Scientists discover mechanism behind chemically induced suppression of
fearful memories

Date:
April 25, 2022
Source:
Tokyo University of Science
Summary:
Fearful events negatively impact the brain. For instance,
war veterans often go through post-traumatic stress disorder
months after the cessation of the triggering event. Now, the
precise mechanism of suppression of such fearful memories has
been uncovered. Using a mouse model, the researchers identified
the associated biochemical pathways, thus paving the way for the
development and clinical evaluation of therapeutic compounds such
as KNT-127.



FULL STORY ========================================================================== Fearful events negatively impact the brain. For instance, war veterans
often go through post-traumatic stress disorder months after the cessation
of the triggering event. Now, in a study led by Tokyo University
of Science researchers, the precise mechanism of suppression of such
fearful memories has been uncovered. Using a mouse model, the researchers identified the associated biochemical pathways, thus paving the way for
the development and clinical evaluation of therapeutic compounds such
as KNT-127.


========================================================================== Tragic events like wars, famines, earthquakes, and accidents create
fearful memories in our brain. These memories continue to haunt us
even after the actual event has passed. Luckily, researchers from Tokyo University of Science (TUS) have recently been able to understand the
hidden biochemical mechanisms involved in the selective suppression of
fearful memories, which is called fear extinction. The researchers, who
had previously demonstrated fear extinction in mice using the chemically synthesized compound "KNT-127," have now identified the underlying
mechanism of this compound's action. Their findings have been published recently inFrontiers in Behavioral Neuroscience.

Prof. Akiyoshi Saitoh, lead author of the study, and Professor at
TUS, muses, "Drugs that treat fear-related diseases like anxiety and posttraumatic stress disorder must be able to help extinguish fear. We previously reported that KNT- 127, a selective agonist of the d-opioid
receptor or DOP, facilitates contextual fear extinction in mice. However,
its site of action in the brain and the underlying molecular mechanism
remained elusive. We therefore investigated brain regions and cellular signaling pathways that we assumed would mediate the action of KNT-127
on fear extinction." "We investigated the molecular mechanism of KNT-127-mediated suppression of fearful memories. We administered KNT-127
to specific brain regions and identified the brain regions involved in promoting fear extinction via delta receptor activation," elaborates
Dr. Daisuke Yamada, co-author of the study, and Assistant Professor
at TUS.

Using a mouse model, the research team performed fear conditioning
test on laboratory mice. During fear conditioning, mice learn to
associate a particular neutral conditioned stimulus with an aversive unconditioned stimulus (e.g., a mild electrical shock to the foot)
and show a conditioned fear response (e.g., freezing).

After the initial fear conditioning, the mice were re-exposed to the conditioning chamber for six minutes as part of the extinction training.

Meanwhile, the fear-suppressing therapeutic "KNT-127" was microinjected
into various regions of the brain, 30 minutes prior to re-exposure. The
treated brain regions included the basolateral nucleus of the amygdala
(BLA), the hippocampus (HPC), and the prelimbic (PL) or infralimbic
subregions (IL) of the medial prefrontal cortex. The following day,
the treated mice were re-exposed to the chamber for six minutes for
memory testing. The fear-suppressing "KNT- 127" that infused into
the BLA and IL, but not HPC or PL, significantly reduced the freezing
response during re-exposure. Such an effect was not observed in mice
that did not receive the KNT-127 treatment, thus confirming the fear- suppressing potential of this novel compound.

Chemical compounds known to inhibit the actions of key intracellular
signaling pathways like PI3K/Akt and MEK/ERK pathways reversed the
therapeutic effect, thereby suggesting the key roles of these two pathways
in influencing KNT-127- mediated fear extinction.

The first author of the study, Ayako Kawaminami, who is currently pursuing research at TUS, says, "The selective DOP antagonist that we used for pretreatment antagonized the effect of KNT-127 administered into the
BLA and IL. Further, local administration of MEK/ERK inhibitor into
the BLA and of PI3K/Akt inhibitor into the IL abolished the effect of
KNT-127. These findings strongly indicated that the effect of KNT-127
is mediated by MEK/ERK signaling in the BLA, by PI3K/Akt signaling in
the IL, and by DOPs in both brain regions.

We have managed to show that DOPs play a role in fear extinction via
distinct signaling pathways in the BLA and IL." PTSD and phobias are
thought to be caused by the inappropriate or inadequate control of fear memories. Currently, serotonin reuptake inhibitors and benzodiazepines
are prescribed during therapy. However, many patients do not derive
significant therapeutic benefits from these drugs. Therefore, there is
an urgent need for the development of new therapeutic agents that have
a different mechanism of action from existing drugs.

Dr. Hiroshi Nagase, a Professor at University of Tsukuba and a coauthor
of the study, concludes, "We have succeeded in creating KNT-127 by
successfully separating convulsion- and catalepsy-inducing actions,
which has so far been extremely difficult. Our findings will provide
useful and important information for the development of evidence-based therapeutics with a new mechanism of action, that is targeting DOP."
Fighting fear with the right therapeutic is the need of the hour, as
anxiety and stress increase globally, and the findings of this study
could help us achieve this objective. We have our fingers crossed.


========================================================================== Story Source: Materials provided by Tokyo_University_of_Science. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ayako Kawaminami, Daisuke Yamada, Shoko Yanagisawa, Motoki
Shirakata,
Keita Iio, Hiroshi Nagase, Akiyoshi Saitoh. Selective d-Opioid
Receptor Agonist, KNT-127, Facilitates Contextual Fear Extinction
via Infralimbic Cortex and Amygdala in Mice. Frontiers in Behavioral
Neuroscience, 2022; 16 DOI: 10.3389/fnbeh.2022.808232 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220425104337.htm

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