Alzheimer’s Aggression Attributable to Circadian Rhythm: Study
Often referred to as “Sundowning”, Alzheimer’s patients regularly experience bouts of restlessness, agitation, irritability, or confusion that can begin or worsen as daylight begins to fade. This pattern may continue for several months and often occurs in those in the moderate to severe stages of dementia. These changes in mood and behavior can be particularly challenging for caregivers and loved ones.
It is thought that sundowning can be a problem for as many as 66% of people with Alzheimer’s disease or other dementias. It can occur at any stage of the disease but it tends to peak in the middle stages of dementia and lessens as the disease progresses.
Now, for the first time, a team of neuroscientists at Beth Israel Deaconess Medical Center (BIDMC) has demonstrated circadian control of aggression in male mice and identified the specific neurons and circuitry regulating the daily pattern. The insight opens the door to potential opportunities for managing the evening-time agitation common in patients with degenerative neurological disorders.
“Sundowning is often the reason that patients have to be institutionalized, and if clinicians can control this circuit to minimize aggressiveness at the end of the day, patients may be able to live at home longer
,” said senior author Clifford B. Saper, MD, Chair of the Department of Neurology at BIDMC. “We examined the biological clock’s brain circuitry and found a connection to a population of neurons known to cause violent attacks when stimulated in male mice. We wanted to know if this represented a propensity for violence at certain times of day.”“The mice were more likely to be aggressive in the early evening around lights out, and least aggressive in the early morning, around lights on,” Saper said. “It looks like aggressiveness builds up in mice during the lights on period, and reaches a peak around the end of the light period.”
In the course of their study, the researchers measured the frequency and intensity of interactions between male mice as “resident mice” defended their territory against “intruder mice” that were introduced into their cages at different times of the day. They reported, for the first time in a published study, that the attacks on the intruder mice showed a circadian pattern of aggression — that is, their intensity and frequency depended on the time of day.
In the second set of experiments, the team manipulated the mice’s master biological clock by tweaking genes in the neurons that regulate it. They found that when they stopped the master clock neurons from being able to make a specific chemical messenger, or neurotransmitter, the mice lost their circadian pattern of aggression. Aggressiveness remained high all the time, showing no highs and lows.
The researchers then used a tool called optogenetics to map the brain circuits involved. The tool uses laser light to stimulate and deactivate targeted brain cells. This revealed that wo parallel pathways between the biological clock and a population of neurons in a sub-region of the hypothalamus (called the VMHvl) known to cause violent attacks when stimulated in male mice.
Taken together, the experiments showed that this circadian circuit kept aggressiveness in check in the early morning; stimulating it prevented attack, while inhibiting it promoted attack.
Because stimulating the neurons in question cools off aggression, Saper suggests that controlling this circuit could potentially make animals – and perhaps people – less aggressive.
