Gut microbes encourage specialized cells to prune back extra connections in brain circuits that control social behavior, new UO research in zebrafish shows. Pruning is essential for the development of normal social behavior.
The researchers also found that these ‘social’ neurons are similar in zebrafish and mice. That suggests the findings might translate between species—and could possibly point the way to treatments for a range of neurodevelopmental conditions.
“This is a big step forward,” said UO neuroscientist Judith Eisen, who co-led the work with neuroscientist Philip Washbourne. “It also sheds light on things that are going on in larger, furrier animals.”
The team reports their findings in two new papers, published in PLOS Biology and BMC Genomics.
While social behavior is a complex phenomenon involving many parts of the brain, Washbourne’s lab previously identified a set of neurons in the zebrafish brain that are required for one particular kind of social interaction.
Normally, if two zebrafish see each other through a glass partition, they’ll approach each other and swim side by side. But zebrafish without these neurons don’t show interest.
Here, the team found a pathway linking microbes in the gut to these neurons in the brain. In healthy fish, gut microbes spurred cells called microglia to prune back extra links between neurons.
Pruning is a normal part of healthy brain development. Like clutter on a counter, extra neural connections can get in the way of the ones that really matter, resulting in muddled messages.
In zebrafish without those gut microbes, the pruning didn’t happen, and the fish showed social deficits.
“We’ve known for a while that the microbiome influences a lot of things during development,” Washbourne said. “But there hasn’t been a lot of concrete data about how the microbiome is influencing the brain. We’ve done quite a bit to push the boundary there.”
In a second paper, the team identified two defining features of this set of social neurons that may be shared by mice and zebrafish. One is that these cells could be identified by having similar genes turned on—a clue that they might serve similar roles in the brains of both species.
Both gut microbiome disruption and poor neural synapse pruning have been linked to a range of neuropsychiatric conditions like autism spectrum disorder.
“If we can tie these together, it might facilitate better therapeutics for a wide range of disorders,” said Joseph Bruckner, a postdoc in the Eisen and Washbourne labs and the first author on the PLOS Biology paper. His next step is figuring out what molecules are linking the bacteria to the microglia, mapping the pathway between microbes and behavior in even more detail.
Host-associated microbiotas guide the trajectory of developmental programs, and altered microbiota composition is linked to neurodevelopmental conditions such as autism spectrum disorder. Recent work suggests that microbiotas modulate behavioral phenotypes associated with these disorders.
We discovered that the zebrafish microbiota is required for normal social behavior and reveal a molecular pathway linking the microbiota, microglial remodeling of neural circuits, and social behavior in this experimentally tractable model vertebrate.
Examining neuronal correlates of behavior, we found that the microbiota restrains neurite complexity and targeting of forebrain neurons required for normal social behavior and is necessary for localization of forebrain microglia, brain-resident phagocytes that remodel neuronal arbors.
The microbiota also influences microglial molecular functions, including promoting expression of the complement signaling pathway and the synaptic remodeling factor c1q. Several distinct bacterial taxa are individually sufficient for normal microglial and neuronal phenotypes, suggesting that host neuroimmune development is sensitive to a feature common among many bacteria.
Our results demonstrate that the microbiota influences zebrafish social behavior by stimulating microglial remodeling of forebrain circuits during early neurodevelopment and suggest pathways for new interventions in multiple neurodevelopmental disorders.
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A large study led by Lund University in Sweden has shown that people with Alzheimer’s disease can now be identified before they experience any symptoms. It is now also possible to predict who will deteriorate within the next few years.
The study is published in Nature Medicine, and is very timely in light of the recent development of new drugs for Alzheimer’s disease.
It has long been known that there are two proteins linked to Alzheimer’s—beta-amyloid, which forms plaques in the brain, and tau, which at a later stage accumulates inside brain cells. Elevated levels of these proteins in combination with cognitive impairment have previously formed the basis for diagnosing Alzheimer’s.
“Changes occur in the brain between ten and twenty years before the patient experiences any clear symptoms, and it is only when tau begins to spread that the nerve cells die and the person in question experiences the first cognitive problems. This is why Alzheimer’s is so difficult to diagnose in its early stages,” explains Oskar Hansson, senior physician in neurology at Skåne University Hospital and professor at Lund University.
He has now led a large international research study that was carried out with 1,325 participants from Sweden, the US, the Netherlands and Australia. The participants did not have any cognitive impairment at the beginning of the study. By using PET scans, the presence of tau and amyloid in the participants’ brains could be visualized.
The people in whom the two proteins were discovered were found to be at a 20-40 times higher risk of developing the disease at follow-up a few years later, compared to the participants who had no biological changes.
“When both beta-amyloid and tau are present in the brain, it can no longer be considered a risk factor, but rather a diagnosis. A pathologist who examines samples from a brain like this, would immediately diagnose the patient with Alzheimer’s,” says Rik Ossenkoppele, who is the first author of the study and is a senior researcher at Lund University and Amsterdam University Medical Center.
He explains that Alzheimer’s researchers belong to two schools of thought—on one hand, those who believe that Alzheimer’s disease cannot be diagnosed until cognitive impairment begins. There is also the group that he himself and his colleagues belong to—who say that a diagnosis can be based purely on biology and what you can see in the brain.
“You can, for example, compare our results to prostate cancer. If you perform a biopsy and find cancer cells, the diagnosis will be cancer, even if the person in question has not yet developed symptoms,” says Rik Ossenkoppele.
Recently, positive results have emerged in clinical trials of a new drug against Alzheimer’s, Lecanemab, which has been evaluated in Alzheimer’s patients. Based on this, the study from Lund University is particularly interesting, say the researchers:
“If we can diagnose the disease before cognitive challenges appear, we may eventually be able to use the drug to slow down the disease at a very early stage. In combination with physical activity and good nutrition, one would then have a greater chance of preventing or slowing future cognitive impairment.
“However, more research is needed before treatment can be recommended for people who have not yet developed memory loss,” concludes Oskar Hansson.
In summary, evidence of advanced Alzheimer’s disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3–5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.
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The most detailed map ever made of the communication links between the hippocampus – the brain’s memory control centre – and the rest of the brain has been created by Australian scientists. And it may change how we think about human memory.
“We were surprised to find fewer connections between the hippocampus and frontal cortical areas, and more connections with early visual processing areas than we expected to see,” said Dr Marshall Dalton, a Research Fellow in the School of Psychology at the University of Sydney. “Although, this makes sense considering the hippocampus plays an important role not only in memory but also imagination and our ability to construct mental images in our mind’s eye.”
The hippocampus is a complex structure that resembles a seahorse and is tucked deep within the brain. As a vital component of the brain, it is important for memory formation and plays a key role in the transfer of memories from short-term to long-term storage. But it also plays a part in navigation, imagining fictitious or future experiences, creating mental imagery of scenes in the mind’s eye, and even in visual perception and decision making.
To generate their map, the team – led by Dr Dalton and including Dr Arkiev D’Souza, Dr Jinglei Lv and Professor Fernando Calamante from the University of Sydney’s Brain and Mind Centre – relied on MRI scans from a neuroimaging database created for the Human Connectome Project (HCP), a research consortium led by the U.S. National Institutes of Health.
They processed the existing HCP data using tailored techniques that they developed. This allowed them to follow the connections from all corners of the brain to their termination points in the hippocampus – something that had never been accomplished before in the human brain.
Most detailed map to date
“What we’ve done is take a much more detailed look at the white matter pathways, which are essentially the highways of communication between different areas of the brain,” said Dr Dalton. “And we developed a new approach that allowed us to map how the hippocampus connects with the cortical mantle, the outer layer of the brain, but in a very detailed way.
“What we’ve created is a highly detailed map of white matter pathways connecting the hippocampus with the rest of the brain. It’s essentially a roadmap of brain regions that directly connect with the hippocampus and support its important role in memory formation.”
Technical limitations inherent to previous MRI investigations of the human hippocampus meant it was only possible to visualise its connections in very broad terms. “But we have now developed a tailored method that allows us to confirm where within the hippocampus different cortical areas are connecting. And that hasn’t been done before in a living human brain,” said Dr Dalton.
Unexpected results
The team was delighted their results largely aligned with data from previous studies overseas over the past few decades, which had relied on post-mortem studies of primate brains. However, the University of Sydney team found that the number of connections between the hippocampus and some brain areas was either much lower (in the case of frontal cortical areas) or higher (in the case of visual processing areas) than expected.
This could indicate that although some pathways were conserved as humans evolved, human brains may also have developed unique patterns of connectivity different from other primates. Further research is needed to tease this apart in more detail.
These differences in connectivity may just be a limitation of the MRI technique – or it could be real. They may, for example, help explain why some of our primate cousins – especially chimpanzees – are better at some memory tasks than humans, especially those relying on short-term memory. Chimpanzees have bested humans at cognitive tasks involving a form of mathematics known as game theory, which relies on short-term memory, pattern recognition and rapid visual assessment.
“Although we have achieved this high-resolution mapping of the human hippocampus, the tract tracing method conducted on non-human primates – which can see down to the cellular level – is able to see more connections than can be discerned with an MRI,” mused Dr Dalton.
“Or it could be that the human hippocampus really does have a smaller number of connections with frontal areas than we expect, and greater connectivity with visual areas of the brain. As the neocortex expanded, perhaps humans evolved different patterns of connectivity to facilitate human-specific memory and visualisation functions which, in turn, may underpin human creativity.
“It’s a bit of a puzzle – we just don’t know. But we love puzzles and will keep investigating.”
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(CAMDEN, NJ) – Internationally known stroke expert Tudor Jovin, MD, chair of the department of neurology and professor of neurology at Cooper Medical School of Rowan University (CMSRU) and medical director of the Cooper Neurological Institute at Cooper University Health Care, is co-principal investigator and lead author of a study published today in The New England Journal of Medicine, one of the world’s leading medical journals.
The randomized, five-year trial conducted in China compared the efficacy of thrombectomy, an innovative minimally invasive surgical procedure, to treat acute basilar artery occlusion (BAO), versus medical therapy only, in 217 patients (110 in the thrombectomy group and 107 in the control group). At the conclusion of the study, the researchers found that the thrombectomy procedure led to a higher percentage of patients with good functional status at 90 days compared to patients who received medical therapy only.
BAO is a rare, but often fatal, type of stroke. The basilar artery is the main artery that supplies blood to the back portion of the brain and the brainstem. Blockage of the basilar artery causes a potentially catastrophic medical condition that leads to death or severe disability in up to 68% of patients who suffer this kind of stroke. Currently, most patients presenting with BAO are treated medically with intravenous, clot-busting medications and supportive care, often with poor results.
“This study shows great promise and progress in treating some of the most devastating kind of strokes. Up until now, the effects and risks of endovascular thrombectomy six to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied,” explained Dr. Jovin. “We know that blockages of the basilar artery are frequently devastating with high morbidity and mortality rates.
“Recognizing the effectiveness of this form of treatment may lead to it being used sooner and more frequently in BAO stroke patients, giving physicians more clinical options,” said Dr. Jovin. “Widespread use of endovascular thrombectomy in these types of stroke could save many lives.”
For more about the study, visit the New England Journal of Medicine.
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Brain changes in autism are comprehensive throughout the cerebral cortex rather than just particular areas thought to affect social behavior and language, according to a new UCLA-led study that significantly refines scientists’ understanding of how autism spectrum disorder (ASD) progresses at the molecular level.
The study, published today in Nature, represents a comprehensive effort to characterize ASD at the molecular level. While neurological disorders like Alzheimer’s disease or Parkinson’s disease have well-defined pathologies, autism and other psychiatric disorders have had a lack of defining pathology, making it difficult to develop more effective treatments.
The new study finds brain-wide changes in virtually all of the 11 cortical regions analyzed, regardless of whether they are higher critical association regions – those involved in functions such as reasoning, language, social cognition and mental flexibility – or primary sensory regions.
“This work represents the culmination of more than a decade of work of many lab members, which was necessary to perform such a comprehensive analysis of the autism brain,” said study author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology and Psychiatry at UCLA.
“We now finally are beginning to get a picture of the state of the brain, at the molecular level, of the brain in individuals who had a diagnosis of autism. This provides us with a molecular pathology, which similar to other brain disorders such as Parkinson’s, Alzheimer’s and stroke, provides a key starting point for understanding the disorder’s mechanisms, which will inform and accelerate development of disease-altering therapies.”
Just over a decade ago, Geschwind led the first effort to identify autism’s molecular pathology by focusing on two brain regions, the temporal lobe and the frontal lobe. Those regions were chosen because they are higher order association regions involved in higher cognition – especially social cognition, which is disrupted in ASD.
For the new study, researchers examined gene expression in 11 cortical regions by sequencing RNA from each of the four main cortical lobes. They compared brain tissue samples obtained after death from 112 people with ASD against healthy brain tissue.
While each profiled cortical region showed changes, the largest drop off in gene levels were in the visual cortex and the parietal cortex, which processes information like touch, pain and temperature.
The researchers said this may reflect the sensory hypersensitivity that is frequently reported in people with ASD.
Researchers found strong evidence that the genetic risk for autism is enriched in a specific neuronal module that has lower expression across the brain, indicating that RNA changes in the brain are likely the cause of ASD rather than a result of the disorder.
One of the next steps is to determine whether researchers can use computational approaches to develop therapies based on reversing gene expression changes the researchers found in ASD, Geschwind said, adding that researchers can use organoids to model the changes in order to better understand their mechanisms.
Other authors include Michael J. Gandal, Jillian R. Haney, Brie Wamsley, Chloe X. Yap, Sepideh Parhami, Prashant S. Emani, Nathan Chang, George T. Chen, Gil D. Hoftman, Diego de Alba, Gokul Ramaswami, Christopher L. Hartl, Arjun Bhattacharya, Chongyuan Luo, Ting Jin, Daifeng Wang, Riki Kawaguchi, Diana Quintero, Jing Ou, Ye Emily Wu, Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Mark Gerstein, and Bogdan Pasaniuc. The authors declared no competing interests.
Funding: This work was funded by grants to Geschwind (NIMHR01MH110927, U01MH115746, P50-MH106438 and R01MH109912, R01MH094714), Gandal (SFARI Bridge to Independence Award, NIMH R01-MH121521, NIMH R01-MH123922 and NICHD-P50-HD103557), and Haney (Achievement Rewards for College Scientists Foundation, Los Angeles Founder Chapter, UCLA Neuroscience Interdepartmental Program).
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About Conference:
International Conference on Neurology and Neuro Disorders
Neurology and Neuro Disorders Conferences, organized by the Pencis group.
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International Research Awards on Neurology and Neuro Disorders
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