Tiny Giants

June 1, 2018

 

The first thing you see is the floor of an autumnal forest, in which the leaves are switching out their summer wardrobe for various shades of orange and brown. Mushrooms are sprouting like California redwood and...sploosh! A giant moose is towering over you like an AT-ST on Endor and his drool is drenching you like that random cloud of Southern rain. Cloudy with a chance of drool! Acorns like giant meteors are falling from the sky and rattling the ground like a herd of wildebeests. Imagine yourself at two months old navigating this world and battling many other elements to collect enough sustenance for the winter... This is exactly the life of a young chipmunk, a tiny giant fighting and thriving in this fantastical world.

Above is a glimpse of the charming 4D short feature film "Tiny Giants" at the South Carolina State Museum, which also happened to be the location of the annual University of South Carolina Neuroscience Retreat this year on May 18th. The field of neuroscience has exploded in the past few years due to the increasing curiosity to understand our own minds. Even Hollywood took an interest with, for example, the Leonardo DiCaprio film Inception, in which a man is trapped within the confines of his own imagination to the point where neither he nor the audience can distinguish between dream and reality. Marvel's Dr. Strange dealt with the spellbinding concept of mind-over-matter, which manifests in the real world as the placebo effect, superhuman athletic abilities, yogis nearly stopping their own heartbeats, the inexplicably healthy impact of positive thinking, among many others (for additional reading, click here). These are just a few examples, but one thing is clear: the human brain is thinking about and trying to understand itself. 

 The Hashemi Lab at the Neuro Retreat 2018

From left to right (clockwise): Alyssa West, Colby "Jack" Witt, Shane Berger, Prof. Parry Hashemi, Anna Marie Buchanon, Melinda Hersey, Kimberly Gibson Sitter (honorary member), Jordan Holmes, and Yangguang Ou 

 

At the retreat this year, presenters discussed the dynamic human brain from birth, through life, to old age. During development, precise organization of neurons and neuronal connections is essential for proper function. Olivia Spead in Prof. F. E. Poulain's lab described how the protein glypican-3 is responsible for the degeneration of misguided dorsal optic tracts, which grow along the wrong path and cross into the ventral side, during development. Improper axon growth results in erroneous topographic mapping by the visual cortex, meaning everything could appear to be upside down. More research is needed to understand if the same mechanism applies to the ventral optic tract.

 

Another aspect of human development is speech. Aphasia is the loss of ability to understand or express speech, usually due to brain damage (e.g. from stroke). Approximately 15% of aphasia patients have agrammatic symptoms, meaning they have reduced sentence complexity, omitted inflections, and omitted prepositions. Prof. D. den Ouden gave an unusual neuroscience lecture by starting with a grammar lesson. He focused on a type of aphasia called Broca's aphasia, which is named after the area of the brain it inflicts. A healthy individual would say "Cinderella read a book," according to den Ouden, but a patient with Broca's aphasia would simply say "Cinderella read." His work with patients showed that patients with Broca's aphasia use verbs with the same frequency but uses them in less complex ways. Using functional magnetic resonance imaging, he and his group were able to map the active brain regions during speech. Research such as these provide us with an appreciation for basic functions we develop so early in life.

 

One of the most controversial topics in development is autism spectrum disorder, which is loosely defined as a disorder that is characterized by difficulty in social interactions and communication but is not limited to a single etiology. Serotonin is an essential neurotransmitter and has widespread roles in both the peripheral and central nervous system. It is thought that it plays a role in autism but the lack of appropriate tools has prevented direct evidence from being collected. In a quest to understand the effect of autism on changes in serotonin levels, Alyssa West (pictured left, photo credit: Jordan Holmes) from Prof. P. Hashemi's lab used fast scan cyclic voltammetry (FSCV) and fast scan controlled adsorption voltammetry (FSCAV) to, for the first time, uncover region-specific serotonin reuptake mechanisms in the prefrontal cortex.  This suggests that there is a heterogenous distribution of different reuptake transporters. She also discovered that serotonin reuptake is altered in a variety of autism spectrum models compared to that in control animals. By furthering the understanding of autism, this research paves the way for potential therapies in the future. Keep an eye out for Alyssa's paper!

 

Humans are social creatures and social interactions are a part of life (for example, Melinda Hersey and Jordan Holmes, pictured right, are socializing and dancing with the laser lights). Social stress goes hand-in-hand with social interactions and can be caused by a wide variety of factors, including something as innocuous as public speaking to traumatic events such as bullying and abuse. Women between the ages of puberty and menopause are twice as susceptible to social anxiety than their male counterpart. Julie Finnell from Prof. S. Wood's lab sought to study the effect of neuroinflammation in the high susceptibiliy of females to stress, specifically focusing on the effect of ovarian hormones on high mobility group box-1 protein (HMGB-1). HMGB-1 is secreted by immune cells and is a pro-inflammatory cytokine mediator. One of the limitations with studying social stress in female rodents is that the same model of social defeat established for males do not apply. Neither females nor males attack females, the basis of the social defeat paradigm. In a new model, the female rodent instead is a witness to a male rodent being attacked or defeated by another male rodent. This is currently the accepted model for female social defeat. Female witnesses were observed to demonstrate greater anxiety as evidenced by burying behavior into the bedding, depressive-like anhedonia, and increased interleukin-1β, a proinflammatory cytokine, in the amygdala five days after the social defeat paradigm. To test their hypothesis, Finnell removed the ovary from female rodents and compared them to sham females, called "intact" females. They found that HMGB-1 did not play a significant role in acute stress, since blocking the major binding site of HMGB-1 did not change the observed behaviors relative to controls. Finnell concluded that the role of HMGB-1 was not clear but may be involved in neuronal homeostasis via regulation of the blood-brain barrier (BBB) and silent synapses. More work was necessary. 

 

In a related work, Katy Pilarzyk from Prof. M. P. Kelly's lab looked at phosphodiesterase 2-A (PDEIIA), an enzyme that degrades cAMP and cGMP, and its role in social memories. Studies showed that social isolation decreased PDEIIA levels. Pilarzyk looked at the effects of both acute and chronic (1hr, 1 day, 1 week, 1 month) social isolation on levels of PDEIIA in the membrane, cytosol, and nucleus of adult mice. She found that only the membrane fraction showed reduced PDEIIA levels but that only 1 hr of social isolation was enough to cause a change. Counterintuitively, chronic social isolation of adolescent mice did not change PDEIIA protein expression. Increases in PDEIIA correlated with decreases in cytosolic proinflammatory cytokine levels and PDEIIA knockouts increased microglia population, reiterating the hypothesis that social stress and neuroinflammation go hand-in-hand. 

 

 

Neuroinflammation is not only co-morbid with social stress but also with depression, a mental health disorder marked by depressed mood and loss of interest. For the longest time, depression was not recognized as a mental illness. It is also difficult to diagnose depression as it would other disorders. There is currently no routine test that could definitively diagnose a depressed patient. One well-known hypothesis, called the monoamine hypothesis, is that serotonin chemistry changes during depression. Based on this hypothesis, drugs such as selective serotonin reuptake inhibitors (SSRIs) are administered to patients in low, chronic doses. It is, however, only effective in 30% of the patients and usually these patients tend to feel worse before feeling better. Prof. P. Hashemi's lab seeks to answer these questions and many more. Melinda Hersey provided direct evidence of the role of acute and chronic neuroinflammation in depression and won the best afternoon poster award (congratulations Melinda!). Shane Berger (pictured left) wanted to understand the effects of pesticide exposure on synaptic serotonin transmission and, subsequently, depression. This work is based on the alarming statistics that farmers exposed to pesticides often have higher rates of depression and suicidal tendencies.

 

 

 

Glutamate, a widespread excitatory neurotransmitter, is said to be elevated in patients with bipolar depression and major depression. Jordan Holmes (pictured above, left) designed a new way to perform enzyme-free glutamate sensing at carbon fiber microelectrodes, paving the way for future in vivo studies. All of these stories were tied together in a big picture lecture by Prof. P. Hashemi (pictured above, right, with her favorite student Colby "Jack" Witt) in the morning symposium, in which she described the issue with depression diagnosis, the work done by her team to understand the etiology of depression, and her dream of making personalized medicine a reality in the future.

 

As the brain ages, it is prone to even more disorders. One prominent example is Alzheimer's disease, which is marked by chronic degeneration of cognitive function over time with short-term memory loss and dementia. As the baby boomers turn 65 years old, there is a growing concern that Alzheimer's disease will become one of the biggest epidemic. One of the distinguishing characteristics of Alzheimer's is the formation of Aβ fibrils, which accumulates in the brain because they are insoluble and cannot cross the BBB. Hope Holt from Prof. M. A. Moss's lab wanted to create a way to remove insoluble oligomers, a precursor to fibrils, by transporting them across the BBB with P-glycoproteins. These proteins are naturally occurring proteins bound to the BBB interface that act as a shuttle and are, interestingly, tagged by Aβ40 for degradation. According to Holt, once in the bloodstream, the oligomers could be readily degraded. One of the problems with current drug administration is that high doses are often needed in order for effective concentrations to reach the brain. If these P-glycoproteins could be engineered to selectively and favorably transport toxic oligomers, then high doses would not be necessary. One caveat of the project is that P-glycoproteins are highly expressed on cancer cells, rendering them multi-drug resistant. Holt warned that caution should be taken for proper design and selective expression. Anna Marie Buchanon (pictured above left) from Prof. P. Hashemi's lab wanted to look at another aspect of Alzheimer's. She used FSCV to measure Cu(II) in vivo in order to understand its role in the formation of Aβ plaques. She also wanted to discover the role of serotonin in Alzheimer's, as these patients have low levels of this neurotransmitter compared to healthy individuals. It is unknown whether this is the cause or the effect.

 

There were numerous other topics discussed at the retreat, including axonal transport by microtubules, highly active antiretroviral therapy, iontropic glutamate receptors, and many more. These topics were not covered in this blog but are nonetheless important facets of the exploding neuroscience field.

The human brain is made up of more than a hundred billion neurons. It is responsible for maintaining homeostasis, controlling rapid and coordinated responses all through the body, complex decision-making, memory formation and storage, and creating the very reality we live in. It is absolutely astounding how these tiny entities are responsible for so much of the world as we know it.

 

One can say that they too are tiny giants.

 

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