neuroscience

The road to Alzheimer’s disease could start with brain changes in the womb

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New research suggests that the origins of Alzheimer’s disease may go all the way back to when a patient is still in the womb, where abnormalities in brain development may lay the groundwork for this memory-depriving illness. These findings could potentially lead to a screening program that identifies at-risk individuals at birth.

Although there is currently no cure for Alzheimer’s, increasing attention is being paid to protective lifestyle changes, which include maintaining physical fitness and consuming a diet rich in fish, fruit, and vegetables. Neurodegenerative diseases are generally diagnosed between the ages of 40 and 60. However, it is believed that clinical symptoms emerge several decades after the onset of decline in specific brain cell connections.

A French team of scientists explain that this decline might stem from molecular-scale anomalies present from childhood, or potentially even earlier.

“We were interested in the amyloid precursor protein, or APP, which is highly expressed throughout the development of the nervous system,” says lead author Bassem Hassan of the Paris Brain Institute.

“It is an exciting research target as its fragmentation produces the famous amyloid peptides, whose toxic aggregation is associated with neuronal death observed in Alzheimer’s disease. We, therefore, suspect that APP may play a central role in the early stages of the disease,” Hassan continues in a media release.

Alzheimer's Disease

In many species, APP is involved in various biological processes, such as repairing cerebral lesions, orchestrating cellular response after oxygen deprivation or controlling brain plasticity.

APP is highly expressed during the differentiation and migration of cortical neurons, which are responsible for functions such as speech and swallowing – functions often compromised by dementia. The complex process of formation from stem cells begins in the fetus from five weeks gestation and is almost complete by 28 weeks.

“In humans, neurogenesis lasts particularly long compared with other species,” explains Khadijeh Shabani, a post-doctoral researcher at Paris Brain Institute. “Neural stem cells remain in a progenitor state for an extended period. Only later do they differentiate into glial cells, astrocytes, or oligodendrocytes that will form the architecture of the brain and spinal cord.”

Until now, it remained unclear how this balance between stem cell proliferation and differentiation into various cell types was regulated. Moreover, it was unknown whether the extended duration of human neurogenesis could potentially contribute to neurodegenerative diseases.

Historically, Alzheimer’s drugs have proved unsuccessful due to their prescription at a stage when the disease has already taken hold. However, this study, published in the journal Science Advances, paves the way for the development of medications that target APP in middle age – or even earlier.

The researchers utilized cell sequencing data from fetuses at 10 weeks and 18 weeks gestation to track APP expression during human brain development. They found that the protein was initially expressed in six cell types and later in 16 types.

By using gene editing to produce neural stem cells lacking APP expression and comparing these modified cells with those from fetuses, the researchers gathered important data.

“This comparison provided us with valuable data,” Shabani explains. “We observed that in the absence of APP, neural stem cells produced many more neurons, more rapidly, and were less inclined to proliferate in the progenitor cell state.”

brain astrocytes
Image of brain cell astrocytes

Specifically, APP regulates neurogenesis timing by influencing two finely-tuned genetic mechanisms – one chemical pathway controlling stem cell proliferation and another triggering the production of new neurons.

“In mouse models, neurogenesis is already very fast – too fast for APP deprivation to accelerate it further. We can imagine that the regulatory role of this protein is negligible in mice, while it is essential in the neurodevelopment of our species: to acquire its final form, our brain needs to generate huge quantities of neurons over a very long period, and according to a definite plan. APP-related abnormalities could cause premature neurogenesis and significant cellular stress, the consequences of which would be observable later,” suggests Hassan.

“Moreover, the brain regions in which early signs of Alzheimer’s disease appear also take the longest to mature during childhood and adolescence.”

There could be a direct link between the timing of human neurogenesis and the mechanisms of neurodegeneration. Given that the number of dementia cases worldwide is expected to triple to over 150 million by 2050 due to ageing populations, finding a therapy that targets the root cause is paramount in medical research.

APP appears to play a critical role in this respect, although further studies are necessary to confirm its centrality. Such research could significantly advance our understanding of Alzheimer’s disease and the brain’s development, potentially leading to early identification methods and new treatments.

Medicine, pills on top of brain MRI scans
(© Katsiaryna – stock.adobe.com)

The Paris Brain Institute team’s findings have added a crucial piece to the Alzheimer’s puzzle. This work suggests a paradigm shift in our understanding, positioning the disease’s origins much earlier in life than previously assumed. If their hypothesis holds true, we may be able to detect those at risk at a much earlier stage, offering the potential for targeted preventative measures and therapies.

In a world where Alzheimer’s cases are set to skyrocket, the implications of this research are vast and could significantly alter our approach to tackling this debilitating disease. The promise of a therapy that intervenes at the cause, rather than just managing symptoms, represents a “holy grail” in medical research. With Alzheimer’s’ seeds potentially sown in the womb, this research offers a new understanding that could bring us closer to achieving this goal.

“These disturbances lead to the formation of a brain that functions normally at birth but is particularly vulnerable to certain biological events – such as inflammation, excitotoxicity or somatic mutations – and certain environmental factors such as a poor diet, lack of sleep, infections, etc.,” the study authors conclude.

“Over time, these different stresses could lead to neurodegeneration – a phenomenon specific to the human species and made particularly visible by the increase in life expectancy.”

‘Mini-brains’ reveal genetic mutation linked to dementia and other diseases

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Lab-made “mini-brains” are helping scientists makes a breakthrough involving a gene implicated in various neurodegenerative diseases linked to old age. These include frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease. Scientists in the United Kingdom say this work may pave the way for new detection methods and treatments to address these awful diseases before symptoms ever appear.

Scientists at the University of Bath explain that in its healthy state, the gene in question (called Angiogenin or ANG) actually plays a very important role in the speed at which undifferentiated stem cells develop into specialized nerve cells. The mutated version of the gene is where things go awry.

In its mutated form, ANG causes stem cells to persist in their original state far longer than they should. In lab experiments, this slowing down of the differentiation process resulted in striking neurodevelopmental defects across nerve cells upon reaching their adult form.

“This suggests nerve-cell degeneration may be primed by defects occurring during early development,” says Dr. Vasanta Subramanian, who led the research from the Department of Life Sciences, in a university release.

During an earlier study, the same Bath research group discovered that ANG, in its healthy form, works to protect nerve cells against damage, degeneration, and any impairment of function. Conversely, the mutated form of the gene makes nerve cells more susceptible to stress (a natural occurrence as cells age and experience wear and tear), eventually leading to premature cell death.

“This new discovery adds to our understanding of Angiogenin and its importance in protecting us from diseases associated with aging,” Dr. Subramanian adds.

Elderly, older hands
pexels.com

To conduct this latest study, the research team chose to focus on a family affected by both frontotemporal dementia and ALS. Genetic testing showed that certain family members had mutations in Angiogenin while others did not.

Scientists grew “mini-brains” in a lab for all the family members. A mini-brain is a tiny 3D structure grown using clusters of human stem cells. They serve as realistic models for scientists to study the step-by-step development of disease, and also serve as ideal structures to screen drugs. Study authors noted striking neurodevelopmental defects in the mini-brains of family members carrying the ANG mutation.

“This seems to indicate that subtle development defects play a role in disease susceptibility or onset,” Dr. Subramanian adds. “I envisage a time when we will be identifying people who are susceptible to these diseases, screening them for genetic mutations and offering early-intervention gene therapy to fix the defects.”

human brain organoid
Section through a human brain organoid showing stem cells containing protective antibodies (stained green and red). The cells’ nuclei are stained blue. Credit: Ross Ferguson and Vasanta Subramanian

In conclusion, Dr. Subramanian stresses the need for more research in order to further clarify the mechanisms by which ANG protects cells and better understand its function in stem cells. This study received funding from the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), BRACE, and the Wellcome Trust VIP award.

“We applaud Dr Subramanian’s innovative research, which could make a big difference in tackling frontotemporal dementia. Better understanding of the Angiogenin gene and its link to FTD could support treatment to slow down or stop the disease in the future. This type of dementia tends to have an early onset between the ages of 45-65 years, and often has a devastating impact during middle age. We are hopeful that this BRACE funded research may play a key role in one day reducing the impact of the condition,” says BRACE CEO Chris Williams.

“Research into the brain and neurological disorders relies in large part on animal models and it is fantastic to see Vasanta’s mini-brain ‘organoids’ delivering new insights into neurodegenerative diseases. It is testament to the utility of these models that they are still being applied to new research questions, almost 15 years after we awarded Vasanta the initial funding to develop human cell-based alternatives to the use of animals in ALS (the most common form of motor neuron disease) research,” comments Dr. Jessica Eddy, NC3Rs Regional Program Manager.

Scientists get one step closer to unraveling the mysteries of time

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 Every second we’re alive, we’re moving through time. How people perceive the “flow of time” is from the past to the present to the future, moving in one direction like an arrow. Scientists from the CUNY Graduate Center Initiative for the Theoretical Sciences say this phenomenon arises from microscopic interactions among particles and cells, but how this actually takes place is still unclear. Now, a new study is helping to unravel this mystery and explain our perception of time.

Researchers note that the “arrow of time” is a concept from the second law of thermodynamics. The principle states that microscopic arrangements of physical systems move from order to disorder, increasing in randomness over time.

As the disorder increases, it becomes more and more difficult for the system to return to an ordered state — making the arrow of time even stronger. Simply put, the universe’s natural tendency to move towards a chaotic state is the fundamental reason humans perceive time to be flowing in one constant direction.

“The two questions our team had were, if we looked at a particular system, would we be able to quantify the strength of its arrow of time, and would we be able to sort out how it emerges from the micro scale, where cells and neurons interact, to the whole system?” explains first author Christopher Lynn, a postdoctoral fellow with the ITS program, in a media release. “Our findings provide the first step toward understanding how the arrow of time that we experience in daily life emerges from these more microscopic details.”

Neurons in your eye help explain our perception of time

The researchers studied time’s arrow by observing specific parts of a single system and the microscopic interactions taking place within it. Specifically, the team examined the neurons that function within the retina of an eye. While deconstructing a single moment in time, the study authors found that they could break down the arrow of time into different pieces — those produced by parts working individually, in pairs, in triplets, or in more complex configurations.

After breaking down the arrow, researchers analyzed existing experiments on how neurons in a salamander’s retina respond to different videos. In one video, a single object moved in random directions across the screen. In the other, the salamander watched a complex nature scene.

While viewing both movies, the study found that the arrow of time emerged from the simple interactions between pairs of neurons — not larger and more complicated groups. Interestingly, the retina displayed a stronger arrow of time while watching the more complex nature scene, instead of just a single object moving around.

Lynn believes this raises questions about how our internal perception of time aligns with the real world.

“These results may be of particular interest to neuroscience researchers,” Lynn concludes. “They could, for example, lead to answers about whether the arrow of time functions differently in brains that are neuroatypical.”

Mapping brain repair and remodeling after stroke

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Researchers at Weill Cornell Medicine have catalogued the cellular response to stroke in a preclinical model, identifying the immune cells involved and the roles they may play in the days and weeks following a stroke.

During a stroke, loss of oxygen leads to brain damage and cell death. It also triggers a powerful inflammatory response in which the brain’s resident immune cells, along with cells recruited from the blood, infiltrate the injured tissue.

The findings, published Jan. 4 in Nature Immunology, could point toward novel approaches to fostering stroke recovery and provide insight into why therapies to control inflammation after a stroke haven’t been successful.

Image of a mouse brain section
Image of a mouse brain section 14 days after stroke. Immune cells called leukocytes (yellow) infiltrate the core of the injury (right edge of brain), surrounded by enlarged blood vessels (magenta). Cell nuclei were stained cyan blue.

“Nearly every one of us knows someone who’s had a stroke. It’s a huge problem,” said senior author Dr. Josef Anrather, a professor of neuroscience and vice chair for research in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. “But in terms of treatment, there is little a physician can do.”

Interventions that restore blood flow to the affected brain region must be administered within hours to be effective. “So most people, more than 80%, receive no therapy at all,” he said.

Understanding how immune cells contribute to repairing and remodeling the brain in the later, chronic phase after a stroke could help doctors minimize the long-term neurological consequences, including dementia and even seizures.

In 2016, Anrather and his colleagues observed that immune cells called monocytes, which are made in the bone marrow, accumulate in the brain following a stroke. Once there, they appeared to undergo a physical transformation: Some sprouted spindly arms, adopting the appearance of the brain’s resident immune cells, the microglia; others grew more amorphous and amoeba-like.

But what, if anything, did this shapeshifting have to do with their behavior?

“We became interested in knowing the function of these different structural characteristics,” said lead study author Lidia Garcia-Bonilla, the Finbar and Marianne Kenny Research Scholar in Neurology and an assistant professor of research in neuroscience at the Brain and Mind Research Institute, Weill Cornell Medicine.

They also wondered whether these cells were contributing to recovery or compounding the damage.

“There are always two sides to the coin,” Anrather said. The same cell type might be harmful in some circumstances but helpful in others. “That might be why the clinical trials of drugs that reduce immune cell infiltration into the brain and inflammation have shown no benefit for stroke.”

The most direct way to assess what a particular cell is doing is to determine which of its many genes are turned on. Working with a preclinical model, they collected immune cells at two days and 14 days after an induced stroke – the blockage of an artery in the brain. They then sequenced the RNA molecules, which encode proteins, produced by each cell. Using this approach, the researchers identified exactly each type of cell they had isolated. It also provided a readout of which genes each cell had switched on, an indication of their roles after the stroke.

The researchers first noticed that a population of microglia were rapidly proliferating. That made sense, Anrather said, “because microglia cover the territory of the brain.” When their numbers are depleted by an injury, such as stroke, the cells multiply to blanket the damaged tissue.

Then they “take out the trash,” Anrather said.

“For the brain to rebuild itself, you have to clean up, remove dead cells,” he said. Indeed, two days after the experimental stroke, the researchers detected a cadre of microglia that switch on genes involved in clearing away cellular debris.

Joining the microglia in this effort were monocytes – white blood cells that responded to the injury. “These cells circulate continuously and don’t really have a job until there is a problem, like an infection, trauma or any kind of tissue death,” Anrather said. “Then they are called in to help clean up.”

Once there, the researchers found, these monocytes transformed themselves into the type of cell that’s needed to get the job done. “They’re like little kids that get educated in the tissue,” Anrather said.

After the acute clean-up phase, the immune response was restructured toward tissue remodeling. Some cellular recruits produced growth factors triggering repair while immunological “professionals” such as T cells were called in to play a neuroprotective role.

By identifying which immune cells will heed the stroke-induced distress call, the researchers provide a novel vehicle for intervention. “Because these cells know how to get to the brain,” Anrather said, “you could use them as a shuttle and engineer them to deliver a therapeutic.”

Furthermore, understanding precisely what these cells do when they get to the brain could be key to developing treatments that can be administered weeks or months after a stroke. “Finding a way to activate the brain’s natural repair mechanism could improve the outcome for stroke patients,” Garcia-Bonilla said.

Unlocking the Fountain of Youth: Brain-Fat Tissue Feedback Loop

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The researchers identified a specific set of neurons in the brain’s hypothalamus that, when active, sends signals to the body’s fat tissue to release energy. Credit: Neuroscience News

Summary: A new study reveals a vital brain-fat tissue feedback loop that plays a pivotal role in aging. The research identifies specific neurons in the hypothalamus that, when activated, signal the body’s fat tissue to release energy, facilitating physical activity and brain function. As this feedback loop deteriorates with age, health problems associated with aging become more prevalent.

Mice with a constantly active feedback loop displayed delayed aging, increased physical activity, and longer lifespans. This groundbreaking research offers potential insights for future interventions in aging and longevity.

Key Facts:

  1. The study unveils a critical brain-fat tissue feedback loop that influences aging and health.
  2. Activation of specific neurons in the hypothalamus triggers the release of fatty acids and enzymes that fuel the body and brain.
  3. Mice with a sustained feedback loop lived longer, were more physically active, and displayed signs of delayed aging.

Source: WUSTL

In recent years, research has begun to reveal that the lines of communication between the body’s organs are key regulators of aging. When these lines are open, the body’s organs and systems work well together. But with age, communication lines deteriorate, and organs don’t get the molecular and electrical messages they need to function properly.

A new study from Washington University School of Medicine in St. Louis identifies, in mice, a critical communication pathway connecting the brain and the body’s fat tissue in a feedback loop that appears central to energy production throughout the body. The research suggests that the gradual deterioration of this feedback loop contributes to the increasing health problems that are typical of natural aging.

The study — published Jan. 8 in the journal Cell Metabolism — has implications for developing future interventions that could maintain the feedback loop longer and slow the effects of advancing age.

The researchers identified a specific set of neurons in the brain’s hypothalamus that, when active, sends signals to the body’s fat tissue to release energy. Using genetic and molecular methods, the researchers studied mice that were programmed to have this communication pathway constantly open after they reached a certain age.

The scientists found that these mice were more physically active, showed signs of delayed aging, and lived longer than mice in which this same communication pathway gradually slowed down as part of normal aging.

“We demonstrated a way to delay aging and extend healthy life spans in mice by manipulating an important part of the brain,” said senior author Shin-ichiro Imai, MD, PhD, the Theodore and Bertha Bryan Distinguished Professor in Environmental Medicine and a professor in the Department of Developmental Biology at Washington University.

“Showing this effect in a mammal is an important contribution to the field; past work demonstrating an extension of life span in this way has been conducted in less complex organisms, such as worms and fruit flies.”

These specific neurons, in a part of the brain called the dorsomedial hypothalamus, produce an important protein — Ppp1r17. When this protein is present in the nucleus, the neurons are active and stimulate the sympathetic nervous system, which governs the body’s fight or flight response.

The fight or flight response is well known for having broad effects throughout the body, including causing increased heart rate and slowed digestion. As part of this response, the researchers found that the neurons in the hypothalamus set off a chain of events that triggers neurons that govern white adipose tissue — a type of fat tissue — stored under the skin and in the abdominal area.

The activated fat tissue releases fatty acids into the bloodstream that can be used to fuel physical activity. The activated fat tissue also releases another important protein — an enzyme called eNAMPT — which returns to the hypothalamus and allows the brain to produce fuel for its functions.

This feedback loop is critical for fueling the body and the brain, but it slows down over time. With age, the researchers found that the protein Ppp1r17 tends to leave the nucleus of the neurons, and when that happens, the neurons in the hypothalamus send weaker signals.

With less use, the nervous system wiring throughout the white adipose tissue gradually retracts, and what was once a dense network of interconnecting nerves becomes sparse. The fat tissues no longer receive as many signals to release fatty acids and eNAMPT, which leads to fat accumulation, weight gain and less energy to fuel the brain and other tissues.

The researchers, including first author Kyohei Tokizane, PhD, a staff scientist and a former postdoctoral researcher in Imai’s lab, found that when they used genetic methods in old mice to keep Ppp1r17 in the nucleus of the neurons in the hypothalamus, the mice were more physically active — with increased wheel-running — and lived longer than control mice. They also used a technique to directly activate these specific neurons in the hypothalamus of old mice, and they observed similar anti-aging effects.

On average, the high end of the life span of a typical laboratory mouse is about 900 to 1,000 days, or about 2.5 years. In this study, all of the control mice that had aged normally died by 1,000 days of age. Those that underwent interventions to maintain the brain-fat tissue feedback loop lived 60 to 70 days longer than control mice.

That translates into an increase in life span of about 7%. In people, a 7% increase in a 75-year life span translates to about five more years. The mice receiving the interventions also were more active and looked younger — with thicker and shinier coats — at later ages, suggesting more time with better health as well.

Imai and his team are continuing to investigate ways to maintain the feedback loop between the hypothalamus and the fat tissue. One route they are studying involves supplementing mice with eNAMPT, the enzyme produced by the fat tissue that returns to the brain and fuels the hypothalamus, among other tissues.

When released by the fat tissue into the bloodstream, the enzyme is packaged inside compartments called extracellular vesicles, which can be collected and isolated from blood.

“We can envision a possible anti-aging therapy that involves delivering eNAMPT in various ways,” Imai said.

“We already have shown that administering eNAMPT in extracellular vesicles increases cellular energy levels in the hypothalamus and extends life span in mice. We look forward to continuing our work investigating ways to maintain this central feedback loop between the brain and the body’s fat tissues in ways that we hope will extend health and life span.”

Funding: This work was supported by the National Institute on Aging of the National Institutes of Health (NIH), grant numbers AG037457 and AG047902; the American Federation for Aging Research; the Tanaka Fund at Washington University School of Medicine; a Glenn Foundation for Medical Research Postdoctoral Fellowship; and a Tanaka Scholarship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

About this aging and neuroscience research news

Author: Diane Williams
Source: WUSTL
Contact: Diane Williams – WUSTL
Image: The image is credited to Neuroscience News

Original Research: Open access.
“DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication” by Shin-ichiro Imai et al. Cell Metabolism

Abstract

DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication

Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications.

We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation.

Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function.

Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan.

Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.

Unlocking the Fountain of Youth: Brain-Fat Tissue Feedback Loop Holds Key

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The researchers identified a specific set of neurons in the brain’s hypothalamus that, when active, sends signals to the body’s fat tissue to release energy. Credit: Neuroscience News

Summary: A new study reveals a vital brain-fat tissue feedback loop that plays a pivotal role in aging. The research identifies specific neurons in the hypothalamus that, when activated, signal the body’s fat tissue to release energy, facilitating physical activity and brain function. As this feedback loop deteriorates with age, health problems associated with aging become more prevalent.

Mice with a constantly active feedback loop displayed delayed aging, increased physical activity, and longer lifespans. This groundbreaking research offers potential insights for future interventions in aging and longevity.

Key Facts:

  1. The study unveils a critical brain-fat tissue feedback loop that influences aging and health.
  2. Activation of specific neurons in the hypothalamus triggers the release of fatty acids and enzymes that fuel the body and brain.
  3. Mice with a sustained feedback loop lived longer, were more physically active, and displayed signs of delayed aging.

Source: WUSTL

In recent years, research has begun to reveal that the lines of communication between the body’s organs are key regulators of aging. When these lines are open, the body’s organs and systems work well together. But with age, communication lines deteriorate, and organs don’t get the molecular and electrical messages they need to function properly.

A new study from Washington University School of Medicine in St. Louis identifies, in mice, a critical communication pathway connecting the brain and the body’s fat tissue in a feedback loop that appears central to energy production throughout the body. The research suggests that the gradual deterioration of this feedback loop contributes to the increasing health problems that are typical of natural aging.

The study — published Jan. 8 in the journal Cell Metabolism — has implications for developing future interventions that could maintain the feedback loop longer and slow the effects of advancing age.

The researchers identified a specific set of neurons in the brain’s hypothalamus that, when active, sends signals to the body’s fat tissue to release energy. Using genetic and molecular methods, the researchers studied mice that were programmed to have this communication pathway constantly open after they reached a certain age.

The scientists found that these mice were more physically active, showed signs of delayed aging, and lived longer than mice in which this same communication pathway gradually slowed down as part of normal aging.

“We demonstrated a way to delay aging and extend healthy life spans in mice by manipulating an important part of the brain,” said senior author Shin-ichiro Imai, MD, PhD, the Theodore and Bertha Bryan Distinguished Professor in Environmental Medicine and a professor in the Department of Developmental Biology at Washington University.

“Showing this effect in a mammal is an important contribution to the field; past work demonstrating an extension of life span in this way has been conducted in less complex organisms, such as worms and fruit flies.”

These specific neurons, in a part of the brain called the dorsomedial hypothalamus, produce an important protein — Ppp1r17. When this protein is present in the nucleus, the neurons are active and stimulate the sympathetic nervous system, which governs the body’s fight or flight response.

The fight or flight response is well known for having broad effects throughout the body, including causing increased heart rate and slowed digestion. As part of this response, the researchers found that the neurons in the hypothalamus set off a chain of events that triggers neurons that govern white adipose tissue — a type of fat tissue — stored under the skin and in the abdominal area.

The activated fat tissue releases fatty acids into the bloodstream that can be used to fuel physical activity. The activated fat tissue also releases another important protein — an enzyme called eNAMPT — which returns to the hypothalamus and allows the brain to produce fuel for its functions.

This feedback loop is critical for fueling the body and the brain, but it slows down over time. With age, the researchers found that the protein Ppp1r17 tends to leave the nucleus of the neurons, and when that happens, the neurons in the hypothalamus send weaker signals.

With less use, the nervous system wiring throughout the white adipose tissue gradually retracts, and what was once a dense network of interconnecting nerves becomes sparse. The fat tissues no longer receive as many signals to release fatty acids and eNAMPT, which leads to fat accumulation, weight gain and less energy to fuel the brain and other tissues.

The researchers, including first author Kyohei Tokizane, PhD, a staff scientist and a former postdoctoral researcher in Imai’s lab, found that when they used genetic methods in old mice to keep Ppp1r17 in the nucleus of the neurons in the hypothalamus, the mice were more physically active — with increased wheel-running — and lived longer than control mice. They also used a technique to directly activate these specific neurons in the hypothalamus of old mice, and they observed similar anti-aging effects.

On average, the high end of the life span of a typical laboratory mouse is about 900 to 1,000 days, or about 2.5 years. In this study, all of the control mice that had aged normally died by 1,000 days of age. Those that underwent interventions to maintain the brain-fat tissue feedback loop lived 60 to 70 days longer than control mice.

That translates into an increase in life span of about 7%. In people, a 7% increase in a 75-year life span translates to about five more years. The mice receiving the interventions also were more active and looked younger — with thicker and shinier coats — at later ages, suggesting more time with better health as well.

Imai and his team are continuing to investigate ways to maintain the feedback loop between the hypothalamus and the fat tissue. One route they are studying involves supplementing mice with eNAMPT, the enzyme produced by the fat tissue that returns to the brain and fuels the hypothalamus, among other tissues.

When released by the fat tissue into the bloodstream, the enzyme is packaged inside compartments called extracellular vesicles, which can be collected and isolated from blood.

“We can envision a possible anti-aging therapy that involves delivering eNAMPT in various ways,” Imai said.

“We already have shown that administering eNAMPT in extracellular vesicles increases cellular energy levels in the hypothalamus and extends life span in mice. We look forward to continuing our work investigating ways to maintain this central feedback loop between the brain and the body’s fat tissues in ways that we hope will extend health and life span.”

Funding: This work was supported by the National Institute on Aging of the National Institutes of Health (NIH), grant numbers AG037457 and AG047902; the American Federation for Aging Research; the Tanaka Fund at Washington University School of Medicine; a Glenn Foundation for Medical Research Postdoctoral Fellowship; and a Tanaka Scholarship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH

Abstract

DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication

Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications.

We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation.

Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function.

Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan.

Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.

MRI Helps Researchers Link Enlarged Spaces in Infant Brains to Higher Risk of Autism, Sleep Disorders

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Researchers Dea Garic, PhD, and Mark Shen, PhD, both at the UNC School of Medicine’s Department of Psychiatry, discovered that infants with abnormally enlarged perivascular spaces have a 2.2 times greater chance of developing autism compared to infants with the same genetic risk. Their research also indicated that enlarged perivascular spaces in infancy are associated with sleep problems seven to 10 years after diagnosis.

“These results suggest that perivascular spaces could serve as an early marker for autism,” said Garic, assistant professor of psychiatry and a member of the Carolina Institute for Developmental Disabilities (CIDD).

The researchers studied infants at increased likelihood for developing autism, because they had an older sibling with autism. They followed these infants from 6-24 months of age, before the age of autism diagnosis. Their study, published in JAMA Network Open, found that thirty% of infants who later developed autism had enlarged perivascular spaces by 12 months. By 24 months of age, nearly half of the infants diagnosed with autism had enlarged perivascular spaces.

Starting 10 years ago, there has been a resurgence of research on the important functions of CSF in regulating brain health and development. Shen’s lab was the first to report that excessive volume of CSF was evident at 6 months of age in infants who would later develop autism. The current study showed that excessive CSF volume at 6 months was linked to enlarged perivascular spaces at 24 months.

Every six hours, the brain expels a wave of CSF that flows through perivascular spaces to remove potentially harmful neuroinflammatory proteins, such as amyloid beta, from building up in the brain. The CSF cleansing process is especially efficient when we are asleep, as the majority of CSF circulation and clearance occurs during sleep.

Disrupted sleep, however, can reduce CSF clearance from perivascular spaces, leading to dilation or enlargement, but this has previously only been studied in animal studies or in human studies of adults. This is the first study of its kind in children.

Shen, senior author of the JAMA Network Open paper, and Garic hypothesized that CSF abnormalities in infancy would be related to later sleep problems, based on  Shen’s earlier research. The current sleep analysis revealed children who had enlarged perivascular spaces at two years of age had higher rates of sleep disturbances at school age.

“Since autism is so highly linked with sleep problems, we were in this unique position to examine CSF dynamics and sleep,” said Garic, who is first author of the paper. “It was really striking to observe such a strong association separated by such a long period of time over childhood. But it really shows how perivascular spaces not only have an effect early in life, but they can have long term effects, too.”

The research was done in conjunction with the Infant Brain Imaging Study (IBIS), a nationwide network of researchers investigating brain development, autism, and related developmental disabilities. The network consists of five universities, of which the University of North Carolina-Chapel Hill is the lead site.

For their study, Garic and Shen analyzed 870 MRIs from IBIS to measure excessive CSF volume and enlarged perivascular spaces. MRIs were obtained from babies during natural sleep at six, 12, and 24 months of age to observe changes over time.

The infant brain undergoes rapid development over this period. Previously, measurement of perivascular spaces was only thought to be clinically relevant for disorders of aging in older adults, such as in dementia. These findings suggest that younger populations may need to be considered and monitored for these types of brain abnormalities.

“Our findings were striking, given that neuroradiologists typically view enlarged perivascular spaces as a sign of neurodegeneration in adults, but this study reported it in toddlers,” said Garic. “This is an important aspect of brain development in the first years of life that should be monitored.”

Garic and Shen hypothesize that excess CSF volume is stagnant, or clogged, and not circulating through the brain as efficiently as it should. For their next research endeavor, the researchers are planning to once again use MRIs to measure CSF in a sleeping infant’s brain, but this time focusing on the physiology and speed of CSF flow throughout the brain.

The research team is also working with other collaborators to quantify the size of perivascular spaces and the severity of behavioral outcomes. The team also plans to extend their research to neurogenetic syndromes associated with autism, such as Fragile X syndrome and Down syndrome.

“Collectively our research has shown that CSF abnormalities in the first year of life could have downstream effects on a variety of outcomes, including later autism diagnosis, sleep problems, neuroinflammation, and possibly, other developmental disabilities,” said Shen.

How Subsecond Changes in Brain Dopamine Levels Impact Human Behavior

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What happens in the human brain when we learn from positive and negative experiences? To help answer that question and better understand decision making and human behavior, scientists are studying dopamine, a neurotransmitter produced in the brain that serves as a chemical messenger, facilitating communication between nerve cells in the brain and the body.

Substantia nigra. Illustration showing a healthy substantia nigra in a human brain and a close-up view of dopaminergic neurons found in the substantia nigra. The substantia nigra plays an important role in reward, addiction, and movement. Degeneration of this structure is characteristic of Parkinson’s disease.

Dopamine is mostly associated with positive emotions, but the results of a study by researchers at Wake Forest University School of Medicine have shown that dopamine release in the human brain plays a crucial role in encoding both reward prediction errors (RPE) and punishment prediction errors (PPE). The investigators carried out subsecond measurements of dopamine release in the brains of human volunteers who were undergoing deep brain stimulation (DBS) surgery, while the individuals undertook a specific task. The findings indicate that dopamine in learning from both positive and negative experiences, allowing the brain to adjust and adapt its behavior based on experience outcomes.

“Traditionally, dopamine is often referred to as ‘the pleasure neurotransmitter,”’ said research lead Kenneth T. Kishida, PhD, associate professor of physiology and pharmacology and neurosurgery at Wake Forest University School of Medicine. “However, our work provides evidence that this is not the way to think about dopamine. Instead, dopamine is a crucial part of a sophisticated system that teaches our brain and guides our behavior. That dopamine is also involved in teaching our brain about punishing experiences is an important discovery and may provide new directions in research to help us better understand the mechanisms underlying depression, addiction, and related psychiatric and neurological disorders.”

Kishida and colleagues reported on their findings in Science Advances, in a paper titled “Subsecond fluctuations in extracellular dopamine encode reward and punishment prediction errors in humans.”

The neurotransmitter dopamine is involved in a range of functions, such as movement, cognition and learning, but abnormal dopamine activity may also underpin different diseases, the authors suggested. “Dopamine neurons are critical for mammalian brain function and behavior, with changes in dopaminergic efficacy believed to underlie a wide range of human brain disorders including substance use disorders, depression, and Parkinson’s disease,” they wrote.

Kishida explained that prior research had shown that dopamine plays an important role in how animals learn from “rewarding”—and possibly “punishing”—experiences. As the authors wrote. “In the mammalian brain, midbrain dopamine neuron activity is hypothesized to encode reward prediction errors that promote learning and guide behavior by causing rapid changes in dopamine levels in target brain regions.” Also, they noted, “ … human functional magnetic resonance imaging experiments suggest that RPE and punishment prediction error (PPE) signals are represented in dopamine-rich regions during learning about appetitive and aversive outcomes. But as Kishida also pointed out, “… little work has been done to directly assess what dopamine does on fast timescales in the human brain.”

For their newly reported study Kishida lab, and collaborators, utilized fast-scan cyclic voltammetry, an electrochemical technique, paired with machine learning, to detect and measure dopamine levels in real-time (i.e., 10 measurements per second). This method can only be performed during invasive procedures such as deep brain stimulation brain surgery. DBS is commonly employed to treat conditions such as Parkinson’s disease, essential tremor, obsessive-compulsive disorder and epilepsy.

Kishida’s team collaborated with Atrium Health Wake Forest Baptist neurosurgeons Stephen B. Tatter, MD, and Adrian W. Laxton, MD,—also both faculty members in the Department of Neurosurgery at Wake Forest University School of Medicine—to insert a carbon fiber microelectrode deep into the brain of three participants at Atrium Health Wake Forest Baptist Medical Center who were scheduled to receive DBS to treat essential tremor.

Ken T. Kishida, PhD, associate professor of physiology and pharmacology at Wake Forest University School of Medicine.
Ken T. Kishida, PhD, associate professor of physiology and pharmacology at Wake Forest University School of Medicine. [Wake Forest University School of Medicine]

The participants, awake in the operating room, played a simple computer game. As they played the game, dopamine measurements were taken in the striatum, a part of the brain that is important for cognition, decision making, and coordinated movements.

During the game, participants’ choices were either rewarded or punished with real monetary gains or losses. “Optimal performance on this task requires participants to learn from positive and negative feedback to select the option on each trial that maximizes the expected reward and minimizes the expected punishment,” the investigators explained.

The game was divided into three stages in which participants learned from positive or negative feedback to make choices that maximized rewards and minimized penalties. Dopamine levels were measured continuously, once every 100 milliseconds, throughout each of the three stages of the game.

“This is the first study in humans to examine how dopamine encodes rewards and punishments and whether dopamine reflects an ‘optimal’ teaching signal that is used in today’s most advanced artificial intelligence research,” Kishida said. “We found that dopamine not only plays a role in signaling both positive and negative experiences in the brain, but it seems to do so in a way that is optimal when trying to learn from those outcomes.”

The authors further noted, “Collectively, our results suggest that human decision-making is influenced by independent, parallel processing of appetitive and aversive experiences and expectations that can affect modulation of dopamine release in striatal regions on rapid timescales (hundreds of milliseconds).”

Kishidi added, “What was also interesting, is that it seems like there may be independent pathways in the brain that separately engage the dopamine system for rewarding versus punishing experiences. Our results reveal a surprising result that these two pathways may encode rewarding and punishing experiences on slightly shifted timescales separated by only 200 to 400 milliseconds in time.”

The investigator believes that this level of understanding may lead to a better understanding of how the dopamine system is affected in individuals with psychiatric and neurological disorders. As the team stated, “… it has not escaped our notice that the PPE aversive learning system has features that suggest a role in anxiety disorders analogous to models of the RPE reinforcement learning system role in addiction, depression, and obsessive-compulsive disorder.” However, additional research will be needed to understand how dopamine signaling is altered in such conditions.

More Parallel “Traffic” Observed in Human Brains than in Animals

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Scientists at the École Polytechnique Fédérale de Lausanne (EPFL) and collaborators compared human brain communication networks with those of macaques and mice and found that only the human brains transmitted information via multiple parallel pathways.

The researchers said their study “Evidence for increased parallel information transmission in human brain networks compared to macaques and male mice,” published in Nature Communications, not only provided new insights into mammalian evolution but also could potentially play a role in neurorehabilitation after brain injury, or in the prevention of cognitive decline in pathologies of advanced age.

“Some people age healthily, while others experience cognitive decline, so we’d like to see if there is a relationship between this difference and the presence of parallel information streams, and whether they could be trained to compensate neurodegenerative processes,” said Alessandra Griffa, PhD, senior postdoctoral researcher.

When describing brain communication networks, Griffa likes to use travel metaphors. Brain signals are sent from a source to a target, establishing a polysynaptic pathway that intersects multiple brain regions “like a road with many stops along the way.”

She explains that structural brain connectivity pathways have already been observed based on networks (“roads”) of neuronal fibers. But as a scientist in the medical image processing lab (MIP:Lab) in EPFL’s school of engineering, and a research coordinator at Lausanne University Hospital’s (CHUV) Leenaards Memory Centre, Griffa wanted to follow patterns of information transmission to see how messages are sent and received. She and her colleagues created “brain traffic maps” that could be compared between humans and other mammals.

Close up photo of two doctors male and female working in laboratory holding digital tablet and analysing mri scan image.

Reconstructing the brain road maps

To achieve this, the researchers used open-source diffusion (DWI) and functional magnetic resonance imaging (fMRI) data from humans, macaques, and mice, which was gathered while subjects were awake and at rest. The DWI scans allowed the scientists to reconstruct the brain “road maps,” and the fMRI scans allowed them to see different brain regions light up along each “road,” which indicated that these pathways were relaying neural information.

They analyzed the multimodal MRI data using information and graph theory, and Griffa says that it is this novel combination of methods that yielded fresh insights.

“By applying a graph- and information-theory approach to assess information-related pathways in male mouse, macaque, and human brains, we show a brain communication gap between selective information transmission in non-human mammals, where brain regions share information through single polysynaptic pathways, and parallel information transmission in humans, where regions share information through multiple parallel pathways,” wrote the investigators.

“In humans, parallel transmission acts as a major connector between unimodal and transmodal systems. The layout of information-related pathways is unique to individuals across different mammalian species, pointing at the individual-level specificity of information routing architecture. Our work provides evidence that different communication patterns are tied to the evolution of mammalian brain networks.”

Animal and human brain schematics
In the mouse and macaque brains, information was sent along a single “road,” while in humans, there were multiple parallel pathways between the same source and target. [Alessandra Griffa CHUV/EPFL CC BY-SA]

“What’s new in our study is the use of multimodal data in a single model combining two branches of mathematics: graph theory, which describes the polysynaptic ‘roadmaps,’ and information theory, which maps information transmission (or ‘traffic’) via the roads,” explained Griffa. The basic principle is that messages passed from a source to a target remain unchanged or are further degraded at each stop along the road, like the telephone game we played as children.”

The researchers’ approach revealed that in the non-human brains, information was sent along a single “road,” while in humans, there were multiple parallel pathways between the same source and target. Furthermore, these parallel pathways were as unique as fingerprints, and could be used to identify individuals.

“Such parallel processing in human brains has been hypothesized, but never observed before at a whole-brain level,” added Griffa.

Griffa explained that the beauty of the model is its simplicity, and its generating new perspectives and research avenues in evolution and computational neuroscience. For example, the findings can be linked to the expansion of human brain volume over time, which has given rise to more complex connectivity patterns.

“We could hypothesize that these parallel information streams allow for multiple representations of reality, and the ability to perform abstract functions specific to humans,” she pointed out.

Although this hypothesis is only speculative, as the study involved no testing of subjects’ computational or cognitive ability, these are questions that Griffa would like to explore in the future.

PTSD Linked to Smaller Cerebellum, Pointing to Potential New Target

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A brain imaging study led by a team at Duke University has shown that adults with posttraumatic stress disorder (PTSD) have smaller cerebellums, suggesting that this part of the brain may represent a target for continued research into PTSD, and potentially the development of new therapeutic approaches.

“The differences were largely within the posterior lobe, where a lot of the more cognitive functions attributed to the cerebellum seem to localize, as well as the vermis, which is linked to a lot of emotional processing functions,” said Ashley Huggins, PhD, who is first author of the team’s published study in Molecular Psychiatry, and who helped to carry out the work as a postdoctoral researcher at Duke in the lab of psychiatrist Raj Morey, MD.

The findings have prompted Huggins, who is now an assistant professor of psychology at the University of Arizona, to start looking for what comes first, a smaller cerebellum that might make people more susceptible to PTSD, or trauma-induced PTSD that leads to cerebellum shrinkage. Huggins also hopes the results will encourage others to consider the cerebellum as an important medical target for those with PTSD. “If we know what areas are implicated, then we can start to focus interventions like brain stimulation on the cerebellum and potentially improve treatment outcomes.”

Huggins and colleagues for the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA)-Psychiatric Genomics Consortium (PGC) PTSD workgroup reported on their finding in a paper titled “Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMAPGC PTSD workgroup.” In their report the authors concluded, “Although the appreciation of the cerebellum for its contributions to cognitive and affective function is relatively recent, the current results bolster a growing literature confirming the cerebellum is not exclusively devoted to motor function and may, in fact, have unique relevance to psychiatric conditions including PTSD … The insights from the current study have revealed a novel treatment target that may be leveraged to improve treatment outcomes for PTSD.”

PTSD is a psychiatric disorder brought about by experiencing or witnessing a traumatic event, such as a car accident, sexual abuse, or military combat. Though most people who endure a traumatic experience are spared from the disorder, “… nearly 10% of trauma survivors develop chronic symptoms of posttraumatic stress disorder (PTSD), a debilitating psychiatric condition characterized by a constellation of symptoms including intrusive memories, avoidance, hypervigilance, and negative changes in mood and cognition,” the team explained.

Researchers have identified several brain regions involved in PTSD, including the almond-shaped amygdala that regulates fear, and the hippocampus, a critical hub for processing memories and routing them throughout the brain.

The grapefruit-sized cerebellum—the name is Latin for “little brain”—by contrast, has received less attention for its role in PTSD. “It’s a really complex area,” Huggins said. In fact, while the cerebellum makes up just 10% of the brain’s total volume but packs in more than half of the brain’s 86 billion nerve cells.

The cerebellum is best known for its role in coordinating balance and choreographing complex movements, like walking or dancing. But there is much more to it than that. The cerebellum can influence emotion and memory, which are impacted by PTSD. “If you look at how densely populated with neurons it is relative to the rest of the brain, it’s not that surprising that it does a lot more than balance and movement,” Huggins noted. The authors pointed out that the cerebellum shares connections with areas of the brain including the prefrontal and limbic areas, “strongly suggesting that it participates in processes beyond motor coordination that may be highly relevant of PTSD,” they noted. The cerebellum is also connected widely with stress-related regions of the brain, such as with the amygdala and hippocampus, which may make it especially vulnerable to traumatic stress, “… potentially leading to the development of PTSD symptoms by disrupting typical brain-mediated stress responses via cerebro-cerebellar circuits,” the team continued. But also, they added, “A growing body of structural and functional magnetic resonance imaging studies has begun to examine the role of the cerebellum in PTSD.”

Researchers have recently observed changes to the size of the tightly-packed cerebellum in PTSD. Most of that research, however, is limited by either a small dataset (fewer than 100 participants), broad anatomical boundaries, or a sole focus on certain patient populations, such as veterans or sexual assault victims with PTSD. And what isn’t known is whether a smaller cerebellum predisposes a person to PTSD or PTSD shrinks the brain region.

To help address these limitations in previous work Morey, along with over 40 other research groups that are part of the data-sharing consortium, pooled together their brain imaging scans to study PTSD as broadly and universally as possible.

They focused on images from 4,215 adult MRI scans, about a third of whom had been diagnosed with PTSD. And even with automated software to analyze the thousands of brain scans, Huggins manually spot-checked every image to make sure that the boundaries drawn around the cerebellum and its many subregions were accurate. “I spent a lot of time looking at cerebellums,” Huggins said.

The result of this thorough methodology was the consistent finding, that the cerebellums of PTSD patients were about two percent smaller than those of control individuals. And zooming in to specific areas within the cerebellum that influence emotion and memory, Huggins found similar cerebellar reductions in people with PTSD. “We found subregional specificity linking PTSD to smaller volumes in the posterior cerebellum, vermis, and flocculonodular cerebellum,” the team noted.

The results in addition indicated that the worse PTSD was for a person, the smaller was their cerebellum. “Focusing purely on a yes-or-no categorical diagnosis doesn’t always give us the clearest picture,” Huggins said. “When we looked at PTSD severity, people who had more severe forms of the disorder had an even smaller cerebellar volume.”

Noting limitations of their study, the authors further concluded in their report, “Overall, these findings argue for a critical role of the cerebellum in the pathophysiology of PTSD, bolstering support for the region’s contributions to processes beyond vestibulomotor function.”

The researchers suggest the results are an important first step at looking at how and where PTSD affects the brain. There are more than 600,000 combinations of symptoms that can lead to a PTSD diagnosis, Huggins explained. Figuring out if different PTSD symptom combinations have different impacts on the brain will also be important to keep in mind.

For now, the researchers hope that their work will raise recognition of the cerebellum as an important driver of complex behavior and processes beyond gait and balance, as well as point to this brain region as a potential target for new and current treatments for people with PTSD. “The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function,” they wrote. “Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.”

Huggins added, “While there are good treatments that work for people with PTSD, we know they don’t work for everyone. If we can better understand what’s going on in the brain, then we can try to incorporate that information to come up with more effective treatments that are longer lasting and work for more people.” And as the authors pointed out, “Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.”