Many of us have witnessed bullying or even was once a victim ourselves. We may remember seeming a cornered victim angrily fighting back against the bully. We can empathize with this person because his or her aggression is “reactive” to the threats. In contrast, “proactive aggression” –as often observed in many bullies– is intentional, independent of external cues and sometimes motivated by aggression itself as a reward. This makes us wonder: what drives a person to hurt another person, unprovoked? While most of past research addresses reactive aggression, little is known about the neural mechanisms of self-initiated aggression. Dr. Dayu Lin, an assistant professor at NYU Langone medical center and an expert of the aggression circuits, sought to unravel the mechanisms that drive aggression-seeking behaviors in a recent study published in Nature Neuroscience.

The Hypothalamus is a brain area that governs our basic survival needs, such as hunger, thirst, body temperature, sleep, sex and aggression. Dr. Lin’s research focuses on the ventrolateral part of the ventromedial hypothalamus (VMHvl), a region previously found to be critical for aggression in male mice. Silencing the VMHvl reduces inter-male aggression, while the stimulation promotes the attack toward other males and even females. An interesting question then would be: does stimulating the VMHvl trigger attack itself or does it build up the motivation to attack?

figure 1

Given resident intruder test­­, the most commonly used aggression assay in which an intruder is added to the home cage of the subject as an external cue, it mainly tests reactive aggression and it is difficult to address the motivation to attack. Using a modified self-initiated aggression (SIA) task (Fig. 1b), researchers in Dr. Lin’s lab separate the aggression-seeking phase from the phase of attack, thus can explore the motivational aspect of aggression . In each session, a male mouse was allowed to freely choose between two nosepoke ports: the mouse would receive free access to a submissive mouse (following a brief waiting period) if it poked the “social port” instead of the “null port”. After training, more than a half (56.6%) of the subjects quickly learned to prefer the social port and has become highly aggressive, attacking the submissive male for most of the trials­­–this recapitulates some core features of proactive aggression.

figure 2.png

To understand the role of the VMHvl in each phase of aggression, the authors implanted electrodes to record the neuronal activities. They found that the neurons have different activation patterns in regard to distinct phases of aggression. For instance, the neuron in Figure 2a fires only when the submissive male is present, while other neurons (Fig. 2b-e) are activated also during the aggression-seeking phase. Figure 2g demonstrates that the activities of subpopulations of neurons peak at different phases (poke/wait/interaction), indicating different populations of VMHvl neurons are relevant to various components of aggression.

To track how VMHvl population activity change along the way animals learn the behavior, the authors use fiber photometry to visualize and measure the change of intracellular calcium. They found that early in training, the population activity only increased in the interaction phase, whereas during late training a robust increase in the population activity was already observed in the aggression-seeking phase, even before poking the port. This result suggests VMHvl neurons undergoes a learning-dependent change in plasticity as the mice learn to become proactively aggressive.

Picture3

To directly test the functional significance of VMHvl neurons in aggression-seeking, the author further silence VMHvl neurons by expressing inhibitory engineered receptors (DREADDi) or stimulate VMHvl neurons using optogenetics. They found that inactivation of the VMHvl reduces aggression-seeking behaviors (Fig 3f.) while stimulation of the VMHvl accelerates aggression-seeking by reducing poking latency (Fig. 3b-d).

Overall, these findings suggest the VMHvl can mediate both aggression-seeking and the action of attack. Dr. Lin’s research has brought new insights to the understanding of the aggression circuits ­– not only by identifying the VMHvl to be critical for proactive aggression, but also demonstrating its dual role in both triggering a behavior and modulating the motivational state to generate the behavior.

 

Please come join us on Tuesday May 3rd, at 4pm in the CNCB  Marilyn Farquhar Seminar Room to hear more about this story from Dr. Dayu Lin!

 

 

Sharon Huang is a first-year student in the neurosciences graduate program currently rotating in Dr. Xin Jin’s lab. Her scientific interests center around how neural circuits dictate social behaviors.

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