NS/ Nine paralysis patients walk again thanks to newly identified neurons

Paradigm
Paradigm
Published in
26 min readNov 23, 2022

Neuroscience biweekly vol. 71, 9th November — 23rd November

TL;DR

  • A new study has identified nerve cells that are altered in response to a spinal cord stimulation technique proven to restore walking ability in people once thought to be permanently paralyzed. The study involved restoring movement in nine patients with severe spinal cord injury before examining damage at a cellular level in a mouse population. This analysis revealed that two populations of neurons in the lumbar spinal cord were prioritized in response to the stimulation. The research is published in Nature.
  • A new approach to stem cell therapy that uses antibodies instead of traditional immunosuppressant drugs robustly preserves cells in mouse brains and has the potential to fast-track trials in humans, a new study suggests. Suppression with monoclonal antibodies enabled the long-term survival of human stem cell transplants in mouse brains for at least six to eight months, while the cell grafts did not survive more than two weeks in most animals when using standard immunosuppressant drugs.
  • Rejuvenating the immune cells that live in tissues surrounding the brain improves fluid flow and waste clearance from the brain — and may help treat or even prevent neurodegenerative diseases such as Alzheimer’s and Parkinson’s, according to a new study.
  • The autonomic nervous system is known as the control center for involuntary bodily processes such as the beating of our hearts and our breathing. The fact that this part of the nervous system also has the ability to spontaneously restore muscle function following a nerve injury was recently discovered. Their findings may form the basis for improving and developing interventions to treat nerve lesions.
  • A scalpel-free, high-tech form of brain surgery pioneered at UVA Health offers long-term relief for patients with essential tremor, a common movement disorder, a five-year review shows.
  • Using an innovative technology that enables imaging of two individuals during live and natural conditions, researchers have identified specific brain areas in the dorsal parietal region of the brain associated with the social symptomatology of autism.
  • Researchers have discovered that the neurotransmitter adenosine effectively acts as a brake to dopamine, another well-known neurotransmitter involved in motor control. The discovery could immediately suggest new avenues of drug development to treat symptoms of Parkinson’s disease, a movement disorder where the loss of dopamine-producing cells has been widely implicated as a cause.
  • We breathe to survive. But a breath of fresh air does more than fill our lungs. New research indicates that breathing impacts our emotions, attention and how we can process the outside world.
  • Beer is one of the oldest and most popular beverages in the world, with some people loving it and others hating the distinct, bitter taste of the hops used to flavor its many varieties. But an especially ‘hoppy’ brew might have unique health benefits. Recent research reports that chemicals extracted from hop flowers can, in lab dishes, inhibit the clumping of amyloid beta proteins, which is associated with Alzheimer’s disease (AD).
  • By studying the visual system of an octopus, researchers hope to understand how its brain organization compares to that of humans and other vertebrates. Their results could provide insight into the evolution of visual systems across species.
  • And more!

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The neurons that restore walking after paralysis

by Kathe C, Skinnider MA, Hutson et al in Nature

A new study has identified nerve cells that are altered in response to a spinal cord stimulation technique proven to restore walking ability in people once thought to be permanently paralyzed. The study involved restoring movement in nine patients with severe spinal cord injury before examining damage at a cellular level in a mouse population. This analysis revealed that two populations of neurons in the lumbar spinal cord were prioritized in response to the stimulation. The research is published in Nature.

Spinal cord injuries disrupt the communication systems between the brain and neurons in the spinal cord that direct movement. Over the last five years, scientists have developed systems that utilize electrical stimulation to help individuals recover from the paralysis that often results from such injuries. These interventions, which have been enhanced further in combination with motor rehabilitation, have changed lives but remain largely unexplained.

In a new paper, a research team at the Swiss Federal Institute of Technology Lausanne (EPFL) working with Jocelyn Bloch, a neurosurgeon at Lausanne University Hospital demonstrated the effectiveness of their technique, termed epidural electrical stimulation. In a clinical trial, a further nine patients saw their walking ability immediately improve after the stimulation was switched on. Some of the patients were able to retain improved motor function even after the stimulation was silenced.

This latter finding suggests that lasting changes are being made to the function of neurons in the spinal cord that underlie these incredible recoveries. Study leader Grégoire Courtine, a neuroscience professor at EPFL, and his team decided to examine in detail what was happening in their patients’ spinal cords.

The team was surprised to note that overall activity in the spinal cord actually decreased in response to the stimulation, suggesting that the response was being driven through smaller subpopulations of neurons rather than an en masse effort.

EESREHAB remodels the spinal cord of humans and mice. a, Body weight support system enabling overground walking and wireless implantable pulse generator operating in closed loop, connected to a paddle lead targeting the dorsal roots that innervate lumbosacral segments. b, Chronophotography showing the transitioning from sitting to walking in a representative participant. c, 18FDG-PET projected onto a personalized model of the spinal cord elaborated from high-resolution MRI (participant ID DM002), showing the metabolic activity of the spinal cord — expressed as standardized uptake value (SUVbw) — in response to walking before and after EESREHAB. d, Bar plots reporting the relative change in normalized FDG-PET metabolic activity during walking before and after EESREHAB, the lower limb motor scores, and the distance covered during the 6-min walk test (n = 9; metabolic activity mixed-effects model: t = −3.2, P = 0.002; lower limb motor scores, paired samples two-tailed t-test: t = 3.7, P = 0.0063; distance covered, paired samples two-tailed t-test: t = 3.5; P = 0.0076). e, Left, body weight support system enabling overground walking in mice, with implantable electrodes to deliver EES. Right, spinal cord visualization of projections from neurons in the motor cortex and glutamatergic (vGluT2ON) neurons in the reticular formation, traced with AAV5-CAG-COMET-GFP and AAV5-CAG-DIO-COMET-tdTomato, respectively. Scale bars, 1 mm. f, Chronophotography of representative mice with SCI only (SCI, EESOFF) or SCI with EESREHAB (EESREHAB, EESOFF). g, Lumbar spinal cord expression of cFos following walking with EESON following SCI or SCI with EESREHAB. Scale bars, 500 μm. h, Walking performance of uninjured mice (n = 3), mice with SCI (n = 10), and mice with SCI and EESREHAB tested with EESOFF (n = 10) or EESON (n = 10) (one-way ANOVA; Tukey’s honest significant difference for SCI versus EESREHAB→EESOFF: P = 3.3 × 10–11). i, The number of neurons expressing cFos(cFosON) (mice with SCI with EESON, n = 4; mice with EESREHAB and EESON, n = 4; independent samples two-tailed t-test: t = –5.7; P = 0.001). h,i, Bars show mean ± s.e.m. with individual points overlaid. *P < 0.05, **P < 0.01, ***P < 0.001.
Molecular cartography of EESREHAB. a, Overview of the eight experimental conditions capturing the key therapeutic features of EESREHAB. A detailed description is provided in Methods, ‘Experimental conditions’. b, Uniform manifold approximation and projection (UMAP) visualization of 20,990 nuclei revealing 36 neuron subpopulations. Five dorsal and ventral populations are highlighted on the basis of their marker genes. In each corner, an UMAP visualization coloured by the expression of classical marker genes reveals the cardinal organization of neuronal subpopulations across dorsal–ventral and excitatory–inhibitory axes51. MN, motor neuron; VI, ventral-inhibitory; VE, ventral-excitatory; CSF-N, cerebrospinal-fluid contacting neurons; Ia-IN, Ia inhibitory interneurons; Rora-I, inhibitory neurons expressing Rora; Rorb-I, inhibitory neurons expressing Rorb. c, Left, visualization of 22,127 barcodes registered to a common coordinate framework highlighting the expression of classical excitatory–inhibitory and ventral–dorsal marker genes. Second from left, the localization of all 36 neuron subpopulations, with each spatial barcode coloured according to cellular identity. Five classical dorsal and ventral populations are highlighted, with the spatial expression of their marker genes shown below the image. Right, RNAscope analysis, confirming the spatial location of these five neuronal subpopulations.

To tease out the groups of neurons responsible, the team worked with mice that had received similar spinal cord injuries. They created maps of gene activity in the mice’s spinal cord neurons, allowing them to track the neurons that were preferentially targeted by the stimulation treatment.

“Our model let us observe the recovery process with enhanced granularity — at the neuron level,” said Courtine in a press release.

They settled on a group of excitatory lumbar interneurons, expressing a gene called Vsx2, that were critical to the mice’s restored walking ability. Interestingly, the same neurons were not needed by healthy mice to walk without stimulation.

The team used advanced light-based stimulation techniques to show that when the Vsx2-expressing neurons were deactivated, mice with spinal cord injuries were no longer able to walk. Mice that had these neurons deactivated chronically were also unable to gain any initial benefit from the stimulation.

The authors acknowledge that walking is additionally controlled by numerous neural populations throughout the brain and spinal cord; those neurons’ locations and connectivity will have to be unearthed in future research.

Nevertheless, this is an important first step in the process, says Bloch.

“Our new study, in which nine clinical trial patients were able to recover some degree of motor function thanks to our implants, is giving us valuable insight into the reorganization process for spinal cord neurons.”

“This paves the way to more targeted treatments for paralyzed patients. We can now aim to manipulate these neurons to regenerate the spinal cord,” added study co-author and EPFL researcher Jordan Squair.

Respiratory rhythms of the predictive mind

by Micah Allen, Somogy Varga, Detlef H. Heck in Psychological Review

“Breathe in… Breathe out…” Or: “take a deep breath and count to ten.” The calming effect of breathing in stressful situations, is a concept most of us have met before. Now Professor Micah Allen from the Department of Clinical Medicine at Aarhus University has come a step closer to understanding how the very act of breathing shapes our brain.

The researchers synthesized results from more than a dozen studies with rodent, monkey, and human brain imaging, and used it to propose a new computational model that explains how our breathing influences the brain’s expectations.

“What we found is that, across many different types of tasks and animals, brain rhythms are closely tied to the rhythm of our breath. We are more sensitive to the outside world when we are breathing in, whereas the brain tunes out more when we breathe out. This also aligns with how some extreme sports use breathing, for example professional marksmen are trained to pull the trigger at the end of exhalation,” explains Professor Micah Allen.

The study suggest that breathing is more than just something we do to stay alive, explains Micah Allen.

“It suggests that the brain and breathing are closely intertwined in a way that goes far beyond survival, to actually impact our emotions, our attention, and how we process the outside world. Our model suggests there is a common mechanism in the brain which links the rhythm of breathing to these events.”

Understanding how breathing shapes our brain, and by extension, our mood, thoughts, and behaviours, is an important goal in order to better prevent and treat mental illness.

“Difficulty breathing is associated with a very large increase in the risk for mood disorders such as anxiety and depression. We know that respiration, respiratory illness, and psychiatric disorders are closely linked. Our study raises the possibility that the next treatments for these disorders might be found in the development of new ways to realign the rhythms of the brain and body, rather than treating either in isolation,” explains Micah Allen.

Stabilising our mind through breathing is a well-known and used tactic in many traditions such as yoga and meditation. The new study sheds light on how the brain makes it possible. It suggests that there are three pathways in the brain that control this interaction between breathing and brain activity. It also suggests that our pattern of breathing makes the brain more “excitable,” meaning neurons are more likely to fire during certain times of breathing

The new study gives researchers a new target for future studies in for example persons with respiratory or mood disorders, and Micah Allen and his group already have already started new projects based on the study.

“We have a variety of ongoing projects that are both building on and testing various parts of the model we have proposed. PhD. Student Malthe Brændholt is conducting innovative brain imaging studies in humans, to try and understand how different kinds of emotional and visual perception are influenced by breathing in the brain,” says Micah Allen.

The team is also collaborating with the Pulmonology team at Aarhus University Hospital, where tools developed in the lab are used to understand whether person suffering from long-covid may have disruptions in the breath-brain alignment. And there are more projects coming, says Micah Allen.

“We will be using a combination of human and animal neuroimaging to better understand how breathing influences the brain, and also utilising exploring how different drugs influence respiratory-brain interaction. We would also like to some day study how lifestyle factors like stress, sleep, and even things like winter swimming influence breath-brain interaction. We are very excited to continue this research,” says Micah Allen.

Magnetic resonance imaging–guided focused ultrasound thalamotomy for essential tremor: 5-year follow-up results

by G. Rees Cosgrove, Nir Lipsman, Andres M. Lozano, Jin Woo Chang, Casey Halpern, Pejman Ghanouni, Howard Eisenberg, Paul Fishman, Takaomi Taira, Michael L. Schwartz, Nathan McDannold, Michael Hayes, Susie Ro, Binit Shah, Ryder Gwinn, Veronica E. Santini, Kullervo Hynynen, W. Jeff Elias in Journal of Neurosurgery

A scalpel-free, high-tech form of brain surgery pioneered at UVA Health offers long-term relief for patients with essential tremor, a common movement disorder, a five-year review shows.

The study offers important insights into the durability of the benefits of focused ultrasound treatment for essential tremor. Five years after treatment, clinical trial participants continued to their treated tremors reduced by more than 70%, the researchers report. There were no progressive or delayed complications.

“It is exciting to see such durable results after an outpatient procedure for a sometimes disabling problem like ET,” said researcher Jeff Elias, MD, a UVA Health neurosurgeon who served as the study’s Principle Investigator. “It is important to note that most of the patients had very long-lasting benefits, but there are some cases where tremor can recur.”

The focused ultrasound procedure focuses sound waves inside the brain to disrupt faulty brain circuits that cause unwanted movement. Unlike traditional brain surgery, it does not require incisions nor opening the skull. The minimally invasive procedure is guided by magnetic resonance imaging (MRI), so doctors can pinpoint the exact right spot in the brain before delivering the treatment.

Initial tests of the procedure at UVA and a small number of other sites often produced dramatic results: Study participants would enter an MRI with their hand shaking uncontrollably and emerge with their ability to write or feed themselves restored.

While promising, those early tests could not reveal how long the benefits of the procedure would last. This new study followed the clinical trial participants for five years and found that they continued to enjoy major reduction in their tremor. Other measures of quality of life were improved as well. Side effects did not occur after the procedure was complete.

“This important trial verifies the long-term benefits and safety of the focused ultrasound procedure that we have performed for hundreds of patients with tremor at UVA,” said Shayan Moosa, MD, a UVA Health neurosurgeon partnering with Elias to perform focused ultrasound procedures. “As this is an incision-less and outpatient treatment, we are able to effectively reduce tremor in patients who may not be able to or may not want to pursue more-invasive options.”

The study described the outcomes of 40 trial participants from the original study cohort. It represents the largest long-term follow-up study of the procedure, known as “unilateral thalamotomy,” possible to conduct so far.

The pioneering clinical trials at UVA and a handful of other sites paved the way for the federal Food and Drug Administration to approve focused ultrasound for the treatment of essential tremor in 2016. That made the procedure available to patients outside clinical trials, though there are still a limited number of hospitals with the advanced technology and expertise needed to offer it.

The FDA also has approved focused ultrasound for the treatment of Parkinson’s disease tremor and dyskinesia (involuntary movements) based on research at UVA Health and elsewhere. UVA is investigating the technology’s potential for a wide variety of other medical applications, from treating cancer to opening the brain’s protective barrier to deliver now-impossible treatments for diseases such as Alzheimer’s.

Based on its highly promising research, UVA launched the world’s first focused ultrasound cancer immunotherapy center earlier this year. The center aims to combine focused ultrasound with immunotherapy to enhance the immune system’s ability to battle cancers.

Alzheimer’s Disease Prevention through Natural Compounds: Cell-Free, In Vitro, and In Vivo Dissection of Hop (Humulus lupulus L.) Multitarget Activity

by Alessandro Palmioli, Valeria Mazzoni, Ada De Luigi, Chiara Bruzzone, Gessica Sala, Laura Colombo, Chiara Bazzini, Chiara Paola Zoia, Mariagiovanna Inserra, Mario Salmona, Ivano De Noni, Carlo Ferrarese, Luisa Diomede, Cristina Airoldi in ACS Chemical Neuroscience

Beer is one of the oldest and most popular beverages in the world, with some people loving and others hating the distinct, bitter taste of the hops used to flavor its many varieties. But an especially “hoppy” brew might have unique health benefits. Recent research published in ACS Chemical Neuroscience reports that chemicals extracted from hop flowers can, in lab dishes, inhibit the clumping of amyloid beta proteins, which is associated with Alzheimer’s disease (AD).

AD is a debilitating neurodegenerative disease, often marked by memory loss and personality changes in older adults. Part of the difficulty in treating the disease is the time lag between the start of underlying biochemical processes and the onset of symptoms, with several years separating them. This means that irreversible damage to the nervous system occurs before one even realizes they may have the disease. Accordingly, preventative strategies and therapeutics that can intervene before symptoms appear are of increasing interest.

One of these strategies involves “nutraceuticals,” or foods that have some type of medicinal or nutritional function. The hop flowers used to flavor beers have been explored as one of these potential nutraceuticals, with previous studies suggesting that the plant could interfere with the accumulation of amyloid beta proteins associated with AD. So, Cristina Airoldi, Alessandro Palmioli and colleagues wanted to investigate which chemical compounds in hops had this effect.

To identify these compounds, the researchers created and characterized extracts of four common varieties of hops using a method similar to that used in the brewing process. In tests, they found that the extracts had antioxidant properties and could prevent amyloid beta proteins from clumping in human nerve cells. The most successful extract was from the Tettnang hop, found in many types of lagers and lighter ales. When that extract was separated into fractions, the one containing a high level of polyphenols showed the most potent antibiotic and aggregation-inhibiting activity. It also promoted processes that allow the body to clear out misfolded, neurotoxic proteins. Finally, the team tested the Tettnang extract in a C. elegans model and found that it protected the worms from AD-related paralysis, though the effect was not very pronounced. The researchers say that although this work may not justify drinking more bitter brews, it shows that hop compounds could serve as the basis for nutraceuticals that combat the development of AD.

Autonomic nerve fibers aberrantly reinnervate denervated facial muscles and alter muscle fiber population

by Vlad Tereshenko, Dominik C. Dotzauer, Matthias Luft, Joachim Ortmayr, Udo Maierhofer, Martin Schmoll, Christopher Festin, Genova Carrero Rojas, Johanna Klepetko, Gregor Laengle, Olga Politikou, Dario Farina, Roland Blumer, Konstantin D. Bergmeister, Oskar C. Aszmann in The Journal of Neuroscience

The autonomic nervous system is known as the control centre for involuntary bodily processes such as the beating of our hearts and our breathing. The fact that this part of the nervous system also has the ability to spontaneously restore muscle function following a nerve injury was discovered by a research group at MedUni Vienna’s Department of Plastic, Reconstructive and Aesthetic Surgery as part of their study recently published in the Journal of Neuroscience. Their findings may form the basis for improving and developing interventions to treat nerve lesions.

The research team led by Vlad Tereshenko and Oskar Aszmann from the Clinical Laboratory for Bionic Limb Reconstruction at MedUni Vienna’s Department of Plastic, Reconstructive and Aesthetic Surgery discovered this facet of the interaction between nerves and muscles — which was previously unknown to science — in the course of its preclinical research on facial nerves and muscles. After a nerve has been injured or severed, it is no longer able to control the motor function of the facial muscles, resulting in facial paralysis in the animal model.

In some cases, the scientists observed spontaneous recovery of muscle function days or weeks after the nerve lesion. Using novel, complex techniques, they were able to establish that the autonomic nervous system takes over the function of the injured nerve, as it were.

“Until now, we were unaware that the autonomic nervous system can control muscle motor function with nerve impulses. As we have seen in our experiments, the parasympathetic nerve fibres form new functional neuromuscular synapses to do this. At the same time, the patterns of the muscle fibres are modified and, hence, the physiological properties of the autonomously reinnervated muscles are changed,” explains first author Vlad Tereshenko, outlining the key findings from the study.

Schematic illustration of aberrant parasympathetic reinnervation of denervated facial muscles. Following facial nerve transection, ipsilateral whisker pad showed spontaneous movement 12 weeks after the denervation. Harvested dilator naris muscle showed muscle fiber change after denervation. The reinnervating fibers were traced to the parasympathetic neural source in the pterygopalatine ganglion. The route of the parasympathetic fibers was established by electrophysiological testing via the sensory infraorbital nerve.

Following injuries or certain diseases, nerves can temporarily or permanently lose their ability to provide motor control to muscles. Well-established therapeutic concepts such as the relocation of nerves or nerve transplants are now available to remedy the resultant motor deficits. However, clinical outcomes may be affected by several factors, such as the slow rate of nerve regeneration or the lack of donor nerves.

“By identifying this previously unknown ability of the autonomic nervous system, we have discovered a new potential actor in nerve reconstruction. The results of our study can therefore help to improve existing therapeutic measures and to develop new ones,” says Vlad Tereshenko, looking into the future.

Follow-up studies are expected to deepen our knowledge of this new facet of the neuromuscular system. One of the questions to be addressed is whether and how autonomic nerve fibres can be surgically relocated in order to restore muscle function on a temporary or permanent basis.

Monoclonal antibody‐mediated immunosuppression enables long‐term survival of transplanted human neural stem cells in mouse brain

by Lisa M. McGinley, Kevin S. Chen, Shayna N. Mason, Diana M. Rigan, Jacquelin F. Kwentus, John M. Hayes, Emily D. Glass, Evan L. Reynolds, Geoffrey G. Murphy, Eva L. Feldman in Clinical and Translational Medicine

A new approach to stem cell therapy that uses antibodies instead of traditional immunosuppressant drugs robustly preserves cells in mouse brains and has potential to fast-track trials in humans, a Michigan Medicine study suggests.

For this study, researchers used monoclonal antibodies to suppress the immune system in mice and compared the results to traditional immunosuppression with the medications tacrolimus and mycophenolate mofetil. They tracked implanted human neural stem cell survival using luciferase, the protein that makes fireflies glow.

Results published in Clinical and Translational Medicine reveal that suppression with monoclonal antibodies enabled long-term survival of human stem cell transplants in mouse brains for at least six to eight months, while the cell grafts did not survive more than two weeks in most animals when using standard immunosuppressant drugs.

“This study makes it clear that using monoclonal antibodies is better for the study of stem cell transplants in the brain and spinal cord over the long term,” said lead author Kevin Chen, M.D., a neurosurgeon at University of Michigan Health and clinical assistant professor of neurosurgery at U-M Medical School. “The cells survived for so long with fewer injections and less toxicity from immunosuppression when using monoclonal antibodies. This will enable more experiments and studies of stem cell therapies, bringing more promise for their future in the neurosciences.”

Researchers sought to combat a longstanding obstacle for stem cell therapy in neurological disease of keeping cells alive when testing them in pre-clinical animal models. Many scientists have relied on immunosuppressant medications to keep the animals’ immune systems from rejecting stem cells, Chen says, but they eventually fail and torpedo the process.

“In many of these experiments, we would only see around a third of animals have cells survive and have no way to interpret the results,” he said. “It gets expensive in stem cell therapy to conduct these experiments and not have the cells survive.”

Traditional immunosuppressant drugs are less selective than monoclonal antibodies, which, in this study, targeted two immune proteins. The antibodies have only been analyzed in a handful of stem cell therapy studies for the nervous system. However, this study tracked cell survival for as long as eight months — one of the longest time points published for stem cells in the brain and spinal cord.

Development and validation of bioluminescent imaging (BLI) to assess transplanted human neural stem cell (hNSC) graft viability in vivo. (A) Fluorescence microscopy of green fluorescent protein (GFP) expression in hNSCs modified to express a dual reporter luc+/GFP+ vector at increasing multiplicity of infection (MOI) 48 h post-transduction. Luciferase assay (B) and trypan blue exclusion viability assay © of hNSC-luc+/GFP+ performed at 72 h post-transduction. (D) In vitro BLI of hNSC-luc+/GFP+ cells at concentrations ranging from 3 × 106 to 5 × 102 per well, with no luciferin and media only controls. (E) In vitro BLI of unlabelled hNSC and dead hNSC-luc+/GFP+ (DC), with hNSC-luc+/GFP+ cells as a positive control. (F) In vivo BLI detection of transplanted hNSC-luc+/GFP+ in 8-week-old C57BL/6J mice on post-operative day (POD) 2 after bilateral injection of 3.6 × 105 hNSC-luc+/GFP+, or unilateral injection of 1.8 × 105 hNSC-luc+/GFP+ (L: left side) with contralateral injection of 1.8 × 105 DC or unlabelled hNSC transplants (n = 2 per group). (G) Representative POD 2 immunohistochemical (IHC) images showing the fimbria fornix target area in C57BL/6J mice, with hNSC-luc+/GFP+ grafts expressing GFP (green) and human-specific nuclear antibody HuNu (red), with contralateral staining of DC or unlabelled hNSC. Data presented as mean ± standard error of the mean (S.E.M.) for luciferase activity and cell viability analysed by ANOVA with Tukey’s post-test for comparisons of multiple groups. **p < .01; ****p < .0001. DC, dead cells; POD, post-operative day

This study lays the groundwork for understanding how transplanted stem cells integrate into the brain, says senior author Eva Feldman, M.D., Ph.D., James W. Albers Distinguished Professor at U-M, the Russell N. DeJong Professor of Neurology and director of the NeuroNetwork for Emerging Therapies at Michigan Medicine.

“Our new findings continue to support advancing stem cell therapies into human clinical trials,” Feldman said. “Stem cell therapy remains a beacon of hope for neurological diseases.”

Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid

by Robert Koeppe, Neal Scott Mason, Colin Masters, Ulricke Obermüller, Song Hu, Gwendalyn J. Randolph, Igor Smirnov, Jonathan Kipnis in Nature

Alzheimer’s, Parkinson’s and many other neurodegenerative diseases are marked by damaging clusters of proteins in the brain. Scientists have expended enormous effort searching for ways to treat such conditions by clearing these toxic clusters but have had limited success.

Now, researchers at Washington University School of Medicine in St. Louis have found an innovative way to improve waste clearance from the brain, and thereby possibly treat or even prevent neurodegenerative conditions. They showed that immune cells surrounding the brain influence how efficiently waste is swept out of the brain, and that such immune cells are impaired in old mice, and in people and mice with Alzheimer’s disease. Further, they found that treating old mice with an immune-stimulating compound rejuvenates immune cells and improves waste clearance from the brain.

“Alzheimer’s has been studied for many years from the perspective of how neurons die, but there are other cells, such as immune cells on the periphery of the brain, that also may play a role in Alzheimer’s,” said senior author Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator. “It doesn’t look likely that we will be able to revive dead or dying neurons, but the immune cells that sit on the borders of the brain are a feasible target for treating age-related brain diseases. They’re more accessible, and could be drugged or replaced. In this study, we treated aged mice with a molecule that can activate aged immune cells, and it worked in improving fluid flow and waste clearance from the brain. This holds promise as an approach to treating neurodegenerative diseases.”

Kipnis is an expert in the blossoming field of neuroimmunology, the study of how the immune system affects the brain in health and disease. In 2015, he discovered a network of vessels that drains fluid, immune cells and small molecules from the brain into the lymph nodes, where many immune system cells reside. Last year, he and colleagues showed that some investigational Alzheimer’s therapies are more effective in mice when paired with a treatment geared toward improving drainage of fluid and debris from the brain.

For this study, Kipnis and Antoine Drieu, PhD — a postdoctoral researcher and the paper’s lead author — set out to understand the role played by the immune cells that live along the brain’s vasculature and in the leptomeninges, the tissues immediately surrounding the brain and spinal cord. They termed these cells parenchymal border macrophages, because they sit at the interface between cerebrospinal fluid and brain tissue.

Studying mice, Kipnis, Drieu and colleagues discovered that such macrophages regulate the motion of blood arteries that, in turn, controls the cleansing flow of fluid through the brain. When these macrophages were depleted or impaired, debris built up in the brain.

“Cerebrospinal fluid flow is impaired in numerous neurodegenerative diseases, such as Alzheimer’s, stroke, Parkinson’s and multiple sclerosis,” Drieu said. “If we can restore fluid flow through the brain just by boosting these macrophages, maybe we can slow the progression of these diseases. It’s a dream, but who knows? It might work.”

Further investigation revealed that parenchymal border macrophages are altered in people with Alzheimer’s disease and mice with an Alzheimer’s-like condition: The immune cells are less able to consume and dispose of waste, and cannot efficiently regulate fluid flow.

Starting at about age 50, people start experiencing a decline in brain fluid flow as part of normal aging. The same thing happens in older mice. Kipnis, Drieu and colleagues showed that the kind of border macrophage most important for waste clearance and fluid flow are scarce in older mice. When they treated old mice with a protein that boosts macrophage activity, the border macrophages started behaving more like those from younger mice. Further, the treatment improved fluid flow and waste clearance from the mice’s brains.

“Collectively, our results show that parenchymal border macrophages could potentially be targeted pharmacologically to alleviate brain clearance deficits associated with aging and Alzheimer’s disease,” said Kipnis, who is also a professor of neurology, of neuroscience and of neurosurgery. “I am discussing with colleagues how we can replace or rejuvenate those cells in aging brains and as a treatment for Alzheimer’s. I hope that one day we will be able to slow down or delay the development of age-related brain diseases with this approach.”

Neural correlates of eye contact and social function in autism spectrum disorder

by Joy Hirsch, Xian Zhang, J. Adam Noah, Swethasri Dravida, Adam Naples, Mark Tiede, Julie M. Wolf, James C. McPartland in PLOS ONE

A hallmark of autism spectrum disorder, ASD, is the reluctance to make eye contact with others in natural conditions. Although eye contact is a critically important part of everyday interactions, scientists have been limited in studying the neurological basis of live social interaction with eye-contact in ASD because of the inability to image the brains of two people simultaneously.

However, using an innovative technology that enables imaging of two individuals during live and natural conditions, Yale researchers have identified specific brain areas in the dorsal parietal region of the brain associated with the social symptomatology of autism. The study, published Nov. 9 in the journal PLOS ONE, finds that these neural responses to live face and eye-contact may provide a biomarker for the diagnosis of ASD as well as provide a test of the efficacy of treatments for autism.

“Our brains are hungry for information about other people, and we need to understand how these social mechanisms operate in the context of a real and interactive world in both typically developed individuals as well as individuals with ASD,” said co-corresponding author Joy Hirsch, Elizabeth Mears and House Jameson Professor of Psychiatry, Comparative Medicine, and of Neuroscience at Yale.

A. Gaze at partner’s eyes: Real Eye condition. Partners viewed each other at an eye-to-eye distance of 140 cm. The eye regions subtended by both the real eyes and the video eyes were 3.3 × 1.5 degrees of visual angle (red boxes). Small green LED indicator lights located to either side of their partner indicated rest and diverted gaze targets. B. Gaze at eyes in video: Video Eye condition. Two 24-inch 16x9 monitors were placed between the participants and a size-calibrated, pre-recorded dynamic video of a face was presented in the same field-of-view as the live interaction. C. Diagram of the Real Eye condition, with participant and lab partner sitting 140 cm apart from each other and LED indicator lights placed 10 degrees to the left and right of the Eye. D. Diagram of the Video Eye condition, with monitors arranged between partners. The face and LED sizes and positions were calibrated to subtend the same visual angles in both conditions.

The Yale team, led by Hirsch and James McPartland, Harris Professor at the Yale Child Study Center, analyzed brain activity during brief social interactions between pairs of adults — each including a typical participant and one with ASD — using functional near-infrared spectroscopy, a non-invasive optical neuroimaging method. Both participants were fitted with caps with many sensors that emitted light into the brain and also recorded changes in light signals with information about brain activity during face gaze and eye-to-eye contact.

The investigators found that during eye contact, participants with ASD had significantly reduced activity in a brain region called the dorsal parietal cortex compared to those without ASD. Further, the more severe the overall social symptoms of ASD as measured by ADOS (Autism Diagnostic Observation Schedule, 2nd Edition) scores, the less activity was observed in this brain region. Neural activity in these regions was synchronous between typical participants during real eye-to-eye contact but not during gaze at a video face. This typical increase in neural coupling was not observed in ASD, and is consistent with the difficulties in social interactions.

“We now not only have a better understanding of the neurobiology of autism and social differences, but also of the underlying neural mechanisms that drive typical social connections,” Hirsch said.

Locomotion activates PKA through dopamine and adenosine in striatal neurons

by Lei Ma, Julian Day-Cooney, Omar Jáidar Benavides, Michael A. Muniak, Maozhen Qin, Jun B. Ding, Tianyi Mao, Haining Zhong in Nature

Researchers at Oregon Health & Science University have discovered that the neurotransmitter adenosine effectively acts as a brake to dopamine, another well-known neurotransmitter involved in motor control.

Scientists found that adenosine operates in a kind of push-pull dynamic with dopamine in the brain.

“There are two neuronal circuits: one that helps promote action and the other that inhibits action,” said senior author Haining Zhong, Ph.D., scientist with the OHSU Vollum Institute. “Dopamine promotes the first circuit to enable movement, and adenosine is the ‘brake’ that promotes the second circuit and brings balance to the system.”

The discovery could immediately suggest new avenues of drug development to treat symptoms of Parkinson’s disease, a movement disorder where the loss of dopamine-producing cells has been widely implicated as a cause.

Scientists have long suspected that dopamine is influenced by an opposing dynamic of neuronal signaling in the striatum — a critical region of the brain that mediates movement along with reward, motivation and learning. The striatum is also the primary brain region affected in Parkinson’s disease by the loss of dopamine-producing cells.

“People for a long time suspected there has to be this push-pull system,” said co-author Tianyi Mao, Ph.D., a scientist at the Vollum who happens to be married to Zhong.

In the new study, researchers for the first time clearly and definitively revealed adenosine as the neurotransmitter that acts in an oppositional sense with dopamine. The study, involving mice, used novel genetically engineered protein probes recently developed in the Zhong and Mao labs. An example of that technology was highlighted last month in a study published in the journal Nature Methods.

Notably, adenosine is also well known as the receptor that caffeine acts upon.

“Coffee acts in our brain through the same receptors,” Mao said. “Drinking coffee lifts the brake imposed by adenosine.”

Cell types and molecular architecture of the Octopus bimaculoides visual system

by Jeremea O. Songco-Casey, Gabrielle C. Coffing, Denise M. Piscopo, Judit R. Pungor, Andrew D. Kern, Adam C. Miller, Cristopher M. Niell in Current Biology

It’s hard for the octopus to pick just one party trick. It swims via jet propulsion, shoots inky chemicals at its foes, and can change its skin within seconds to blend in with its surroundings.

A team of University of Oregon researchers is investigating yet another distinctive feature of this eight-armed marine animal: its outstanding visual capabilities.

In a new paper, they lay out a detailed map of the octopus’ visual system, classifying different types of neurons in a part of the brain devoted to vision. The map is a resource for other neuroscientists, giving details that could guide future experiments. And it could teach us something about the evolution of brains and visual systems more broadly, too.

Associate professor Cris Niell’s lab in the Institute of Neuroscience studies vision, mostly in mice. But a few years ago, postdoctoral researcher Judit Pungor brought a new species to the lab: the California two-spot octopus.

While not traditionally used as a study subject in the lab, the cephalopod quickly captured the interest of UO neuroscientists.

Unlike mice, which are not known for having good vision, “octopuses have an amazing visual system, and a large fraction of their brain is dedicated to visual processing,” Niell said. “They have an eye that’s remarkably similar to the human eye, but after that, the brain is completely different.

The last common ancestor between octopuses and humans was 500 million years ago, and the species have since evolved in very different contexts. So scientists didn’t know whether the parallels in visual systems extended beyond the eyes, or whether the octopus was instead using completely different kinds of neurons and brain circuits to achieve similar results.

“Seeing how the octopus eye convergently evolved similarly to ours, it’s cool to think about how the octopus visual system could be a model for understanding brain complexity more generally,” said Mea Songco-Casey, a graduate student in Niell’s lab and the first author on the paper. “For example, are there fundamental cell types that are required for this very intelligent, complex brain?”

Here, the team used genetic techniques to identify different types of neurons in the octopus’ optic lobe, the part of the brain that’s devoted to vision.

They picked out six major classes of neurons, distinguished based on the chemical signals they send. Looking at the activity of certain genes in those neurons then revealed further subtypes, providing clues to more specific roles.

In some cases, the researchers pinpointed particular groups of neurons in distinctive spatial arrangements, for instance, a ring of neurons around the optic lobe that all signal using a molecule called octopamine. Fruit flies use this molecule, which is similar to adrenaline, to increase visual processing when the fly is active. So it could perhaps have a similar role in octopuses.

“Now that we know there’s this very specific cell type, we can start to go in and figure out what it does,” Niell said.

About a third of the neurons in the data didn’t quite look fully developed. The octopus brain keeps growing and adding new neurons over the animal’s lifespan. These immature neurons, not yet integrated into brain circuits, were a sign of the brain in the process of expanding.

However, the map didn’t reveal sets of neurons that clearly transferred over from humans or other mammalian brains, as the researchers thought it might.

“At the obvious level, the neurons don’t map onto each other; they’re using different neurotransmitters,” Niell said. “But maybe they’re doing the same kinds of computations, just in a different way.”

Digging deeper will also require getting a better handle on cephalopod genetics. Because the octopus hasn’t traditionally been used as a lab animal, many of the tools that are used for precise genetic manipulation in fruit flies or mice don’t yet exist for the octopus, said Gabby Coffing, a graduate student in biology professor Andrew Kern’s lab who worked on the study.

“There are a lot of genes where we have no idea what their function is, because we haven’t sequenced the genomes of a lot of cephalopods,” Pungor said. Without genetic data from related species as a point of comparison, it’s harder to deduce the function of particular neurons.

Niell’s team is up for the challenge. They’re now working to map the octopus brain beyond the optic lobe, seeing how some of the genes they focused on in this study show up elsewhere in the brain. They are also recording from neurons in the optic lobe, to determine how they process the visual scene.

In time, their research might make these mysterious marine animals a little less murky — and shine a little light on our own evolution, too.

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