchi, T., Guthman, E. M., Acharya, P., Hinson, J., Fleming, W., Witten, I. B., ... & Falkner, A. L. (2024). Independent inhibitory control mechanisms for aggressive motivation and action. Nature Neuroscience, 1-14.