Thalamus is critical hub in neural circuits that maintain working memory and in those that prepare for movement

From NINDS Press Release:

Brain “relay” also key to holding thoughts in the mind

Wednesday, May 3, 2017

 

Cartoon of brain circuit that may help holds thoughts in mind

Hold that thought
Scientists showed that neurons connecting the thalamus to the prefrontal cortex helped mouse brains hold thoughts in mind.
Halassa lab, NYU Langone Medical Center

 

Halassa lab, NYU Langone Medical Center

Thalamus eyed as potential treatment target for schizophrenia’s working memory deficits

Long assumed to be a mere “relay,” an often-overlooked egg-like structure in the middle of the brain also turns out to play a pivotal role in tuning-up thinking circuity. A trio of studies in mice funded by the National Institutes of Health revealed that the thalamus sustains the ability to distinguish categories and hold thoughts in mind.

By manipulating activity of thalamus neurons, scientists were able to control an animal’s ability to remember how to find a reward. In the future, the thalamus might even become a target for interventions to reduce cognitive deficits in psychiatric disorders such as schizophrenia, researchers say.

“If the brain works like an orchestra, our results suggest the thalamus may be its conductor,” explained Michael Halassa, M.D., Ph.D., of New York University (NYU) Langone Medical Center, a BRAINS Award grantee of the NIH’s National Institute of Mental Health (NIMH), and also a grantee of the National Institute of Neurological Disorders and Stroke (NINDS). “It helps ensembles play in-sync by boosting their functional connectivity.”

Three independent teams of investigators led by Halassa, Joshua Gordon, M.D., Ph.D., formerly of Columbia University, New York City, now NIMH director, in collaboration with Christoph Kellendonk, Ph.D. of Columbia,  and Karel Svoboda, PhD, at Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia, in collaboration with Charles Gerfen, Ph.D., of the NIMH Intramural Research Program, report on the newfound role for the thalamus online May 3, 2017 in the journals Nature and Nature Neuroscience.

The prevailing notion of the thalamus as a relay was based on its connections with parts of the brain that process inputs from the senses. But the thalamus has many connections with other parts of the brain that have yet to be explored, say the researchers.

Two of the groups investigated a circuit that connects the mid/upper (mediodorsal) thalamus with the prefrontal cortex (PFC), the brain’s thinking and decision making center. Brain imaging studies have detected decreased connectivity in this circuit in patients with schizophrenia, who often experience working memory problems.

Halassa and colleagues found that neurons in the thalamus and PFC appear to talk back and forth with each other. They monitored neural activity in mice performing a task that required them to hold in mind information about categories, so that they could act on cues indicating which of two doors hid a milk reward.

Optogenetically suppressing neuronal activity in the thalamus blocked the mice’s ability to choose the correct door, while optogenetically stimulating thalamus neural activity improved the animals’ performance on the working memory task. This confirmed a previously known role for the structure, extending it to the specialized tasks Halassa and colleagues used and demonstrating for the first time a specific role in the maintenance of information in working memory.

What kind of information was the thalamus helping to maintain? The researchers found sets of neurons in the PFC that held in memory the specific category of information required in order to choose the correct door. They determined that the thalamus did not (at least in this case) relay such specific category information, but instead broadly provided amplification that was crucial in sustaining memory of the category in the PFC. It accomplished this by boosting the synchronous activity, or functional connectivity, of these sets of PFC neurons.

“Our study may have uncovered the key circuit elements underlying how the brain represents categories,” suggested Halassa.

Gordon and colleagues saw similar results when they tested how the same circuit controlled a mouse’s ability to find milk in a maze. The animals had to remember whether they had turned left or right to get their reward prior to a brief delay – and do the opposite. Also using optogenetics, the study teased apart differing roles for subgroups of PFC neurons and interactions with the brain’s memory hub, the hippocampus.

Thalamus inputs to the PFC sustained the maintenance of working memory by stabilizing activity there during the delay. “Top-down” signals from the PFC back to the thalamus supported memory retrieval and taking action. Consistent with previous findings, inputs from the hippocampus were required to encode in PFC neurons the location of the reward – analogous to the correct door in the Halassa experiment.

“Strikingly, we found two separate populations of neurons in the PFC. One encoded for spatial location and required hippocampal input; the other was active during memory maintenance and required thalamic input,” noted Gordon. “Our findings should have translational relevance, particularly to schizophrenia. Further study of how this circuit might go awry and cause working memory deficits holds promise for improved diagnosis and more targeted therapeutic approaches.”

In their study, the Janelia team and Gerfen similarly showed that the thalamus plays a crucial role in sustaining short-term memory, by cooperating with the cortex through bi-directional interactions. Mice needed to remember where to move after a delay of seconds, to gather a reward. In this case, the thalamus was found to be in conversation with a part of the motor cortex during planning of those movements. Neuronal electrical monitoring revealed activity in both structures, indicating that they together sustain information held in the cortex that predicted in which direction the animal would subsequently move. Optogenetic probing revealed that the conversation was bidirectional, with cortex activity dependent on thalamus and vice versa.

“Our results show that cortex circuits alone can’t sustain the neural activity required to prepare for movement,” explained Gerfen. “It also requires reciprocal participation across multiple brain areas, including the thalamus as a critical hub in the circuit.”

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Study indicates that pattern of neuronal activity is specific for each memory

From NINDS Press Release:

NIH scientists try to crack the brain’s memory codes

Thursday, June 1, 2017

Studies of epilepsy patients uncover clues to how the brain remembers

Cracking the brain’s memory codes
Scientists at NIH used electrical recordings to study how the human brain remembers.
Courtesy of Zaghloul lab, NIH/NINDS.

In a pair of studies, scientists at the National Institutes of Health explored how the human brain stores and retrieves memories. One study suggests that the brain etches each memory into unique firing patterns of individual neurons. Meanwhile, the second study suggests that the brain replays memories faster than they are stored.

The studies were led by Kareem Zaghloul, M.D., Ph.D., a neurosurgeon-researcher at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Persons with drug resistant epilepsy in protocols studying surgical resection of their seizure focus at the NIH’s Clinical Center enrolled in this study. To help locate the source of the seizures, Dr. Zaghloul’s team surgically implanted a grid of electrodes into the patients’ brains and monitored electrical activity for several days.

“The primary goal of these recordings is to understand how to stop the seizures. However, it’s also a powerful opportunity to learn how the brain works,” said Dr. Zaghloul.

For both studies, the researchers monitored brain electrical activity while testing the patients’ memories. The patients were shown hundreds of pairs of words, like “pencil and bishop” or “orange and navy,” and later were shown one of the words and asked to remember its pair.

In one study, published in the Journal of Neuroscience, the patients correctly remembered 38 percent of the word pairs they were shown. Electrical recordings showed that the brain waves the patients experienced when they correctly stored and remembered a word pair often occurred in the temporal lobe and prefrontal cortex regions. Nevertheless, the researchers showed that the waves that appeared when recalling the words happened faster than the waves that were present when they initially stored them as memories.

“Our results suggest the brain replays memories on fast forward,” said Dr. Zaghloul.

In the second study, published in Current Biology, the researchers used a new type of grid, called a high density microelectrode array, to monitor the activity of dozens of individual neurons during the memory tests. The arrays were implanted into the middle temporal gyrus, a part of the brain thought to control word, face and distance recognition.

In this study, the patients correctly remembered 23 percent of the word pairs. When the researchers looked at the electrical recordings, they found that the pattern of neurons that fired when the patients correctly recalled a word pair appeared to be similar to the pattern of neurons that fired when they first learned the pair. Moreover, the results showed that the overall activity of the neurons was specific to each individual word pair and was quietest when the patients correctly remembered a pair, suggesting that the brain only uses a small proportion of neurons to represent each memory.

“These results support the idea that each memory is encoded by a unique firing pattern of individual neurons in the brain,” concluded Dr. Zaghloul.

 

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SCN astrocytes are important in circadian rhythm

From Washington University in St. Louis:

Clock stars: Astrocytes keep time for brain, behavior

Star-shaped cells around neurons prove to be surprisingly important players in body’s clock

Until recently, work on biological clocks that dictate daily fluctuations in most body functions, including core body temperature and alertness, focused on neurons, those electrically excitable cells that are the divas of the central nervous system.

Asked to define the body’s master clock, biologists would say it is two small spheres — the suprachiasmatic nuclei, or SCN — in the brain that consist of 20,000 neurons. They likely wouldn’t even mention the 6,000 astroglia mixed in with the neurons, said Erik Herzog, a neuroscientist in Arts & Sciences at Washington University in St. Louis. In a March 23 advance online publication from Current Biology, Herzog and his collaborators show that the astroglia help to set the pace of the SCN to schedule a mouse’s day.

The astroglia, or astrocytes, were passed over in silence partly because they weren’t considered to be important. Often called “support cells,” they were supposed to be gap fillers or place holders. Their Latin name, after all, means “starry glue.”

Then two things happened. Scientists discovered that almost all the cells in the body keep time, with a few exceptions such as stem cells.  And they also began to realize that the astrocytes do a lot more than they had thought. Among other things, they secrete and slurp neurotransmitters and help neurons  form strengthened synapses to consolidate what we’ve learned. In fact, scientists began to speak of the tripartite synapse, emphasizing the role of an astrocyte in the communication between two neurons.

So for a neuroscientist like Herzog, the obvious question was: What were the astrocytes doing in the SCN?  Were they keeping time? And if they were keeping time, how did the astrocyte clocks interact with the neuron clocks?

Herzog answered the first question in 2005 — yes, astrocytes have daily clocks — but then the research got stuck. To figure out what the astrocytes were doing in living networks of cells and in living animals, the scientists had to be able to manipulate them independently of the neurons with which they are entwined. The tools to do this simply didn’t exist.

Now, Herzog’s graduate student Matt Tso, the first author on the paper, has solved the problem. The tools he devised allow astrocytes in the SCN to be independently controlled. Using his toolkit, the lab ran two experiments, altering the astrocyte clocks and monitoring the highly ritualized, daily behavior of wheel-running in mice.

The scientists were surprised by the results, to be published in the April 7 print  issue of Current Biology. In both experiments, tweaks to the astrocyte clocks reliably slowed the mouse’s sense of time. “We had no idea they would be that influential,” Tso said.

The scientists are already planning follow-up experiments.

Figuring out how and where these clocks function in the brain and body is important because their influence is ubiquitous. For his part, Herzog is already looking at the connections between circadian rhythm and brain cancer, pre-term birth, manic depression and other diseases.

Astrocytes clock in

A biological clock is a series of interlocking reactions that act somewhat like a biochemical hourglass. An accumulating protein eventually shuts down its own production, much as the sand eventually drains from the top half of the hourglass. But then —through the magic of feedback loops — the biochemical hourglass, in effect, turns itself over and starts again.

At first, scientists were aware only of the clock in the SCN. If it is destroyed in an animal such as a rat, the rat will sleep for the same amount of time but in fits and starts instead of for long periods.

In 2005, Herzog demonstrated that astrocytes, like neurons, have internal clocks. His test subjects made the cover of an issue of the Journal of Neuroscience that year.

But then the genes that make up the biological clock began to be found in many different kinds of cells: lung, heart, liver, and sperm. Hair cells, by the way, prefer to grow in the evening.

So Herzog began to wonder about astrocytes in the SCN. Were they, too, keeping time?

To find out, he coupled a bioluminescent protein to a clock gene and then isolated astrocytes in a glass dish. He found that the astrocytes brightened and dimmed rhythmically, proof that they were keeping time.

The obvious next step was to look at the astrocytes not only in a glass dish but also in SCN slices and in living animals. But that turned out to be easier said than done. “We burned through two postdocs trying to get these experiments to work,” Herzog said.

So it is a technical triumph that Tso was able to make the astrocytes light up when they were expressing clock genes and to add or delete clock genes in the astrocytes while leaving the neurons intact, Herzog said.

To manipulate the astrocytes in the SCN independently of neurons, the scientists needed a way to target the astrocytes alone. The key turned out to a structural protein that helps to give astrocytes their branching structure, here linked to a protein that fluoresces green. Credit: LPDWiki.

As a first step, collaborator Michihiro Mieda from Kanazawa University created a “conditional reporter” that switched on a firefly luciferase whenever a clock gene was being expressed in a cell of interest. Tso delivered the tiny switch to the astrocytes inside a virus.

In slices of a mouse SCN with this reporter in place, the scientists could see that the star-shaped cells were expressing the clock gene in a rhythmic pattern. This proved that astrocytes keep time in living tissue where they are interacting with one another and with neurons, as well as when they are isolated in a dish.

Next, the scientists used the new gene-editing tool CRISPR-Cas9 to delete a clock gene in only the astrocytes of the SCN of living mice. They then monitored the mice for changes in the time they started running on a wheel each day.

Running is an easily measured behavior that provides a reliable indication of the state of the underlying body clock. A mouse in constant darkness will start running on a wheel approximately every 23.7 hours, typically deviating by less than 10 minutes from this schedule.

In this SCN slice, cells expressing an astrocyte-specific structural protein that had been stained red (top right panel) matched up well with cells that had been equipped to fluoresce green when they were expressing a clock gene (middle right panel), demonstrating that the scientists could watch astrocytes tick in the biological clock. Credit: Herzog lab.

“When we deleted the gene in the astrocytes, we had good reason to predict the rhythm would remain unchanged,” Tso said. “When people deleted this clock gene in neurons, the animals completely lost rhythm, which suggests that the neurons are necessary to sustain a daily rhythm.”

Instead, when astrocyte clock was deleted, the SCN clock ran slower. The mice climbed into their wheels one hour later than usual every day.

“This was quite a surprise,” Tso said.

The results of the next experiment were even more exciting for them. The scientists began with a mouse that has a mutation making its clocks run fast and then “rescued” this mutation in astrocytes but not in neurons. This meant that the astrocyte clocks were running at the normal pace but the neuron clocks were still fast.

“We expected the SCN to follow the neurons’ pace. There are 10 times more neurons in the SCN than astrocytes. Why would the behavior follow the astrocytes’? ” Tso said.

But that is exactly what they did. The mice with the restored astrocyte clocks climbed into their wheels two hours later than mice whose astrocytes and neurons were both fast-paced.

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“Mini-brains” in peripheral nervous system may analyze and interpret sensations

From University of Leeds Health News:

Discovery of ‘mini-brains’ could change understanding of pain medication

Discovery of ‘mini-brains’ could change understanding of pain medication

The body’s peripheral nervous system could be capable of interpreting its environment and modulating pain, neuroscientists have established, after studying how rodents reacted to stimulation.

Until now, accepted scientific theory has held that only the central nervous system – the brain and spinal cord – could actually interpret and analyse sensations such as pain or heat.

The peripheral system that runs throughout the body was seen to be a mainly wiring network, relaying information to and from the central nervous system by delivering messages to the ‘control centre’ (the brain), which then tells the body how to react.

In recent years there has been some evidence of a more complex role for the peripheral nervous system, but this study by Hebei Medical University in China and the University of Leeds highlights a crucial new role for the ganglia, a collection of ‘nodules’.

See how the ganglia in the peripheral system could play a key role in interpreting pain.

Previously these were believed to act only as an energy source for messages being carried through the nervous system. In addition, researchers now believe they also have the ability to act as ‘mini-brains’, modifying how much information is sent to the central nervous system.

The five year study found that nerve cells within the ganglia can exchange information between each other with the help of a signalling molecule called GABA, a process that was previously believed to be restricted to the central nervous system.

The findings are published today in the Journal of Clinical Investigation and have potential future implications for the development of new painkillers, including drugs to target backache and arthritis pain.

Pain relief drugs

Current pain relief drugs are targeted at the central nervous system and often have side effects that can include addiction and tolerance issues.

The new research opens up the possibility of a route for developing non-addictive and non-drowsy drugs, targeted at the peripheral nervous system. Safe therapeutic dosage of these new drugs can also be much higher, potentially resulting in higher efficacy.

Whilst the study showed a rodent’s peripheral nervous system was able to interpret the type of stimulation it was sensing, further research is still needed to understand how sensations are interpreted and whether these results apply to humans.

In addition, the theory would need to be adopted by drug development companies and extensively tested before laboratory and clinical trials of a drug could be carried out. Should the findings be adopted, a timescale of at least 15-20 years might be required to produce a working drug.

Nerve arrangements

Neuroscientist Professor Nikita Gamper, who led the research at both universities, said: “We found the peripheral nervous system has the ability to alter the information sent to the brain, rather than blindly passing everything on to the central nervous system.

“We don’t yet know how the system works, but the machinery is definitely in place to allow the peripheral system to interpret and modify the tactile information perceived by the brain in terms of interpreting pain, warmth or the solidity of objects.

“Further research is needed to understand exactly how it operates, but we have no reason to believe that the same nerve arrangements would not exist in humans.

“When our research team looked more closely at the peripheral system, we found the machinery for neuronal communication did exist in the peripheral nervous system’s structure. It is as if each sensory nerve has its own ‘mini-brain’, which to an extent, can interpret incoming information.”

[…]

Professor Gamper believes the findings may present a challenge to the accepted ‘Gate Control Theory of Pain’. The theory holds that a primary ‘gate’ exists between the peripheral and central nervous systems, controlling what information is sent to the central system.

The study now suggests the transmission of information to the central nervous system must go through another set of gates, or more accurately a process similar to a volume control, where the flow of information can be controlled by the peripheral nervous system.

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Dendrites more electrically active than soma of neurons; perform digital and analog computations

From UCLA Newsroom:

Brain is 10 times more active than previously measured, UCLA researchers find

Dan Gordon | March 09, 2017

Neuron

Enter a caption

Shelley Halpain/UC San DiegoUCLA scientists discovered that dendrites (shown here in green) are not just passive conduits for electrical currents between neurons.


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A new UCLA study could change scientists’ understanding of how the brain works — and could lead to new approaches for treating neurological disorders and for developing computers that “think” more like humans.

The research focused on the structure and function of dendrites, which are components of neurons, the nerve cells in the brain. Neurons are large, tree-like structures made up of a body, the soma, with numerous branches called dendrites extending outward. Somas generate brief electrical pulses called “spikes” in order to connect and communicate with each other. Scientists had generally believed that the somatic spikes activate the dendrites, which passively send currents to other neurons’ somas, but this had never been directly tested before. This process is the basis for how memories are formed and stored.

Scientists have believed that this was dendrites’ primary role.

But the UCLA team discovered that dendrites are not just passive conduits. Their research showed that dendrites are electrically active in animals that are moving around freely, generating nearly 10 times more spikes than somas. The finding challenges the long-held belief that spikes in the soma are the primary way in which perception, learning and memory formation occur.

“Dendrites make up more than 90 percent of neural tissue,” said UCLA neurophysicist Mayank Mehta, the study’s senior author. “Knowing they are much more active than the soma fundamentally changes the nature of our understanding of how the brain computes information. It may pave the way for understanding and treating neurological disorders, and for developing brain-like computers.”

The research is reported in the March 9 issue of the journal Science.

Scientists have generally believed that dendrites meekly sent currents they received from the cell’s synapse (the junction between two neurons) to the soma, which in turn generated an electrical impulse. Those short electrical bursts, known as somatic spikes, were thought to be at the heart of neural computation and learning. But the new study demonstrated that dendrites generate their own spikes 10 times more often than the somas.

Video: Animation of a neuron firing electrical spikes

The researchers also found that dendrites generate large fluctuations in voltage in addition to the spikes; the spikes are binary, all-or-nothing events. The somas generated only all-or-nothing spikes, much like digital computers do. In addition to producing similar spikes, the dendrites also generated large, slowly varying voltages that were even bigger than the spikes, which suggests that the dendrites execute analog computation.

“We found that dendrites are hybrids that do both analog and digital computations, which are therefore fundamentally different from purely digital computers, but somewhat similar to quantum computers that are analog,” said Mehta, a UCLA professor of physics and astronomy, of neurology and of neurobiology. “A fundamental belief in neuroscience has been that neurons are digital devices. They either generate a spike or not. These results show that the dendrites do not behave purely like a digital device. Dendrites do generate digital, all-or-none spikes, but they also show large analog fluctuations that are not all or none. This is a major departure from what neuroscientists have believed for about 60 years.”

Because the dendrites are nearly 100 times larger in volume than the neuronal centers, Mehta said, the large number of dendritic spikes taking place could mean that the brain has more than 100 times the computational capacity than was previously thought.

Recent studies in brain slices showed that dendrites can generate spikes. But it was neither clear that this could happen during natural behavior, nor how often. Measuring dendrites’ electrical activity during natural behavior has long been a challenge because they’re so delicate: In studies with laboratory rats, scientists have found that placing electrodes in the dendrites themselves while the animals were moving actually killed those cells. But the UCLA team developed a new technique that involves placing the electrodes near, rather than in, the dendrites.

Using that approach, the scientists measured dendrites’ activity for up to four days in rats that were allowed to move freely within a large maze. Taking measurements from the posterior parietal cortex, the part of the brain that plays a key role in movement planning, the researchers found far more activity in the dendrites than in the somas — approximately five times as many spikes while the rats were sleeping, and up to 10 times as many when they were exploring.

“Many prior models assume that learning occurs when the cell bodies of two neurons are active at the same time,” said Jason Moore, a UCLA postdoctoral researcher and the study’s first author. “Our findings indicate that learning may take place when the input neuron is active at the same time that a dendrite is active — and it could be that different parts of dendrites will be active at different times, which would suggest a lot more flexibility in how learning can occur within a single neuron.”

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Phasic inhibition in the hippocampal CA1 region may be crucial to memory consolidation

From IST Austria:

The rhythm that makes memories permanent

Scientists at IST Austria identify mechanism that regulates rhythmic brain waves • Inhibition at synapses is the key to make memories permanent

Every time we learn something new, the memory does not only need to be acquired, it also needs to be stabilized in a process called memory consolidation. Brain waves are considered to play an important role in this process, but the underlying mechanism that dictates their shape and rhythm was still unknown. A study now published in Neuron shows that one of the brain waves important for consolidating memory is dominated by synaptic inhibition.

So-called sharp wave ripples (SWRs) are one of three major brain waves coming from the hippocampus. The new study, a cooperation between the research groups of Professors Peter Jonas and Jozsef Csicsvari at the Institute of Science and Technology Austria (IST Austria), found the mechanism that generates this oscillation of neuronal activity in mice. “Our results shed light on the mechanisms underlying this high-frequency network oscillation. As our experiments provide information both about the phase and the location of the underlying conductance, we were able to show that precisely timed synaptic inhibition is the current generator for sharp wave ripples.” explains author Professor Peter Jonas.

When neurons oscillate in synchrony, their electrical activity adds together so that measurements of field potential can pick them up. SWRs are one of the most synchronous oscillations in the brain. Their name derives from their characteristic trace when measuring local field potential: the slow sharp waves have a triangular shape with ripples, or fast field oscillations, added on. SWRs have been suggested to play a key role in making memories permanent. In this study, the researchers wanted to identify whether ripples are caused by a temporal modulation of excitation or of inhibition at the synapse, the connection between neurons. For Professor Jozsef Csicsvari, a pooling of expertise was crucial in answering this question: “SWRs play an important role in the brain, but the mechanism generating them has not been identified so far – probably partly because of technical limitations in the experiments. We combined the Jonas group’s experience in recording under voltage-clamp conditions with my group’s expertise in analyzing electrical signals while animals are behaving. This collaborative effort made unprecedented measurements possible and we could achieve the first high resolution recordings of synaptic currents during SWR in behaving mice.”

The neuroscientists found that the frequency of both excitatory and inhibitory events at the synapse increased during SWRs. But quantitatively, synaptic inhibition dominated over excitation during the generation of SWRs. Furthermore, the magnitude of inhibitory events positively correlated with SWR amplitude, indicating that the inhibitory events are the driver of the oscillation. Inhibitory events were phase locked to individual cycles of ripple oscillations. Finally, the researchers showed that so-called PV+ interneurons – neurons that provide inhibitory output onto other neurons – are mainly responsible for generating SWRs.

The authors propose a model involving two specific regions in the hippocampus, CA1 and CA3. In their model SWRs are generated by a combination of tonic excitation from the CA3 region and phasic inhibition within the CA1 region. Jian Gan, first author and postdoc in the group of Peter Jonas, explains the implications for temporal coding of information in the CA1 region: “In our ripple model, inhibition ensures the precise timing of neuronal firing. This could be critically important for preplay or replay of neuronal activity sequences, and the consolidation of memory. Inhibition may be the crucial player to make memories permanent.”

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Certain gut bacteria may contribute to misfolded proteins and inflammation in neurodegenerative diseases

From U of L School of Medicine News:

Study demonstrates role of gut bacteria in neurodegenerative diseases

Research at UofL funded by The Michael J. Fox Foundation shows proteins produced by gut bacteria may cause misfolding of brain proteins and cerebral inflammation
Study demonstrates role of gut bacteria in neurodegenerative diseases

Robert P. Friedland, M.D.

Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. In more than 90 percent of cases, physicians and scientists do not know what causes these processes to occur.

Robert P. Friedland, M.D., the Mason C. and Mary D. Rudd Endowed Chair and Professor of Neurology at the University of Louisville School of Medicine, and a team of researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS.

Alpha-synuclein (AS) is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Friedland has hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. He also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain.

The research, which was supported by The Michael J. Fox Foundation, involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of AS in the intestines and the brain and increased cerebral AS aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of AS aggregates, compared with nematodes not exposed to the bacterial amyloid. A research group led by neuroscientist Shu G. Chen, Ph.D., of Case Western Reserve University, performed this collaborative study.

This new understanding of the potential role of gut bacteria in neurodegeneration could bring researchers closer to uncovering the factors responsible for initiating these diseases and ultimately developing preventive and therapeutic measures.

“These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer’s disease, Parkinson’s disease and ALS,” Friedland said. “This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut.”

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