Meaghan Race

Young Blood for Old Brains

Tony Wyss-Coray professor at Stanford University School of Medicine presented his research on the ability to rejuvenate old tissues by exposing them to a younger environment through blood transfusion. His work involves parabiosis of mice, which is the surgical connection of a young mouse and an older mouse. In the study, three month old mice (approximately a 20 year old human) were paired up with 18 month old mice (65 year old human). The older mice were exposed to the young systematic environment for a five-week period and a number of significant conclusions were taken from the study. More neural cell activity, higher synaptic activity, high levels of genes involved in memory, less inflammation of the brain, and improved memory were all improvements seen. Unfortunately, due to the fact that the animals were connected, a behavioral study was not conducted. Also the old blood factors can have a negative effect on the younger mice by accelerating their aging process. To eliminate these factors, the next step taken was to use plasma transfer to see if the same effects would be present since parabiosis is not an effective clinical procedure. Young human blood was injected into B6 mice and improved memory function was seen; cord plasma increased hippocampal expression of IE and it increased the number of c-fos expressing neurons in old hippocampus. Memory tests and fear conditioning were two forms of assessment on top of molecular based testing. Currently clinical trials in humans are being conducted using the parameters of 1 pint of blood, donated from a population of twenty year olds, once a week given to Alzheimer’s patients. The ultimate goal is to increase health span rather than life span, allowing for individuals to live healthy longer by rejuvenating tissue and slowing neurodegeneration.

Young Blood

Shelli Dyer
UConn Health Center
October 27, 2015

The Fountain of Youth, a fabled spring believed to rejuvenate those who bathe in it, has a long history of leading explorers on quests for its discovery. The 16th century Spanish conquistador, Juan Ponce de León, allegedly voyaged the Atlantic in search for new land that contained the vitality-restoring fountain. Ponce, of course, never found the restorative water and some modern historians argue that Ponce was never actually in search for everlasting life, but rather gold and land.

The legend of the magical spring will endure, however, because humans have an innate desire for longevity. While the Fountain of Youth will remain a myth, it turns out that longevity may not, according to Stanford University professor Tony Wyss-Coray. By connecting the circulatory systems of young and aged mice using heterochronic parabiosis, research showed that young blood rejuvenated diverse peripheral organs including the heart, pancreas, and liver in the aged mice. These results suggested that the systemic environment might be involved in aging, leading Dr. Wyss-Coray and his team to hypothesize that the circulatory factors could also impact the aging of the brain.

In following studies, Wyss-Coray and others sought to determine if their hypothesis was true. The results showed that young blood had a rejuvenating effect within the central nervous system (CNS) of the aged mice. Exposing old brains to young blood in the parabiosis model using mice:

• Strengthened synapses in the dentate gyrus (DG)
• Upregulated genes involved in learning and memory
• Increased neural stem and progenitor cells
• Improved cerebral blood flow

Although the factors mediating these changes remain unclear, these findings suggest that systemic factors may play a therapeutic role in treating degenerative diseases and diseases of aging. In our quest longevity, we can view our scientists as the modern day explorers for the Fountain of Youth. For thousands of years, every culture and civilization across the world has dreamed of finding the key to prolonged life, and Dr. Wyss-Coray brings us closer.

Julianna Maisano
Professor Raskin
Neuroscience Across the Curriculum
2 November 2015
Tony Wyss-Coray’s Lecture, Young Blood for Old Brains
On Tuesday, October 26, 2015 Dr. Tony Wyss-Coray, a neuroscientist from the Stanford University School of Medicine spoke about his research on the immune system and injury responses in aging and neurodegeneration (Wyss-Coray Laboratory, 2015). A Professor of Neurology and member of the Veterans Affairs Palo Alto Health Care System, Dr. Wyss-Coray has devoted his time to researching the process of aging, specifically the role the blood plays throughout the process. To conduct his research, Dr. Wyss-Coray and his team uses parabiosis, a clinical research method that anatomically joins joining of two individuals to examine the effects of physiological processes (Wyss-Coray, 2015).
Aging can be defined as an alteration intercellular communication, a process with happens all throughout the body. While the process of aging impacts us all, it is one that can effect us all differently and at different times. Blood, our source of life and connection between organs, is representative of aging properties as well. To determine if aging in blood was a true determinant in regulating the aging process, Dr. Wyss-Coray examined hormone like proteins within the blood. He found that the rate at which plasma ages is dependent upon both genetic and environmental factors.
To validate whether or not our blood is truly the source of the “Fountain of Youth” Dr. Wyss-Coray and his team used parabiosis to surgically connected young and old mice to see if the healthy aspects of blood plasma in the young mouse transferred over to the blood of the old mouse to slow the aging process. He concluded that the brain from an older mouse can appear younger and cause the mouse to act more youthful when exposed to this specific systemic environment.
Dr. Wyss-Coray’s novel research studies on the parabiosis in mice allows us to better understand the role the blood plays in the process of aging. While it is known that cord plasma is an excellent source of rejuvenation for cells, the knowledge can now be used to determine if plasma levels are able to rejuvenate the brain. He discovered that brains of old mice are much more suceptible to change than we think they are and are able to experience rejuvenation. His current and future research hopes to examine hippocampal activity within the mice through various functional memory tests, such as the Barnes maze to further evaluate memory and the aging process in mice. Dr. Wyss-Coray is optimistic that his research will be able to aid in the research of one of the most well known and studied neurodegenerative diseases that is typically associated with aging, Alzheimer’s disease. He is currently treating Alzheimer’s patients with plasma form twenty-year-old donors to look for functional and cognitive improvements. To conclude, Dr. Wyss-Coray stated that the fountain of youth not only exists, but runs inside of us, it is in our blood.
References
Wyss-Coray Laboratory. (2015). Retrieved from http://web.stanford.edu/group/twclab/cgi-bin/

Wyss-Coray, T. (2015, October 26). Young Blood for Old Brains. Lecture Lecture presented 25th
Year Celebration of the Neuroscience Program in Washington Room, Hartford, CT.

TRINITY
TRIPOD Hartford, CT
Reprint
The Trinity Tripod w Trinity College w 300 Summit Street w Hartford, CT 06106
2
that certain anti-inflammatory drugs might help prevent the onset of specific neurodegenerative
disorders.
Additional studies suggest that injecting the blood plasma of younger mice into
older mice shows an increase in cognitive function for mice. In a series of studies, a
colleague of Professor Wyss-Coray at Stanford Medical School injected elderly mice with
the blood plasma of younger mice. A number of his findings defied the traditional aging
models— though, further research is needed to see how long these effects last. This
research suggests that the fountain of youth may not be at the furthest reaches of the Earth,
but rather inside each of us.

Neocortical Dynamics
Brown University professor Christopher Moore gave a presentation about “computing beyond neurons” focusing on combining multiple levels of electrophysiology, imaging, and optogenetics. Moore discussed the three main studies on perception currently taking place in his research laboratory: induction of neocortical gamma rhythms driving enhanced perception; 2 photon imaging of large scale network correlations and trial dynamics predicting perception; multi-electrode optogenetic and perceptual of cortical prediction. In addition to these three projects Moore has utilized different screening techniques to study his hemo-neural hypothesis, looking at the role of blood flow in information processing. Hemodynamics plays a role in information processing through modulation of neural activity (Moore & Cao, 2008). This modulation occurs due to diffusible factors and mechanical and thermal interactions which alter information processing capacity in local neural networks. Moore works with awake mice and 2 photon calcium imaging in vasodilation to study the modulation and neocortical sensory processing.
Literature Cited
Moore, Christopher, and Rosa Cao. “The Hemo-neural Hypothesis: On the Role of Blood Flow in Information Processing.” J Neurophysiol (2008).

Revelations
Nathaniel Thiemann
10/15/15
I’m quite fond of what I study, because every time I start to get bored with science I learn something new that challenges my preconceived notions on life. We as humans try our best to define and model pretty much every natural phenomena there is. However, as history has shown, our attempts to explain these phenomena can often be proved wrong at any moment when new evidence arises. These moments make us aware of how short-sighted and inadequate our attempts to explain phenomena can be. I had one of these moments last week while listening to Christopher Moore’s talk during a common hour talk regarding his research at Brown University.
Professor Moore conducts his research in the Neuroscience department at Brown’s graduate school, where he works with mice to learn more about our own physiology. His lab uses optogenetics, which utilizes genetic engineering to induce bioluminescence in subjects, in order to image alert subjects at the cellular level. The use of optogenetics essentially turns cells into a rate meter, which can be used to measure a multitude of variables like change in intracellular Ca2+ concentration. Professor Moore and his lab used optogenetics to examine whether blood flow acted as a neuromodulator in mice. Enter my cathartic moment from last week, their results indicated that functional vascular response (hyperemia) forms a closed-interconnected-system between neural and astrocyte activity. In layman’s terms this means that increased blood flow through a region of the brain correlates to increased neural activity in that region. Professor Moore supported his hypothesis with images of neuronal dendrites wrapped around blood vessels, which could be stimulated from a number of mechanical, thermal, and chemical (namely gaseous NO) interactions.
Leonardo Da Vinci once wrote of connecting the unconnected and urged people to, “Realize that everything connects to everything else.” As a skeptic, I can poke more than a few holes in that generalization. However, there is some truth to Da Vinci’s statement, our world works in an intricate chain of systems which are all interconnected with other systems. This chain of systems ranges from the subatomic systems that hold matter together to the ecosystems we live in, and beyond to the workings of the universe. Therefore, it shouldn’t be very surprising that our own body has a similar amount of interconnected systems within it, as proposed by the hemo-neural network. It makes sense that our evolutionarily tuned bodies would integrate our two major sources of communication in the body (the nervous system and our cardiovascular system) to improve the rate of information sharing possible.
It is important to remember that the hemo-neural hypothesis is not yet accepted. However, the hypothesis essentially reaffirms and strengthens the principle that scientists currently use to justify fMRI results. Therefore, to me the question is not whether hyperemia is a neuromodulator, but what else is? Some believe that the human gut biome may be another neuromodulator that has not yet been fully investigated. While I have no plans to investigate this matter myself, I look forward to seeing what new facts science will reveal to me in the future.

Lizzy Foley
Neuroscience Across Curriculum — COLL 118

On Tuesday, October 5th, those of us present at the common hour talk had the pleasure of hearing Chris Moore’s presentation as part of the 25th Anniversary of the Neuroscience Program. Moore attended Oberlin College, where he studied both philosophy and neuroscience, and went on to receive his Ph.D from MIT. After working at MIT’s McGovern Institute for Brain Research, Moore moved on to Brown University where he currently studies the interconnected role of blood flow and information processing as well as optogenetics in rodent models.

To begin his talk, Moore explained his main interest in understanding how the brain is dynamic. Such overarching interest led him to study the dynamic neurological mechanism that is responsible for tactile perception. In rodent animal models, Moore has applied optogenetics, which to me was novel scientific technique. Moore described his ability to genetically modify his animal models to have neurons with light-sensitive ion channels, allowing for light to control the cells. This technique makes it possible to turn specific neurons on and off, so that the effect on the nervous system and behavior could be studied.

In the first study that he mentioned, Moore observed the whisker system in his rodent mouse models. He wanted to see if enhancing gamma wave oscillations, which have been previously thoughts to be involved in perception, would increase cognizance of the stimulation of the whisker system. He applied optogenetics to use light to induce fast spiking interneurons that led to gamma wave oscillations. Ultimately, his findings indicated that inducing gamma wave oscillations increased the perception of less relevant, or naturalistic, stimuli. Such findings could be used to help those with attention issues.

The second study mentioned revolved around the development of the Hemo-Neural Hypothesis. Moore discussed the idea that blood flow in the brain has been long thought to serve merely as a metabolic support system. His research suggests, however, that blood flow and the role of the vascular system also plays a role in the modulation of neural activity and ultimately in information processing. Moore mentioned the hypermeia, which Professor Masino clarified to those of us who were unfamiliar with this term, is the process when there is increased blood flow to populations of activated neurons that is excessive. Ultimately, Moore clearly identified that such blood flow is not being driven by metabolism, as many scientists presently believe. Instead, he stated that the fact that the mechanism that changes the flow of blood also impacts neural activity suggests that hemodynamics are involved in information processing. Such theory is unique among the current concepts of the relevance of hemodynamics, however as Moore clearly discussed his research, it seemed logical and worthy of much more in depth examination.

Overall, Moore’s talk introduced me to new research techniques, neurological terms, and new ways of thinking about blood flow in the brain. Moore left an impression on the audience as true scientist, as he always questions how and why things function in a certain way. So far in his career, Moore has not let widely accepted theory reduce his new findings that may change the way in which we view simplistic processes, such as hemodynamics. Moore ended his talk by mentioning that as a scientist it is imperative to have all research open with others in order to collaborate in the hopes of coming to a greater understanding.

Elizabeth Dirico
Neuroscience across the curriculum
October 13th 2015
Could Blood Flow Shape Our Perception?
In line with popular belief, my previous understanding of hemodynamics was that vasculature systematically dilates and constricts in order to allocate the delivery of nutrients to a target region of bodily tissue. However Chris Moore, called me to question my previous perceptions with his compelling research that suggests that this in fact could be a great over simplification in the role of blood flow.
Chris Moore is a Brown University professor and leading researchers behind the revolutionary Hemo-neural Hypothesis, the idea that Hemodynamics (vaso constriction/dilation) can influence neural activity. This past week, the Trinity College community had the privilege of attending a lecture presented by Moore. He began by describing a multitude of complex laboratory techniques and equipment that he in collaboration with his Grad students had been designing for the past few decades. He then drew significance to these by postulating his original research question, is there a correlation between hemodynamic and cognitive perception? A question that was ahead of his time in that the technology needed to test this theory was not yet in existence. So began his long journey to design equipment that could adequately test this question.
Moore’s finding were compiled in his 2008 publication The hemo-neural hypothesis: on the role of blood flow in information processing. The majority of his research focuses on the neocortex, a region in the brain that is coincidentally responsible for both processing information and regulating blood flow. Overall, there is overwhelming evidence that suggests a linkage exists between blood flow and perception. For Example, a remarkable number of shared mechanisms and similar anatomical organization indicates that the physiological components are in place for the two systems to work synergistically with one another. Similarly, another way of looking at patterns of increased blood flow is to consider that they are akin to the sub threshold neural activity of the brain. Such a theory could explain how blood flow can be directed to a highly specific location such as a single glomerulus within the olfactory bulb. Additionally, Moore spoke of single cells that he found to be resting right atop vasculature and believed to play a role in modulating blood flow based on signals received from the brain.
Chris Moore continues to research and develop his hemodynamic hypothesis along side his graduate students to whom he credited a large portion of his success. In his closing remarks he emphasized the importance of collaboration, forgoing the pursuit of a scientific breakthrough in the interest of recognition and working jointly to combine brainpower and resources with competitors for the good of scientific advancement.

Julianna Maisano

Neuroscience Across the Curriculum
12 October 2015
Christopher Moore’s Lecture, Neocortical Dynamics: Computation Beyond Neurons
On Tuesday, October 6, 2015, Christopher Moore, a Professor of Neuroscience at Brown Univeristy spoke about his research in understanding how dynamic the brain truly is. To do this, Dr. Moore and his research team analyzed cell-type specific activity in 2-photon imaging. By combing multiple levels of electrophysiology imaging and optogenetics with behavior, calcium signals across the cortex are able to be examined. Through the development of new electrophysiological tools, neuronal networks can be mapped, recorded and controlled at distinct times during certain behaviors. During his lecture, Dr. Moore discussed his past and present recent projects on the inner workings of neurons through electrophysiology and hemo-neural dynamics.
To date, Dr. Moore has been working on studies that involve neocortical dynamics in both top-down and bottom-up perception. He noted that during top-down perception, gamma rhythms drive perception, however during bottom-up perception, multi-electrode and optogenetics aid in how things are perceived. To analyze behavior and perception, Dr. Moore analyzed the sensory impact of repeated synchronization of fast-spiking interneurons (FS), top understand the response activity pattern believed to underlie neocortical gamma oscillations (Siegle et al., 2014). Through the use of new electrophysiology systems such as OP-EEG, bioluminescence, and BLOG or GLOG, stimuli that are hard to perceive and require neocortical circuitry, will be able to be analyzed, especially if they are in need of consistent attention and detection (Siegle et al., 2014).
In his lecture, Dr. Moore also spoke of his research concerning the hemo-neural hypothesis. Dr. Moore has hypothesized that hemodynamics, local dilations as in fMRI, drive neural excitability on the time scale of milliseconds to seconds. To test the validity of his theory, Dr. Moore set out to analyze neuro-vascular coupling, the key factors that contribute to vascular disease, and the neuromodulator of informational processing. Local vaso-dilations are used to predict information in the neocortex. The vasculature forms a densely interconnected network in close opposition to the neighboring neurons in which the cells are also found to sit on top of the vasculature. By using fMRI techniques, Dr. Moore is able to stimulate an area of the brain that controls specific movements to analyze increased blood flow to these areas. To add, Dr. Moore has also analyzed hyperemia, to which he defined as an excess of blood in the vessels supplying an organ or other part of the body. Hyperemia does not have a role in regulating metabolism, however, the condition does increase the tendency of cells to over-shoot in oxygen supply, which in some cases enables blood flow to be considered a neuro-modulator (Moore, 2015).
Despite the progress Dr. Moore and his research team have made, there are limitations to the types of research that he and his team are able to conduct. Dr. Moore has experienced challenges in testing the impact of vaso-dilation on neurons in vivo, as the use of anesthesia can be controversial and the use of electrodes for 2-photon calcium imaging can be difficult. To conclude his lecture, Dr. Moore discussed the future of his research. He noted that selective vascular motion is derived from neural activity and that by moving small bodily features such as whiskers we can look directly into the cortex to analyze brain activity.
References

Moore, C. (2015, October 6). Neocortical Dynamics: Computation Beyond Neurons. Lecture.

Siegle, J., Pritchett, D., & Moore, C. (2014). Gamma-range synchronization of fast-spiking
interneurons can enhance detection of tactile stimuli. Nature Neuroscience Nat Neuroscience, 1371-1379.

Tommy Hum-Hyder
Neuroscience Across the Curriculum

October 10, 2015

Last week, Chris Moore Ph.D of Brown University spoke about his research in optogenetics, which includes techniques such as 2-photon imaging, ultra-light flex drive. Ongoing research in the Moore lab seeks to use “BLOG,” or bio-luminescence optogenetics, which allows specific neurons to be activated in the presence of light. Instead of just flashing light on an organism, there exist enzymes that, along with their substrates, can produce photons, thereby making light within the organism that can then activate certain neurons. In the future, BLOG could be coupled with certain pharmacological agents that could bring about a fuller understanding of the mechanism of certain diseases and how to best improve the brain and behavior. Moore then spoke about the Hemo-Neural hypothesis, which believes that that increases in blood flow to certain parts of the brain correlate to an increase in neural processes. The Hemo-Neural hypothesis is integral in the clinical efficacy of fMRI scans. However, many opponents of the Hemo-Neural hypothesis believe that the increase in blood flow is simply due to metabolism, or the fact that neurons “need to eat.” While Moore does concede that neurons simply need fuel in order to function, he supports the Hemo-Neural hypothesis because it seems to corroborate our understanding of vascular disease and the neuromodular capabilities of information processing. Therefore, without the Hemo-Neural hypothesis, it may take significantly more time to understand these diseases.