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neuroscience

Social isolation and the adolescent brain

We can’t read Emory neuroscientist Shannon Gourley’s papers on social isolation in adolescent mice, without thinking about how the COVID-19 pandemic is affecting children and teenagers. Much of the experimental work was completed before the pandemic began. Still, in the future, researchers will be studying the effects of the pandemic on children, in terms of depression and anxiety, or effects on relationships and education. They could look to neuroscience studies such as Gourley’s for insights into brain mechanisms.

What will the social isolation of the pandemic mean for developing brains?

In the brain, social isolation interferes with the pruning of dendritic spines, the structures that underly connections between neurons. One might think that more dendritic spines are good, but the brain is like a sculpture taking shape – the spines represent processes that are refined as humans and animals mature.

Mice with a history of social isolation have higher spine densities in regions of the brain relevant to decision-making, such as the prefrontal cortex, the Emory researchers found.

In a recently published review, Gourley and her co-authors, former graduate student Elizabeth Hinton and current MD/PhD Dan Li, say that more research is needed on whether non-social enrichment, such as frequent introduction of new toys, can compensate for or attenuate the effects of social isolation.

This research is part of an effort to view adolescent mental health problems, such as depression, obesity or substance abuse, through the prism of decision-making. The experiments distinguish between goal-oriented behaviors and habits. For humans, this might suggest choices about work/school, food, or maybe personal hygiene. But in a mouse context, this consists of having them poke their noses in places that will get them tasty food pellets, while they decode the information they have been given about what to expect. 

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Alternative model for Alzheimer’s neurodegeneration

In recent debate over the FDA’s approval of the Alzheimer’s drug aducanumab, we’ve heard a lot about the “amyloid hypothesis.” In that context, it’s refreshing to learn about a model of Alzheimer’s neurodegeneration that doesn’t start with the pathogenic proteins amyloid or Tau.

Instead, a new paper in Alzheimer’s & Dementia from Emory neuroscientist Shan Ping Yu and colleagues focuses on an unusual member of the family of NMDA receptors, signaling molecules that are critical for learning and memory. Their findings contain leads for additional research on Alzheimer’s, including drugs that are already FDA-approved that could be used preventively, and genes to look at for risk factors.

“It’s not just another rodent model of Alzheimer’s,” Yu says. “We are emphasizing a different set of mechanisms leading to neurodegeneration.”

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Insights into Parkinson’s balance problems

Loss of balance and falls are big concerns for people living with Parkinson’s disease and their caregivers. Researchers at Emory and Georgia Tech recently published a paper in PLOS ONE providing insights into how sensory and motor information are misrouted when people with Parkinson’s are attempting to adjust their balance.

When the researchers examined 44 people with Parkinson’s, their history of recent falls correlated with the presence and severity of abnormal muscle reactions. This could help clinicians predict whether someone is at high risk of falling and possibly monitor responses to therapeutic interventions.

People with Parkinson’s tend to lose their balance in situations when they are actively trying to control their center of mass, like when they are getting up from a chair or turning around. Disorganized sensorimotor signals cause muscles in the limbs to contract, such that both a muscle promoting a motion and its antagonist muscle are recruited. It’s like stepping on the gas and the brake at the same time, says J. Lucas McKay, who is first author of the paper.

Physical therapists are sometimes taught that balance reactions in Parkinson’s patients are slower than they should be.

“We show this is not true,” McKay says. “The reactions are on-time but disorganized.”

The paper extends groundbreaking work on how muscles maintain balance, conducted by co-author Lena Ting in animals and healthy young humans, to people with Parkinson’s. Co-authors of the PLOS One paper include Ting and Parkinson’s specialists Madeleine Hackney and Stewart Factor, director of Emory’s movement disorders program. McKay is assistant professor of neurology and biomedical informatics.

McKay says that sensorimotor problems may be a result of degeneration of regions of the brain, outside of and after the dopaminergic cells in the basal ganglia.

“We have to speculate, but the sensory misrouting would be occurring in brain regions like the thalamus — not usually the ones we think about in Parkinson’s, such as the basal ganglia,” he says. “This suggests that future therapies involving these areas could reduce falls.”

The set-up that researchers used to measure balance reactions resembles an earthquake simulator, and was designed and customized by Ting. The photo shows one of the Parkinson’s study participants, being watched by a physical therapy student.

The apparatus can produce around 1 g of acceleration inside of 12 inches of travel, which is “definitely enough to knock someone over,” McKay says.

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Cajoling brain cells to dance

“Flicker” treatment is a striking non-pharmaceutical approach aimed at slowing or reversing Alzheimer’s disease. It represents a reversal of EEG: not only recording brain waves, but reaching into the brain and cajoling cells to dance. One neuroscientist commentator called the process “almost too fantastic to believe.”

With flashing lights and buzzing sounds, researchers think they can get immune cells in the brain to gobble up more amyloid plaques, the characteristic clumps of protein seen in Alzheimer’s. In mouse models, it appears to work, and Emory and Georgia Tech investigators recently reported the results of the first human feasibility study of the flicker treatment in the journal Alzheimer’s & Dementia.

“So far, this is very preliminary, and we’re nowhere close to drawing conclusions about the clinical benefit of this treatment,” said neurologist James Lah, who supervised the Flicker study at Emory Brain Health Center. “But we now have some very good arguments for a larger, longer study with more people.”

The good news: most participants in the study could tolerate the lights and sounds, and almost all stuck with the eight-week regimen of experimental treatment. (Some even joined an optional extension.) In addition, researchers observed that brain cells were dancing to the tunes they piped in, at least in the short term, and saw signs of a reduction in markers of inflammation. Whether the approach can have a long-term effect on neurodegeneration in humans is still to be determined.

Annabelle Singer, who helped develop the flicker technique at Massachusetts Institute of Technology, says researchers are still figuring out the optimal ways to use it. Recent studies have been assessing how long and how often people should experience the lights and sounds, and more are underway.

“We need to collect all the information we have about how to measure someone’s progress,” says Singer, who is now an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

In the feasibility study, ten people diagnosed with mild cognitive impairment used goggles and headphones that provided light/sound stimulation at home for an hour every day. This video from Georgia Public Broadcasting’s Your Fantastic Mind series demonstrates what that was like.

“To me — It’s not painfully loud. And the lights are not as bright as you would think they are… I don’t find them to be annoying,” says retired psychotherapist Jackie Spierman in the video.

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The earliest spot for Alzheimer’s blues

The Emory laboratories of Keqiang Ye and David Weinshenker recently published a paper on ApoE, the most common genetic risk factor for late-onset Alzheimer’s. The findings, published in Acta Neuropathologica, suggest how the risk-conferring form of ApoE (ApoE4) may exacerbate pathology in the locus coeruleus.

The LC, part of the brainstem, is thought to be the first region of the brain where pathological signs predicting future cellular degeneration show up. The LC (“blue spot”) gets its name from its blue color; it regulates attention, arousal, stress responses and cognition. The LC is also the major site for production of the neurotransmitter norepinephrine.

ApoE, which packages and transports cholesterol, was known to modulate the buildup of the toxic protein fragment beta-amyloid, but this proposed mechanism goes through Tau. Tau is the other pesky protein in Alzheimer’s, forming neurofibrillary tangles that are the earliest signs of degeneration in the brain. Tau pathology correlates better with dementia and cognitive impairments than beta-amyloid, which several proposed Alzheimer’s therapeutics act on.

The new paper shows that ApoE4 inhibits the enzyme VMAT2, which packages norepinephrine into vesicles. As a result, free/unpackaged norepinephrine lingers in the cytoplasm, and forms a harmful oxidative byproduct that triggers enzymatic degradation of Tau. Thus, norepinephrine may have a “too hot to handle” role in Alzheimer’s – with respect to the LC — somewhat analogous to dopamine in Parkinson’s, which has also been observed to form harmful byproducts. Dopamine and norepinephrine are similar chemically and both are substrates of VMAT2, so this relationship is not a stretch.

Model of how norepinephrine byproduct DOPEGAL triggers locus coeruleus degeneration through Tau

The Emory results make the case for inhibiting the enzyme AEP (asparagine endopeptidase), also known as delta-secretase, as an approach for heading off Alzheimer’s. AEP is the Tau-munching troublemaker, and is activated by the norepinephrine byproduct DOPEGAL

An alternative approach may be to inhibit monoamine oxidase (MAO-A above) enzymes — several old-school antidepressants are available that accomplish this.

At Emory, Ye’s lab has been tracing connections for AEP/delta-secretase in the last few years, and Weinshenker’s group is expert on all things norepinephrine, so the collaboration makes sense.

Delta-secretase’s name positions it in relation to beta- and gamma-secretase, enzymes for processing APP (amyloid precursor protein) into beta-amyloid, but AEP/delta-secretase has the distinction of having its fingers in both the beta-amyloid and Tau pies.

We have to caution that most of the recent research on delta-secretase has been in mouse models. Ye’s collaborators in China have been testing an inhibitor of delta-secretase in animals but it has not reached human studies yet, he reports. That said, this work has been oriented toward figuring out the web of interactions between known players such as ApoE and Tau, whose importance has been well-established in studies of humans with Alzheimer’s.

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Oxytocin delivery via nanoparticles

The neuropeptide oxytocin, known for promoting social interactions, has attracted interest as a possible treatment for autism spectrum disorder. A challenge is getting the molecule past the blood-brain barrier. Many clinical studies have used delivery via nasal spray, but even then, oxytocin doesn’t last long in the body and shows inconsistent effects.

Emory neuroscientist Andrew Escayg has been collaborating with Mercer/LSU pharmacologist Kevin Murnane on a nanoparticle delivery approach that could get around these obstacles. One of Escayg’s primary interests is epilepsy — specifically Dravet syndrome, a severe genetic form of epilepsy — and oxytocin has previously displayed anti-seizure properties in animal models.

Escayg and Murnane’s recent paper in Neurobiology of Disease shows that when oxytocin is packaged into nanoparticles, it can increase resistance to induced seizures and promote social behavior in a mouse model of Dravet syndrome.

This suggests properly delivered oxytocin could have benefits on both seizures and behavior. In addition to seizures, children and adults with Dravet syndrome often have autism – see this Spectrum News article on the connections.

Escayg reports he is planning a collaboration with oxytocin expert Larry Young at Yerkes, who Tweeted “This is a promising new area of oxytocin research” when the paper was published. Senior postdoc Jennifer Wong has already been working on extending the findings to other mouse models of epilepsy and adding data on spontaneous seizure frequency.

The nanoparticle approach could be used for other neuropeptides such as neuropeptide Y, proposed as a treatment mode for anxiety disorders/PTSD, and hypocretin, the missing molecule in narcolepsy. Murnane formed a company when he was at Mercer to develop the technology.

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Two birds with one stone: amygdala ablation for PTSD and epilepsy

The amygdala is a region of the brain known for its connections to emotional responses and fear memories, and hyperreactivity of the amygdala is associated with symptoms of PTSD (post-traumatic stress disorder). That said, it’s quite a leap to design neurosurgical ablation of the amygdala to address someone’s PTSD. This type of irreversible intervention could only be considered because of the presence of another brain disorder: epilepsy.

In a case series published in Neurosurgery, Emory investigators describe how for their first patient with both refractory epilepsy and PTSD, observations of PTSD symptom reduction were fortuitous. However, in a second patient, before-and-after studies could be planned. In both, neurosurgical ablation of the amygdala significantly reduced PTSD symptoms as well as reducing seizure frequency.

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Fragile X: $8 million NIH grant supports next-generation neuroscience

Supported by a $8 million, five-year grant, an Emory-led team of scientists plans to investigate new therapeutic approaches to fragile X syndrome, the most common inherited intellectual disability and a major single-gene cause of autism.

Fragile X research represents a doorway to a better understanding of autism, and learning and memory. The field has made strides in recent years. Researchers have a good understanding of the functions of the FMR1 gene, which is silenced in fragile X syndrome.

Still, clinical trials based on that understanding have been unsuccessful, highlighting limitations of current mouse models. Researchers say the answer is to use “organoid” cultures that mimic the developing human brain.

The new grant continues support for the Emory Fragile X Center, first funded by the National Institutes of Health in 1997. The Center’s research program includes scientists from Emory as well as Stanford, New York University, Penn and the University of Southern California. The Emory Center will be one of three funded by the National Institutes of Health; the others are at Baylor College of Medicine and Cincinnati Children’s Hospital Medical Center.

The co-directors for the Emory Fragile X Center are Peng Jin, PhD, chair of human genetics, and Stephen Warren, PhD, William Patterson Timmie professor and chair emeritus of human genetics. In the 1980s and 1990s, Warren led an international team that discovered the FMR1 gene and the mechanism of trinucleotide repeat expansion that silences the gene. This explained fragile X syndrome’s distinctive inheritance pattern, first identified by Emory geneticist Stephanie Sherman, PhD.

“Fragile X research is a consistent strength for Emory, stretching across several departments, based on groundbreaking work from Steve and Stephanie,” Jin says. “Now we have an opportunity to apply the knowledge we and our colleagues have gained to test the next generation of treatments.”

Fragile X researchers from three Emory departments, following COVID-19 spacing guidelines in the laboratory. From left to right: Peng Jin, Gary Bassell, Zhexing Wen and Nisha Raj.

Looking ahead, a key element of the Center’s research will involve studying the human brain in “disease in a dish” models, says Gary Bassell, PhD, chair of cell biology. Nisha Raj, PhD, a postdoctoral fellow in Bassell’s lab, has been studying how FMR1 regulates localized protein synthesis at the brain’s synapses.

“What we’re learning is that there may be different RNA targets in human and mouse cells,” he says. “There’s a clear need to regroup and incorporate human cells into the research.”

Microscope images of fragile X human brain organoids, courtesy of Zhexing Wen. Green represents cytoplasmic Nestin while red represents nuclear Sox2; both are markers for neural progenitor cells.
Microscope image of fragile X human brain organoids, courtesy of Zhexing Wen. Green represents cytoplasmic Nestin while red represents nuclear Sox2; both are markers for neural progenitor cells. 

Center investigator Zhexing Wen, PhD, has developed techniques for culturing brain organoids (image above), which reproduce features of human brain development in miniature. Wen, assistant professor of psychiatry and behavioral sciences, cell biology and neurology at Emory, has used organoids to model other disorders, such as schizophrenia and Alzheimer’s disease. 

The organoids are formed from human brain cells, coming from induced pluripotent stem cells, which are in turn derived from patient-donated tissues. Emory’s Laboratory of Translational Cell Biology, directed by Bassell, has developed several lines of induced pluripotent stem cells from fragile X syndrome patients.

“All of the investigators are sharing these valuable resources and collaborating on multiple projects,” Bassell says.

Principal investigators in the Emory Fragile X Center are Jin, Warren, Bassell, and Wen, along with Eric Klann, PhD at New York University, Lu Chen, PhD, and 2013 Nobel Prize winner Thomas Südhof, MD. Chen and Südhof are neuroscientists at Stanford.

Co-investigators include biostatistician Hao Wu, PhD and geneticist Emily Allen, PhD at Emory, neuroscientist Guo-li Ming, MD, PhD, at University of Pennsylvania, and biomedical engineer Dong Song, PhD, at University of Southern California.
 
Allen, Warren and Jin are part of an additional grant to Baylor, Emory and University of Michigan investigators, who are focusing on FXTAS (fragile X-associated tremor-ataxia syndrome) and FXPOI (fragile X-associated primary ovarian insufficiency). These are conditions that affect people with fragile X premutations.

Fragile X syndrome is caused by a genetic duplication on the X chromosome, a “triplet repeat” in which a portion of the gene (CGG) gets repeated again and again. Fragile X syndrome affects about one child in 5,000, and is more common and more severe in boys. It often causes mild to moderate intellectual disabilities as well as behavioral and learning challenges. About a third of children affected have characteristics of autism, such as problems with eye contact, social anxiety, and delayed speech. 
 
The award for the Emory Fragile X Center is administered by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with funding from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

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Hedgehog pathway outside cilia

Emory geneticist Tamara Caspary is an expert on the Hedgehog pathway, critical for brain development. In particular, she and her colleagues have been studying a gene that is part of the Hedgehog pathway called Arl13b, which is mutated in Joubert syndrome, affecting development of the cerebellum and brain stem.

The Arl13b protein was known to be enriched in primary cilia, tiny hair-like cellular structures with a signaling/navigation function in neuronal development. However Caspary’s lab, in a collaboration with Frederic Charron’s group in Montreal, has found that Arl13b can also function outside cilia: in axons and growth cones.

The Hedgehog pathway has several roles, some in specifying what embryonic cells will become, and others in terms of guiding growing axons, the scientists conclude in their new paper in Cell Reports.

“Arl13b regulates Shh [Sonic Hedgehog] signaling through two mechanisms: a cilia-associated one to specify cell fate and a cilia localization-independent one to guide axons,” they write.  A related preprint, confirming Arl13b’s extra-ciliary role in mouse development, has been posted on bioRxiv.

 

 

 

 

 

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Stage fright: don’t get over it, get used to it

Stage fright: don’t get over it, get used to it, advises Emory neuroscientist Anwesha Banerjee in her recent talk at TEDx Decatur. Many can feel empathy with the situation Banerjee describes. It was her first public presentation eight years ago, facing “a room full of scientists, who for whatever reason, did not look very happy that day.”

“What if I fail in front of the crowd? What if everybody thinks I’m an idiot?”

That feeling of scrutiny might have an evolutionary relationship to the fear of being eaten by a predator, she speculates.

Through participating in Toastmasters International, she has made public speaking more of a habit. She contrasts the two parts of the brain: the amygdala, tuner of emotional responses, with the basal ganglia, director of habits.

“I still get stage fright,” she says. “In fact, I have it right now, thinking how all you predators might try to eat me up! But my brain pays less attention to it.”

Banerjee is a postdoctoral scientist in cell biologist Gary Bassell’s lab, studying myotonic dystrophy. In 2017, she was funded by the Myotonic Dystrophy Foundation to create a mouse model of the neurological/sleep symptoms of myotonic dystrophy.

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