Scientists eager to explain brain rhythm boost's broad impact in Alzheimer's models
December 11, 2019
Science Daily/Picower Institute at MIT
Neuroscientists lay out the the few knowns and many unknowns that must be understood to determine why sensory stimuluation of 40Hz brain rhythms have broad effects, particularly in Alzheimer's models.
The sweeping extent to which increasing 40Hz "gamma" rhythm power in the brain can affect the pathology and symptoms of Alzheimer's disease in mouse models has been surprising, even to the MIT neuroscientists who've pioneered the idea. So surprising, in fact, they can't yet explain why it happens.
In three papers, including two this year in Cell and Neuron, they've demonstrated that exposing mice to light flickering or sound buzzing at 40Hz, a method dubbed "GENUS" for Gamma Entrainment Using Sensory stimuli, strengthens the rhythm across the brain and changes the gene expression and activity of multiple brain cell types. Pathological amyloid and tau protein buildups decline, neurons and their circuit connections are protected from degeneration and learning and memory endure significantly better than in disease model mice who do not receive GENUS.
In a new review article in Trends in Neurosciences two researchers leading those efforts lay out the few knowns and many unknowns that must be understood to determine how the widespread effects take place. It's a challenge they relish because the answers could both break new scientific ground and help them improve how GENUS could become a therapeutic or preventative approach for people.
"While we know it affects pathology in mice, we want to understand how because that will help us understand and refine potential treatment," said lead author Chinnakkaruppan Adaikkan, a postdoc in the lab of senior author Li-Huei Tsai, Picower Professor of Neuroscience and director of The Picower Institute for Learning and Memory.
Adaikkan has been interested in understanding how neural activity produces brain rhythms since his doctoral research. At MIT, he is channeling that passion into understanding how sensory stimulation can entrain oscillations.
"That's what drives me to come to the lab every day to study these mechanisms," Adaikkan said. "When we got the data from the first mouse where we recorded from the visual cortex, the hippocampus and the prefrontal cortex we were surprised to see that visual stimulation entrains in these brain regions. That was very exciting but we have a very long way to go to understand how this happens."
The new paper raises that question and many others for the field. What cells underlie the brain's response to GENUS? How do gamma rhythms engage non-neuronal cells such as astrocytes and microglia? How does it propagate beyond the brain regions responsible for perception? How extensively can enhancing gamma affect cognition? Does long-term stimulation affect brain circuit connections and how they change?
Cell roles
Studies of how groups of neurons engage in coherent oscillations of electrical activity have yielded two models to explain gamma rhythms. Both involve an interplay between excitatory and inhibitory neurons but differ on which type leads the interaction, Adaikkan and Tsai wrote. In his work, Adaikkan is attempting to dissect the roles of specific neuron types in GENUS and how closely those patterns mirror other sources of gamma, such as that invoked by cognitive tasks.
GENUS affects more than neurons. Tsai's lab has found that microglia change their gene expression, their physical form, their protein-consuming behavior and their inflammatory response depending on the Alzheimer's model involved. Work from another group showed that blocking vesicle release in astrocytes can hinder gamma power in mice and Tsai's group found that auditory GENUS recruits an increase reactive astrocytes, which are more inclined to consume pathological proteins.
The new paper offers three hypotheses about how such "glial" cells are involved: They might contribute directly to gamma entrainment by regulating the flow of ions that carry electrical charge; even if they don't contribute to rhythms, their ionic sensitivity may still make them responsive to gamma changes; they might instead be affected by changes in levels of neurotransmitters as a result of gamma.
Moreover, different glia may also become involved because of their proximity to electrical couplings between neurons called synapses, or because of how their activity is otherwise governed by neural activity.
The broader brain
That GENUS extends to the hippocampus, which is key for memory, and the prefrontal cortex, which is key for cognition, is likely a factor in how it preserves brain function. But again there are competing models for how increased gamma could facilitate multi-regional communication. In one, the authors write, coherence at the same frequency optimizes communication, while in the other model, one region's gamma activity directly drives activity in regions downstream. New experiments that directly manipulate inter-regional circuits, they argue, could help resolve which model better explains gamma entrainment's effects.
Finally, the effects of GENUS on brain function and behavior also aren't fully explained. The Tsai lab's has shown significant effects on spatial memory and some effects on other forms of memory, depending on the stimulation method. Other studies have shown that stimulating brain rhythms by other means, such as via genetic or optogenetic manipulations in mice, or via transcranial stimulation in humans, can also improve functions such as working memory. Adaikkan is interested in closing a gap between those studies and the Tsai lab's work: Most studies measure cognitive performance during stimulation, while the Tsai lab has done so after the conclusion of repeated stimulation. He said he'd like to also test how mice perform while GENUS is actively underway.
"Our lab is excited to tackle these many hypotheses and to see how the field tackles many more," Tsai said. "GENUS has created many intriguing new questions for neuroscience."
https://www.sciencedaily.com/releases/2019/12/191211115624.htm
In Alzheimer's research, scientists reveal brain rhythm role
October 23, 2019
Science Daily/Picower Institute at MIT
In the years since her lab discovered that exposing Alzheimer's disease model mice to light flickering at the frequency of a key brain rhythm could stem the disorder's pathology, MIT neuroscientist Li-Huei Tsai and her team at The Picower Institute for Learning and Memory have been working to understand what the phenomenon may mean both for fighting the disease and understanding of how the brain works.
Two papers earlier this year in Cell and in Neuron replicated and substantially extended the initial findings reported in Nature in 2016 and clinical trials with human volunteers recently began. In a special lecture at the Society for Neuroscience Annual Meeting in Chicago Oct. 22, Tsai will share the latest research updates on what she's found -- and the new questions she is asking -- about using light and sound to strengthen the brain' s 40Hz "gamma" rhythm, a technique she calls "GENUS," for Gamma Entrainment Using Sensory stimuli.
"We are eager to learn as much as we can about GENUS for two main reasons," said Tsai, Picower Professor of Neuroscience in the Department of Brain and Cognitive Sciences and a founder of MIT's Aging Brain Initiative. "We hope our findings in mice will translate to helping people with Alzheimer's disease, though it's certainly too soon to tell and many things that have worked in mice have not worked in people. But there also may be exciting implications for fundamental neuroscience in understanding why stimulating a specific rhythm via light or sound can cause profound changes in multiple types of cells in the brain."
Gamma and Alzheimer's disease
In 2016, Tsai and colleagues showed that Alzheimer's disease model mice exposed to a light flickering at 40 Hz for an hour a day for a week had significantly less buildup of amyloid and tau proteins in the visual cortex, the brain region that processes sight, than experimental control mice did. Amyloid plaques and tangles of phosphorylated tau are both considered telltale hallmarks of Alzheimer's disease.
But the study raised new questions: Could GENUS prevent memory loss? Could it prevent the loss of neurons? Does it reach other areas of the brain? And could other senses be stimulated for beneficial effect?
The new studies addressed those questions. In March, the team reported that sound stimulation reduced amyloid and tau not only in the auditory cortex, but also in the hippocampus, a crucial region for learning and memory. GENUS-exposed mice also performed significantly better on memory tests than unstimulated controls. Simultaneous light and sound, meanwhile, reduced amyloid across the cortex, including the prefrontal cortex, a locus of cognition.
In May, another study reported similar advances from exposing Alzheimer's model mice to light for 3 or 6 weeks. Coordinated increases in gamma rhythm power were evident across the brains of GENUS-exposed mice. Memory improved compared to controls. More neurons survived and they maintained more circuit connections, called synapses. In her talk, Tsai will share data showing that longer-term GENUS light exposure also reduced amyloid and tau across the cortex.
Encouraged by the results, the lab has begun human trials. At SfN Tsai will present some initial data, indicating that GENUS safely increases gamma rhythm power and synchrony across the brain in healthy people.
Gamma "signatures" in the brain
Tsai's team has also been working to understand the mechanisms underlying the changes they see. The research has revealed that brain rhythms appear to exert a great deal of influence over the activity of multiple cell types in the brain.
Neuroscientists have known about rhythms for more than a century, but they have only recently begun to acknowledge that they might affect how the brain works. Gamma is associated with brain functions like sensory processing, working memory and spatial navigation, but scientists have long debated whether they are consequential or mere byproducts.
But Tsai will describe how her studies show that increasing gamma power and synchrony with sensory stimulation causes changes in neurons, brain immune cells called microglia, and the brain's vasculature. These changes may be "signatures" of gamma's significance, she says.
Increasing gamma power causes neurons to reduce processing of amyloid precursor protein and changes endosomal physiology as well, the team has found. In Alzheimer's model mice, neuronal gene expression related to synaptic function and biochemical transport within cells is reduced, but with GENUS exposure, gene expression related to those functions improves.
Microglia similarly experience major changes after GENUS exposure, all three studies have found. Gene expression becomes less inflammatory and more consistent with capturing and disposing of amyloid. Indeed, they hunt amyloid more effectively, the data show, and they secrete less of an inflammatory marker.
The March study with audio stimulation showed that amid GENUS exposure, blood vessels in the brain expand and more amyloid co-locates with a protein that draws amyloid to the vessels. The results suggest increased gamma power may help drive a mechanism for clearing amyloid out of the brain.
In several new experiments, Tsai says, the lab is continuing to study these underlying mechanistic changes. Related conference posters from her lab at the conference describe some of that work. The results of these new experiments may both help improve the possibility of translating GENUS for clinical use and further demonstrate the importance of rhythms in affecting brain function.
https://www.sciencedaily.com/releases/2019/10/191023093435.htm