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Calcium waves in the brain alleviate depressive symptoms and increase
neural plasticity (07-07-2016)
Researchers at the RIKEN Brain Science Institute in
Japan have discovered that the benefits of
stimulating the brain with direct current come from
its effects on astrocytes — not neurons — in the
mouse brain. Published in Nature Communications, the
work shows that applying direct current to the head
releases synchronized waves of calcium from
astrocytes that can reduce depressive symptoms and
lead to a general increase in neural plasticity —
the ability of neuronal connections to change when
we try to learn or form memories.
Transcranial direct current stimulation (tDCS) is a
well-known and effective procedure that has been
used for decades to clinically treat major
depression. The procedure is non-invasive, lasts
about 30 minutes, and involves targeting specific
brain areas by applying weak electric current
through the head. In addition to reducing symptoms
of depression, it has even been shown to enhance
learning and synaptic plasticity in both humans and
animals.
(top) Low spontaneous calcium activity in a normal
mouse followed by tDCS-induced calcium surges.
(bottom) tDCS-induced calcium surges are absent in
IP3 Receptor 2 knockout mice, indicating that the
calcium surges originate in astrocytes, not neurons.
“While we have known the clinical benefits of this
kind of stimulation for quite some time,” notes team
leader Hajime Hirase, “our research is aimed at
understanding the cellular mechanisms through which
its effects are made possible.”
Because calcium levels in astrocytes — a type of
non-neural glial cell in the brain — have recently
been shown to be important for transmitting signals
that help neurons form connections with each other,
Hirase and his team decided to examine brain
activity during transcranial direct current
stimulation using calcium imaging.
To accomplish this, they first made a transgenic
mouse that expresses a fluorescent calcium-indicator
protein in astrocytes and a subset of neurons in the
brain. With this setup, they were able to image
brain-wide calcium activity with a standard
fluorescence microscope.
When they monitored calcium levels, they found that
transcranial stimulation caused large amplitude
surges of calcium. “Surprisingly, the calcium surges
occurred very quickly after stimulation onset,”
explains lead author Hiromu Monai, “and appeared
synchronized all over the cortex not only near the
stimulated location.”
The calcium surges were absent when the same
experiment was performed on mice in which rising
calcium levels in astrocytes were prevented, either
through knocking out a key receptor or by
pharmacologically blocking another one. This allowed
the researchers to know that astrocytes, not
neurons, were the source of the waves. This was
confirmed when they expressed the fluorescent marker
using two different recombinant adeno-associated
viruses, allowing them to distinguish calcium in
neurons from calcium in astrocytes.
Next, they examined the importance of the calcium
surges using a mouse model for stress-induced
depression. While transcranial stimulation can
normally reduce depression-like behavior in these
mice, it failed when they blocked the astrocytic
calcium surges. “This suggests that the positive
effects of transcranial direct current stimulation
on depression lie in these wide-spread calcium
surges,” says Monai. “But, we also wanted to
investigate their effects on neural plasticity in
general.”
To examine this role of astrocytic calcium surges,
the team looked at changes in sensory responses
after transcranial stimulation. They measured the
responses to flashes of light and whisker
perturbation, and found that they were more than 50%
greater after stimulation — an effect that lasted
for 2 hours after stimulation was over. These
plastic changes in neuronal responses disappeared
when calcium surges in astrocytes were prevented,
indicating their importance in helping to change the
connectivity between neurons.
“That this mechanism is mediated by astrocytic
activity is exciting and hints that astrocytes could
be a major therapeutic target for neuropsychiatric
diseases,” notes Hirase. “Additionally, glial
activation by transcranial direct current
stimulation should be carefully examined in primates
(including humans), and perhaps safety standards
should to be re-evaluated from the standpoint of
glia.
See also
Brain stimulation may reduce anorexia symptoms
(2016-03-29) Link...
For more information
Hiromu Monai, Masamichi Ohkura, Mika Tanaka, Yuki Oe,
Ayumu Konno, Hirokazu Hirai, Katsuhiko Mikoshiba,
Shigeyoshi Itohara, Junichi Nakai, Youichi Iwai, and
Hajime Hirase,
Calcium imaging reveals glial involvement in
transcranial direct current stimulation-induced
plasticity in mouse brain.
Nature Communications, doi: 10.1038/ncomms11100 Link...