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April 9, 2018

Cyclical Alzheimer’s Aggression Pathway Uncovered

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    Patients with Alzheimer’s disease and other forms of dementia commonly exhibit increased aggression, delirium, and agitation during the early evening, a phenomenon known as "sundowning". These symptoms take a huge toll on patients’ families and caregivers, and are the most common reason that patients are institutionalized. Until now, however, it hasn’t been known whether this daily pattern of waxing and waning agitation and hostility is directly regulated by the body’s central circadian clock.

    Studies by researchers at the Beth Israel Deaconess Medical Center (BDMC) have now demonstrated the circadian control of aggression propensity in male mice, and identified a neural circuit within the brain’s central circadian clock, the suprachiasmatic nucleus of the hypothalamus (SCN), which modulates this daily rhythm of aggression.

    Headed by Clifford B. Saper, M.D., chair of the Department of Neurology at BIDMC, the researchers say their findings in mice are consistent with the increased aggression observed in humans during sundowning, suggesting that a pathway equivalent to that identified in mice could be disturbed in patients with neurodegenerative diseases.

    "Our results in mice mimic the patterns of increased aggression seen in patients during sundowning," Dr. Saper says. "This new research suggests this pathway may be compromised in neurodegenerative diseases. Examining changes to this pathway in patients could provide insight into future interventions that could greatly improve the quality of life for patients and caregivers alike." The BIDMC team, working with international collaborators, reports its findings in Nature Neuroscience, in a paper entitled, “A hypothalamic circuit for the circadian control of aggression.”

    Circadian rhythm disruption is a prominent feature of multiple neurodegenerative, neurodevelopmental, and neuropsychiatric diseases that are also associated with verbal and physical aggression, the authors write. “However, whether the central circadian clock directly regulates aggression, a complex motivated behavior, and the circuit basis by which it may do so remains unknown.”

    The team hypothesized that the tendency to display aggressive behavior changes across the 24-hour day, and that the SCN’s central circadian clock might regulate the rhythm in aggressive propensity via a signalling pathway to neurons within the ventromedial nucleus of the hypothalamus (VMHvl), which have previously been shown to directly regulate attack behavior in male mice.

    The team first carried out a series of observational studies, which confirmed that the tendency of male mice to display aggressive behaviour towards a male intruder displayed a daily rhythm. “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," Dr. Saper states. "It looks like aggressiveness builds up in mice during the lights on period, and reaches a peak around the end of the light period." The effects weren’t just due to the presence of light, however. Mice kept in total darkness displayed similar patterns of aggression during the daytime and night-time hours.

    When the researchers then disabled GABA neurotransmitter signalling via neurons in the supraventricular zone (SPZ)—which functions as a post-synaptic relay between the SCN clock and downstream structures—the mice lost their rhythmic tendencies to aggression, and became more aggressive overall. Optogenetically based circuit mapping and a series of genetically targeted neuronal manipulations then confirmed the presence of direct functional synaptic connectivity between the SPZ neurons, the vast majority of which are GABAergic, the authors point out, and the VMHvl aggression locus. “We uncover[ed] a previously undescribed, functional, polysynaptic circuit connecting the SCN clock with VMHvl neurons known to regulate attack behaviour,” they state.

    The team's studies also identified a parallel pathway from the SPZ through another set of neurons in the central VMH (VMHc), to the VMHvl neurons, “forming an intra-VMH circuit that, upon activation, also drives attack behaviour…Our data strongly suggest that input from the SCN clock to VMHvl neurons, either directly from SPZ neurons or indirectly through VMHc neurons, may increase or decrease the rate of this progression and the intensity or duration of consummatory attack behavior, depending on the time of day of the encounter.”

    The researchers conclude that a better understanding of how the SCN clock and its primary synaptic relay, the SPZ, modulate aggressive behavior will have “important implications” for treating patients with neurological disorders associated with circadian dysfunction and physical and verbal aggression. “Our results showing that disruption of SPZGABA output produces increased behavioral aggression during the early resting phase (early in the light period, for mice) are temporally consistent with the increased aggression seen during sundowning, suggesting that the SCN→SPZ→VMH pathway may be com- promised in such neurodegenerative diseases.”

    They suggest that examining neuropathological changes to the same pathway in patients with Alzheimer’s disease and other neurological conditions could provide key insights that could help to direct the development of new approaches to improving the quality of life for both patients and their caregivers.

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