Origins of “Rage” Identified in Brain

Study in mice may lead to better understanding of aggression in other animals, including humans.

Violent, unprovoked outbursts in male mice have been linked to changes in a brain structure tied to the control of anxiety and fear, according to a report by researchers from NYU Langone Medical Center to be published in the journal Current Biology online Feb. 11, 2016.

Damage or lost function in the animals’ midbrain wall structure — the lateral septum — was found to trigger a cascade of activity in other brain regions that produced “septal rage.” These sudden, violent acts, mostly attacks on other mice, have long been seen in rodents with a damaged lateral septum, and in some birds, researchers say.

“Our latest findings show how the lateral septum in mice plays a gatekeeping role, simultaneously ‘pushing down the brake’ and ‘lifting the foot off the accelerator’ of violent behavior,” says study senior investigator Dayu Lin, PhD, an assistant professor at NYU Langone’s Druckenmiller Neuroscience Institute.

The lateral septum, Lin notes, is physically connected to, and receives electrical signals from, the part of the brain that controls emotion and learning (the hippocampus). The lateral septum also projects into and receives signals from the brain region most broadly tied to aggression and hormone production (the hypothalamus).

Lin emphasizes that septal rage is not known to occur in humans, but that studying male aggression in mice might help to map the circuitry involved in controlling other forms of aggression, including violent behavior in humans.

Among the study’s key findings was that stimulating brain cells in the lateral septum controlled other brain cells, notably in a centrally located region of the hypothalamus, identified anatomically as the ventrolateral part of the ventromedial hypothalamus. Previous research by Lin had shown this brain region to be highly active during natural aggression but, until now, had not identified the other parts of the brain that interact with it in this context.

By “exciting” selected groups of brain cells with light from a surgically inserted probe, Lin and her colleagues changed the activity of cells in the lateral septum, and found that they could start, stop, and re-start aggressive outbursts in the study mice.

According to Lin, interrupting the connection between the lateral septum and ventromedial hypothalamus did not affect the mice’s sexual behavior, and did not in other experiments stop male mice from attempting to have sex with female mice. This is important, Lin says, because it demonstrates that two innate behaviors, aggression and sexual behavior, can be adjusted separately.

The scientists also found that when excited, lateral septum cells increased activity in one set of brain cells in the ventrolateral part of the ventromedial hypothalamus, even as they decreased activity in another nerve cell set in the same region. Indeed, the cells most active during mice attacks were those suppressed to the greatest degree during septal stimulation, while the cells suppressed during aggression were most active when the lateral septum was stimulated. Lin says this finding suggests that the lateral septum is a “smart” gatekeeper of aggression, suppressing attack-excited cells while activating attack-inhibited cells.

Image of the lateral septum in a mouse brain.
This is an image of mouse brain shows lateral septum (in green). Credit: Current Biology and Cell Press.

“Our research provides what we believe is the first evidence that the lateral septum directly ‘turns the volume up or down’ in aggression in male mice, and it establishes the first ties between this region and the other key brain regions involved in violent behavior,” says Lin.

The research team next plans to investigate which specific brain cells in the lateral septum control male aggression, and under what conditions they are activated to promote or halt the behavior. Lin says her long-term goal is to determine whether or not therapeutic means can be found to control aggression without compromising other social and cognitive functions.

[divider]About this neuroscience research[/divider]

Funding: Funding support for the latest experiments, which took five years to complete, was provided by the National Institute of Mental Health grant RO1-MH101377. Additional funding support was provided by the Ester A. and Joseph Klingenstein Fund, Whitehall Foundation, Sloan Foundation, McKnight Foundation, and Mather’s Foundation.

Besides Lin, other NYU Langone scientists involved in this research were Li Chin Wong, PhD; Li Wang, BS; James D’amour, PhD; Genghe Chen, BS; Takashi Yamaguchi, PhD; Brian Chang, BS; Hannah Bernstein, BS; Xuedi You, BS; James Feng, BS; and Robert Froemke, PhD.

Source: David March – NYU Langone Medical Center
Image Credit: The image is credited to Current Biology and Cell Press.
Original Research: Abstract for “Effective Modulation of Male Aggression through Lateral Septum to Medial Hypothalamus Projection” by Li Chin Wong, Li Wang, James A. D’Amour, Tomohiro Yumita, Genghe Chen, Takashi Yamaguchi, Brian C. Chang, Hannah Bernstein, Xuedi You, James E. Feng, Robert C. Froemke, and Dayu Lin in Current Biology. Published online February 11 2016 doi:10.1016/j.cub.2015.12.065


Abstract

Effective Modulation of Male Aggression through Lateral Septum to Medial Hypothalamus Projection

Highlights

•Inhibiting LS increases aggression, whereas its activation suppresses ongoing attack
•Activating the LS-VMHvl projection inhibits attack but not mounting behaviors
•LS sends monosynaptic GABAergic inputs to the VMHvl glutamatergic cells
•The LS-VMHvl pathway inhibits attack-excited cells but activates attack-inhibited cells

Summary
Aggression is a prevalent behavior in the animal kingdom that is used to settle competition for limited resources. Given the high risk associated with fighting, the central nervous system has evolved an active mechanism to modulate its expression. Lesioning the lateral septum (LS) is known to cause “septal rage,” a phenotype characterized by a dramatic increase in the frequency of attacks. To understand the circuit mechanism of LS-mediated modulation of aggression, we examined the influence of LS input on the cells in and around the ventrolateral part of the ventromedial hypothalamus (VMHvl)—a region required for male mouse aggression. We found that the inputs from the LS inhibited the attack-excited cells but surprisingly increased the overall activity of attack-inhibited cells. Furthermore, optogenetic activation of the projection from LS cells to the VMHvl terminated ongoing attacks immediately but had little effect on mounting. Thus, LS projection to the ventromedial hypothalamic area represents an effective pathway for suppressing male aggression.

“Effective Modulation of Male Aggression through Lateral Septum to Medial Hypothalamus Projection” by Li Chin Wong, Li Wang, James A. D’Amour, Tomohiro Yumita, Genghe Chen, Takashi Yamaguchi, Brian C. Chang, Hannah Bernstein, Xuedi You, James E. Feng, Robert C. Froemke, and Dayu Lin in Current Biology. Published online February 11 2016 doi:10.1016/j.cub.2015.12.065

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