While we’re stuck in a worsening pandemic, mice are doing better
From
Science Daily
The first article is on reversing age-related memory loss, the second is on dreams and the third and final is on weight loss.
– Will Collette,
editor
Scientists
reverse age-related memory loss in mice
University of Cambridge
Scientists at Cambridge and Leeds have successfully reversed age-related memory loss in mice and say their discovery could lead to the development of treatments to prevent memory loss in people as they age.
In a study published today in Molecular
Psychiatry, the team show that changes in the extracellular matrix of the
brain -- 'scaffolding' around nerve cells -- lead to loss of memory with
ageing, but that it is possible to reverse these using genetic treatments.
Recent evidence has emerged of the role of perineuronal nets (PNNs) in neuroplasticity -- the ability of the brain to learn and adapt -- and to make memories. PNNs are cartilage-like structures that mostly surround inhibitory neurons in the brain.
Their main function is to
control the level of plasticity in the brain. They appear at around five years
old in humans, and turn off the period of enhanced plasticity during which the
connections in the brain are optimised. Then, plasticity is partially turned
off, making the brain more efficient but less plastic.
PNNs contain compounds known as chondroitin sulphates. Some of these, such as chondroitin 4-sulphate, inhibit the action of the networks, inhibiting neuroplasticity; others, such as chondroitin 6-sulphate, promote neuroplasticity. As we age, the balance of these compounds changes, and as levels of chondroitin 6-sulphate decrease, so our ability to learn and form new memories changes, leading to age-related memory decline.
Researchers at the University of
Cambridge and University of Leeds investigated whether manipulating the
chondroitin sulphate composition of the PNNs might restore neuroplasticity and
alleviate age-related memory deficits.
To do this, the team looked at
20-month old mice -- considered very old -- and using a suite of tests showed that
the mice exhibited deficits in their memory compared to six-month old mice.
For example, one test involved seeing whether mice recognised an object. The mouse was placed at the start of a Y-shaped maze and left to explore two identical objects at the end of the two arms. After a short while, the mouse was once again placed in the maze, but this time one arm contained a new object, while the other contained a copy of the repeated object.
The researchers measured the amount of the time the mouse
spent exploring each object to see whether it had remembered the object from
the previous task. The older mice were much less likely to remember the object.
The team treated the ageing mice
using a 'viral vector', a virus capable of reconstituting the amount of 6-sulphate
chondroitin sulphates to the PNNs and found that this completely restored
memory in the older mice, to a level similar to that seen in the younger mice.
Dr Jessica Kwok from the School of
Biomedical Sciences at the University of Leeds said: "We saw remarkable
results when we treated the ageing mice with this treatment. The memory and
ability to learn were restored to levels they would not have seen since they
were much younger."
To explore the role of chondroitin
6-sulphate in memory loss, the researchers bred mice that had been
genetically-manipulated such that they were only able to produce low levels of
the compound to mimic the changes of ageing. Even at 11 weeks, these mice
showed signs of premature memory loss. However, increasing levels of chondroitin
6-sulphate using the viral vector restored their memory and plasticity to
levels similar to healthy mice.
Professor James Fawcett from the
John van Geest Centre for Brain Repair at the University of Cambridge said:
"What is exciting about this is that although our study was only in mice,
the same mechanism should operate in humans -- the molecules and structures in
the human brain are the same as those in rodents. This suggests that it may be
possible to prevent humans from developing memory loss in old age."
The team have already identified a
potential drug, licensed for human use, that can be taken by mouth and inhibits
the formation of PNNs. When this compound is given to mice and rats it can
restore memory in ageing and also improves recovery in spinal cord injury. The
researchers are investigating whether it might help alleviate memory loss in
animal models of Alzheimer's disease.
The approach taken by Professor
Fawcett's team -- using viral vectors to deliver the treatment -- is
increasingly being used to treat human neurological conditions. A second team
at the Centre recently published research showing their use for repairing
damage caused by glaucoma and dementia.
The study was funded by Alzheimer's
Research UK, the Medical Research Council, European Research Council and the
Czech Science Foundation.
Eyes wide
shut: How newborn mammals dream the world they're entering
Yale University
As a newborn mammal opens its eyes
for the first time, it can already make visual sense of the world around it.
But how does this happen before they have experienced sight?
A new Yale study suggests that, in a
sense, mammals dream about the world they are about to experience before they are
even born.
Writing in the July 23 issue
of Science, a team led by Michael Crair, the William Ziegler III
Professor of Neuroscience and professor of ophthalmology and visual science,
describes waves of activity that emanate from the neonatal retina in mice
before their eyes ever open.
This activity disappears soon after
birth and is replaced by a more mature network of neural transmissions of
visual stimuli to the brain, where information is further encoded and stored.
"At eye opening, mammals are
capable of pretty sophisticated behavior," said Crair, senior author of
the study, who is also vice provost for research at Yale." But how do the
circuits form that allow us to perceive motion and navigate the world? It turns
out we are born capable of many of these behaviors, at least in rudimentary
form."
In the study, Crair's team, led by
Yale graduate students Xinxin Ge and Kathy Zhang, explored the origins of these
waves of activity. Imaging the brains of mice soon after birth but before their
eyes opened, the Yale team found that these retinal waves flow in a pattern
that mimics the activity that would occur if the animal were moving forward
through the environment.
"This early dream-like activity
makes evolutionary sense because it allows a mouse to anticipate what it will
experience after opening its eyes, and be prepared to respond immediately to
environmental threats," Crair noted.
Going further, the Yale team also
investigated the cells and circuits responsible for propagating the retinal
waves that mimic forward motion in neonatal mice. They found that blocking the
function of starburst amacrine cells, which are cells in the retina that
release neurotransmitters, prevents the waves from flowing in the direction
that mimics forward motion. This in turn impairs the development of the mouse's
ability to respond to visual motion after birth.
Intriguingly, within the adult
retina of the mouse these same cells play a crucial role in a more
sophisticated motion detection circuit that allows them to respond to environmental
cues.
Mice, of course, differ from humans
in their ability to quickly navigate their environment soon after birth.
However, human babies are also able to immediately detect objects and identify
motion, such as a finger moving across their field of vision, suggesting that
their visual system was also primed before birth.
"These brain circuits are
self-organized at birth and some of the early teaching is already done,"
Crair said. "It's like dreaming about what you are going to see before you
even open your eyes."
Mice
treated with this cytokine lose weight by ‘sweating’ fat
University
of Pennsylvania School of Medicine
Treating
obese mice with the cytokine known as TSLP led to significant abdominal fat and
weight loss compared to controls, according to new research published Thursday
in Science from researchers in the Perelman School of Medicine
at the University of Pennsylvania. Unexpectedly, the fat loss was notassociated
with decreased food intake or faster metabolism. Instead, the researchers
discovered that TSLP stimulated the immune system to release lipids through the
skin's oil-producing sebaceous glands.
"This
was a completely unforeseen finding, but we've demonstrated that fat loss can
be achieved by secreting calories from the skin in the form of energy-rich
sebum," said principal investigator Taku Kambayashi, MD, PhD,an associate
professor of Pathology and Laboratory Medicine at Penn, who led the study with
fourth-year medical student Ruth Choa, PhD. "We believe that we are the
first group to show a non-hormonal way to induce this process, highlighting an
unexpected role for the body's immune system."
The
animal model findings, Kambayashi said, support the possibility that increasing
sebum production via the immune system could be a strategy for treating obesity
in people.
The
Hypothesis
Thymic
stromal lymphopoietin (TSLP) is a cytokine -- a type of immune system protein
-- involved in asthma and other allergic diseases. The Kambayashi research
group has been investigating the expanded role of this cytokine to activate
Type 2 immune cells and expand T regulatory cells. Since past studies have
indicated that these cells can regulate energy metabolism, the researchers
predicted that treating overweight mice with TSLP could stimulate an immune
response, which could subsequently counteract some of the harmful effects of
obesity.
"Initially,
we did not think TSLP would have any effect on obesity itself. What we wanted
to find out was whether it could impact insulin resistance," Kambayashi
said. "We thought that the cytokine could correct Type 2 diabetes, without
actually causing the mice to lose any weight."
The
Experiment
To
test the effect of TSLP on Type 2 diabetes, the researchers injected obese mice
with a viral vector that would increase their bodies' TSLP levels. After four
weeks, the research team found that TSLP had not only affected their diabetes
risk, but it had actually reversed the obesity in the mice, which were fed a
high-fat diet. While the control group continued to gain weight, the weight of
the TSLP-treated mice went from 45 grams down to a healthy 25 grams, on average,
in just 28 days.
Most
strikingly, the TSLP-treated mice also decreased their visceral fat mass.
Visceral fat is the white fat that is stored in the abdomen around major
organs, which can increase diabetes, heart disease, and stroke risk. These mice
also experienced improved blood glucose and fasting insulin levels, as well as
decreased risk of fatty liver disease.
Given
the dramatic results, Kambayashi assumed that the TSLP was sickening the mice
and reducing their appetites. However, after further testing, his group found
that the TSLP-treated mice were actually eating 20 to 30 percent more, had
similar energy expenditures, base metabolic rates, and activity levels, when
compared to their non-treated counterparts.
The
Findings
To
explain the weight loss, Kambayashi recalled a small observation he had
previously ignored: "When I looked at the coats of the TSLP-treated mice,
I noticed that they glistened in the light. I always knew exactly which mice
had been treated, because they were so much shinier than the others," he
said.
Kambayashi
considered a far-fetched idea -- was their greasy hair a sign that the mice
were "sweating" out fat from their skin?
To
test the theory, the researchers shaved the TSLP-treated mice and the controls
and then extracted oils from their fur. They found that Kambayashi's hypothesis
was correct: The shiny fur contained sebum-specific lipids. Sebum is a
calorically-dense substance produced by sebocytes (highly specializedepithelial
cells) in the sebaceous glands and helps to form the skin barrier. This
confirmed that the release of oil through the skin was responsible for the
TSLP-induced fat loss.
The
Conclusions
To
examine whether TSLP could potentially play a role in the control of oil
secretion in humans, the researchers then examined TSLPand a panel of 18
sebaceous gland-associated genes in a publicly-available dataset. This revealed
that TSLPexpression is significantly and positively correlated with sebaceous
gland gene expression in healthy human skin.
The
study authors write that, in humans, shifting sebum release into "high
gear" could feasibly lead to the "sweating of fat" and weight
loss. Kambayashi's group plans further study to test this hypothesis.
"I
don't think we naturally control our weight by regulating sebum production, but
we may be able to highjack the process and increase sebum production to cause
fat loss. This could lead to novel therapeutic interventions that reverse
obesity and lipid disorders," Kambayashi said.
