• Instability of brain activity during sle

    From ScienceDaily@1:317/3 to All on Tue Feb 1 21:30:40 2022
    Instability of brain activity during sleep and anesthesia underlies the pathobiology of Alzheimer's disease, study finds

    Date:
    February 1, 2022
    Source:
    Tel-Aviv University
    Summary:
    A new study revealed a pathological brain activity that
    precedes the onset of Alzheimer's first symptoms by many years:
    increased activity in the hippocampus during anesthesia and sleep,
    resulting from failure in the mechanism that stabilizes the neural
    network. The researchers believe that the discovery of this abnormal
    activity during specific brain states may enable early diagnosis
    of Alzheimer's, eventually leading to a more effective treatment
    of a disease that still lacks effective therapies.



    FULL STORY ==========================================================================
    A new study at Tel Aviv University revealed a pathological brain activity
    that precedes the onset of Alzheimer's first symptoms by many years:
    increased activity in the hippocampus during anesthesia and sleep,
    resulting from failure in the mechanism that stabilizes the neural
    network. The researchers believe that the discovery of this abnormal
    activity during specific brain states may enable early diagnosis of Alzheimer's, eventually leading to a more effective treatment of a
    disease that still lacks effective therapies.


    ==========================================================================
    The study was led by Prof. Inna Slutsky and doctoral students Daniel
    Zarhin and Refaela Atsmon from the Sackler Faculty of Medicine and
    the Sagol School of Neuroscience at Tel Aviv University. Additional participants in the study include: Dr. Antonella Ruggiero, Halit Baeloha,
    Shiri Shoob, Oded Scharf, Leore Heim, Nadav Buchbinder, Ortal Shinikamin,
    Dr. Ilana Shapira, Dr. Boaz Styr, and Dr. Gabriella Braun, all from
    Prof. Slutsky's laboratory. Collaborations with the laboratory teams of
    Prof. Yaniv Ziv of the Weizmann Institute, and Prof.

    Yuval Nir of TAU were essential for the project. Prof. Tamar Geiger,
    Dr. Michal Harel, and Dr. Anton Sheinin of Tel Aviv University, as well
    as researchers from Japan, also contributed to the study. The article
    was published in the scientific journal Cell Reports.

    Prof. Slutsky: "According to the recent study published this month in
    the Lancet Public Health journal, the number of people with dementia
    worldwide will increase from 50m in 2019 to more than 150m in 2050,
    growing by ~370% in North Africa and the Middle East. In Israel, a 145% increase is predicted, compared to ~74% in Western Europe. This huge
    increase in the prevalence of Alzheimer's due to the expected rise
    in population growth and in life expectancy will continue unless we
    develop effective treatments. This is clearly an alert for investing in dementia research and its most frequent form -- Alzheimer's disease." "Innovative imaging technologies developed in recent years have revealed
    that amyloid deposits, a hallmark of Alzheimer's disease pathology,
    are formed in patients' brains as early as 10-20 years before the
    onset of typical symptoms such as memory impairment and cognitive
    decline. Unfortunately, most efforts to treat Alzheimer's disease by
    reducing the amount of amyloid-beta proteins and their aggregation
    have failed. If we could detect the disease at the pre- symptomatic
    stage, and keep it in a dormant phase for many years, this would be
    a tremendous achievement in the field. We believe that identifying a
    signature of aberrant brain activity in the pre-symptomatic stage of Alzheimer's and understanding the mechanisms underlying its development
    is a key to effective treatment." The researchers used animal models
    for Alzheimer's, focusing on the hippocampal region of the brain,
    which plays a key role in memory processes, and is known to be impaired
    in Alzheimer's patients. At first, they measured cell activity in the hippocampus when the model animal was awake, active, and exploring its surroundings. For this they used advanced methods that measure brain
    activity at a resolution of single neurons.

    Daniel Zarhin: "Previous studies have examined cell activity in the
    brains of anesthetized animals in a model for Alzheimer's and found overactivity in the hippocampus and cortex. To my surprise, when I
    examined the model animals, I found no difference between the activity
    of neurons and synapses in their hippocampus and corresponding activity
    in the control group of healthy animals." In light of these findings,
    the researchers decided to examine activity in the hippocampus in
    other states of consciousness -- under anesthesia and during natural
    sleep. Refaela Atsmon: "It is known that neuronal activity of the
    hippocampus decreases during sleep in healthy animals. But when I
    examined model animals in early stages of Alzheimer's, I found that
    their hippocampal activity remained high even during sleep. This is due
    to a failure in the physiological regulation, never before observed
    in the context of Alzheimer's disease." Daniel Zarhin found similar dysregulation in model animals under anesthesia: neuronal activity does
    not decline, the neurons operate in a manner that is too synchronized,
    and a pathological electrical pattern is formed, similar to 'quiet'
    seizures in epileptic patients. Halit Baeloha, who is researching sleep problems related to Alzheimer's disease, emphasizes that the discovered disruption begins before the onset of the typical sleep disturbances
    observed in Alzheimer's patients.



    ========================================================================== Prof. Slutsky: "We found that brain states that block responses to the environment -- such as sleep and anesthesia -- expose abnormal activity
    which remains hidden when the animal is awake, and this happens before
    the symptoms of Alzheimer's disease are observed. Even though this
    abnormal activity can be detected during sleep, it is much more frequent
    under anesthesia. Therefore, it would be important to test whether
    short anesthesia can be used for early diagnosis of Alzheimer's ."
    At the next stage of the study, the researchers asked what causes the abnormality. To this end, they relied on findings from previous studies
    from Prof. Slutsky's laboratory and other researchers on homeostasis
    of neural networks: each neural circuit has a set point of activity,
    maintained by numerous stabilizing mechanisms. These mechanisms are
    activated when the balance is disturbed, restoring neuronal activity to
    its original set point.

    Is a disruption of these homeostatic mechanisms the main cause of aberrant brain activity during sleep and anesthesia in Alzheimer's disease animal models? To test this, Dr. Antonella Ruggiero examined the effect of
    various anesthetics on neurons grown on a chip and found that they
    lower the set point of neuronal activity. In healthy neural networks,
    activity remained low over time, but in neural networks expressing
    familial Alzheimer's mutations, the lowered set point recovers quickly,
    despite the presence of anesthetics. In another experiment, Dr. Ruggiero increased neuronal activity, and once again she found a failure in the mechanisms responsible for restoring activity to its normal set point
    in neurons expressing Alzheimer's mutations.

    The researchers now sought to examine a potential drug for the impaired regulatory mechanism. Prof. Slutsky: "The instability in neuronal activity which we found in this study is known from epilepsy. In a previous study
    we discovered that an existing drug for multiple sclerosis may help
    epilepsy patients by activating a homeostatic mechanism that lowers the
    set point of neural activity. Doctoral student Shiri Shoob examined
    the effect of the drug on hippocampal activity in the animal model
    for Alzheimer's and found that in this case also the drug stabilizes
    activity and reduces pathological activity observed during anesthesia."
    Prof. Slutsky concludes: "The results of our study may help early
    diagnosis of Alzheimer's, and even provide a solution for instability
    of neuronal activity in Alzheimer's disease. Firstly, we discovered
    that anesthesia and sleep states expose pathological brain activity in
    the early stages of Alzheimer's disease, before the onset of cognitive
    decline. We also proposed the cause of the pathological activity --
    failure of a very basic homeostatic mechanism that stabilizes electrical activity in brain circuits. Lastly, we showed that a known medication
    for multiple sclerosis suppresses this type of anesthesia- induced
    aberrant brain activity." The researchers now plan to collaborate with
    medical centers in Israel and worldwide to test whether the mechanisms discovered in animal models can also be identified in patients with
    early-stage Alzheimer's disease. For this purpose, they propose to
    incorporate EEG monitoring into surgical procedures, to measure brain
    activity of patients under anesthesia. They hope that their findings
    will promote early diagnosis and drug development for the most common
    form of late-onset dementia.

    special promotion Explore the latest scientific research on sleep and
    dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by Tel-Aviv_University. Note: Content
    may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Daniel Zarhin, Refaela Atsmon, Antonella Ruggiero, Halit Baeloha,
    Shiri
    Shoob, Oded Scharf, Leore R. Heim, Nadav Buchbinder, Ortal
    Shinikamin, Ilana Shapira, Boaz Styr, Gabriella Braun, Michal Harel,
    Anton Sheinin, Nitzan Geva, Yaniv Sela, Takashi Saito, Takaomi
    Saido, Tamar Geiger, Yuval Nir, Yaniv Ziv, Inna Slutsky. Disrupted
    neural correlates of anesthesia and sleep reveal early circuit
    dysfunctions in Alzheimer models. Cell Reports, 2022; 38 (3):
    110268 DOI: 10.1016/ j.celrep.2021.110268 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/02/220201115157.htm

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