Do you anger easily at dusk? So do most other people (and mice)

You know the scenario – after a hard day at work, sometimes nothing sounds better than plopping down on the couch and relaxing in peace and quiet. Instead, you get home and are irritated to find that one of your roommates has left dishes piling up in the sink, and the other one wants to emotionally unload on you about a recent argument with a mutual friend. At any other time of day you might be able to let these things go, but right now you’re worried you might just lose it.

For many of us, this evening anger is a near daily occurrence. In this case, it could be that the stress of your workday or the fact that you skipped lunch is making you feel more likely to lash out. Another possible explanation is that your biological clock has decided that now is the time to act aggressively.

Scientists have long suspected that emotional states may be regulated in part by biological rhythms, and even Aristotle astutely observed that human temperament seemed to be influenced by time. The master circadian clock, which resides in the suprachiasmatic nucleus (SCN) located deep at the base of the brain, drives our biological rhythms. By integrating information about the cycle of light and dark in the environment and the body’s own internal state, the SCN sets the pace for important processes like sleep, metabolism, and hormone release on an approximately 24-hour schedule.

While the mechanisms the SCN uses to time these processes are areas of intense study, we have a comparatively poor understanding of if and how the SCN affects the regulation of emotion. 

This lack of understanding has consequences – there’s a strong correlation between disruptions to the circadian system and several disorders associated with increased aggression. Few examples are as dramatic as sundowning syndrome, a mysterious phenomenon observed in Alzheimer’s and dementia patients in which fits of anger and delirium occur most frequently in the early evening.

Despite its importance, demonstrating a definitive role for the SCN in driving emotional rhythms in humans poses a number of technical challenges. As with many problems in neuroscience, scientists often turn to mouse models to drive progress.

In a new study published in Nature Neuroscience, a team based at Harvard Medical School demonstrated that mice are more likely to attack other mice during the early evening than at other times of day, suggesting aggressive behavior occurs with a daily rhythm. Importantly, the group discovered a circuit connecting the SCN to neurons in the ventromedial hypothalamus (VMH), a brain region previously shown to drive attack behavior in mice. This is the first demonstration of a mechanism for the SCN in the regulation of aggression.

The team’s first step was to confirm that indeed aggressive behavior displays a daily rhythm. To do this, they used the resident-intruder model, in which an “intruder” mouse is introduced into the home cage of a “resident” mouse, prompting the resident to defend its territory. By studying the frequency and intensity of the resident’s attacks on intruders at different times of day, the team found that aggressive behavior was most likely to occur about an hour after the lights turned off, even more so than at other points during the night.

Now that the researchers had demonstrated aggression occurred with a predictable rhythm, they could begin to manipulate neurons in an effort to characterize the neural circuit mediating the rhythmic behavior. They started by disrupting the release of the neurotransmitter GABA from neurons in the subparaventricular zone (SPZ), a well-known relay station connecting the SCN to several other parts of the brain. The rhythm of aggression completely disappeared from the SPZ-disrupted mice, and they became more aggressive overall.

Because GABA acts as a signal for neurons to decrease their activity, the researchers hypothesized that the SPZ might be inhibiting the activity of the VMH at different times of day, thus driving the rhythm of aggressive behavior. To test their idea, the researchers infected SPZ neurons with light-sensitive proteins that allowed them to selectively activate or silence their activity with lasers, and simultaneously recorded electrical responses in VMH neurons. They found that the SPZ was inhibiting the VMH more strongly at times they predicted based on the mouse’s behavioral rhythm, and that this timing information came from neurons in the SCN.

After taking a closer look at the VMH neurons mediating attacking behavior, the researchers found that the SPZ projected to not just one, but two distinct groups of VMH neurons, demonstrating the existence of two parallel pathways by which the SCN could drive rhythms of aggression. When researchers used DREADDS to acutely activate this second group of VMH neurons, the average resident mouse spent considerably more time attacking an intruder mouse, and did so much more rapidly.

Overall, the experiments suggest that the newly discovered circuit acts to curb aggression in the early morning, and that disrupting it drives a mouse to attack. This idea leads the authors to propose that the ability to control this circuit would grant control over aggressive behavior. In the future, such an ability may serve as an important therapeutic tool for disorders like sundowning syndrome, which the authors also suggest could be caused by a compromise of this circuit in neurodegenerative diseases.

It remains to be seen whether a similar functional circuit exists in humans, and it’s certainly reasonable to question the resemblance between aggressive behavior in mice and people. However, these results provide a nice biological context for several recent behavioral studies providing more evidence for rhythms of aggression in humans. One such study examined the emotional content in a set of over 800 million Tweets posted by Twitter users in the UK over the course of four years, and found that anger and several other emotions displayed both daily and seasonal rhythms.

While there's still a lot of work to do, the finding that emotions are rhythmically modulated will be important to consider, not only in how we think about mental health and neurological disease, but also in our daily social interactions.