The Question of Memory

By Jessica Nelson, Graduate School

 

 

The question of memory, according Manuj Ahuja, is one of the great mysteries of science. How exactly does the brain work? How do we form and store memories? Where do our thoughts and consciousness come from? These questions have long fascinated him, and this fascination brought him to Auburn University.

Ahuja's doctoral research in the Department of Pharmacal Sciences involves an ancient remedy and one of today's most frightening conditions, Alzheimer's disease. Despite increasing attention to this debilitating disorder which decimates the memory, we do not yet really understand the disease. Ahuja explains that Alzheimer's is multifactorial, with several factors in the brain working together to produce the condition we call Alzheimer's. We have identified several of these factors, he says, but we don't know the root cause, the basic why someone gets the disease.

Along with his advisor, Muralikrishnan Dhanasekaran, and their collaborator, Vishnu Suppiramaniam, Ahuja investigates the potential for new entities, specifically the plant centella asiatica, in the treatment of Alzheimer's. Currently, treatment options involve slowing the disease's progress and easing symptoms – until we know why people get it and how it works, an outright cure seems unlikely. Ahuja explains their focus on herbal remedies, "The herbal drugs, they have so many constituents, and we believe that the drugs can work against all those multi-factors."

Centella asiatica is their focus because first, it is a known antioxidant with anti-inflammatory properties, Ahuja says. It is currently approved by the FDA for wound healing because of these qualities. Furthermore, centella asiatica, known as jal brahmi in parts of India, was used in the Ayurvedic tradition as a cognitive enhancer as well as for wound healing. Recently, some clinical trials have shown the herb to be effective in improving memory in humans.

If it is true that the drug has neuroprotective and cognitive enhancing properties, then eventually scientists can hope to identify exactly what in the substance improves memory, and either synthesize or extract it for use in treating memory disorders like Alzheimer's, Ahuja says. And while the primary goal is to treat the disease, they also hope to be able to use what they find to learn more about how and why a person develops it.

He compares this path of discovery to quinine, used to treat malaria. "They found that these drugs from the plants have these beneficial effects. Then they wanted to extract which part of them is causing the beneficial effects. Then they made compounds to go and bind to the target. Then they have to find the target, and then they find out the pathophysiology of the disease." Perhaps you could compare it to a mystery novel – when they can find out how the murder is committed, they can deduce the culprit.

But that is in the future. For now, they have to validate their behavioral studies, which showed that transgenic mice – mice altered to have Alzheimer 's disease – performed better in a maze when they had been treated with centella asiatica.

"Right now people know that it has a cognitive enhancing effect," Ahuja says of his drug, "but we do not know the cellular and molecular pathways by which it is causing these effects. We want to find out what are these pathways, what are the cellular molecules, what happens in the brain when we take this drug."

This is all part of the determined march of science. They know something is working, but scientifically speaking, we don't know something is true until we know why it is true.

Ahuja summarizes their work. "After that we extract the proteins from the brain, put them into a gel to isolate them, and from that we measure how much protein is present in each group." They would compare an untreated control group, a transgenic group and then one that is treated. "Then you measure different proteins. If a drug is increasing the bad protein and decreasing the good protein, and my drug is reversing that, then that drug is neuroprotective." And they are definitely finding that centella asiatica does just that, he says.

His collaboration with Suppiramaniam gives Ahuja access to the labs where his electrophysiological studies are conducted. They are looking closely at synapses in the hippocampus, the principal area of the brain where memory is formed and stored. Synapses are the electrical connections between neurons that pass on information. If the synapses in the hippocampus are sending more information after treatment, then we know, Ahuja says, that there is a concrete boost to memory. Their initial study showed that both input and output were increased, an encouraging find.

From there, they moved on to take a closer look with a study called single channel analysis.

The tools used in the single channel analysis are absurdly small. In his lab, Ahuja points out a micro pipette – a small glass tube that tapers off to an impossibly fine point, and a tiny beaker that belongs in a doll's laboratory.

"So what I am actually doing is I am putting a single channel in the membrane – in a micro pipette." This tube is filled with intracellular fluid, and the beakers contain an electrode and extracellular fluid, all of which recreate the brain environment and allow the synapse to function as it would in the body.

Then they send current through the channel, or receptor, and read the output on a computer screen. Ahuja has dozens of graphs that show the activity in receptors, and points out what they look for. Spikes on the graph show when the synapse allows data through. A good result would show that the connection is open longer or more often. Ahuja clicks rapidly through different files, indicating hours of painstaking work with these tiny bits of memory.

Also ongoing in the lab is a process that Ahuja calls extracellular field recording in which he looks for activity in what is called the Schaffer collateral pathway, an area that is associated with learning and memory formation.

In another room, he is studying a bad protein called amyloid beta, considered the primary pathological marker for Alzheimer's disease. This protein causes cell death, and is one of the factors leading to Alzheimer's. When working with transgenic mice, the model most commonly used involves altering the animals to have deposits of amyloid beta in their brains. Ahuja says that several of the current treatments for Alzheimer's work by clearing away these deposits, which does slow the progress of the disease. He is also testing his drug for this property.

Further down the road, he wants to investigate whether centella asiatica can address other conditions affecting memory, such as fetal alcohol syndrome. "That would be a good study by itself," he says. "It's my whole PhD!" He would have to develop a new animal model, but he is excited about the possibilities for developing treatment for this condition as well.

One of the things that he has noticed and liked about Auburn is a recurring theme among graduate students, "Research is very friendly here," he says. "There is not that tension between the labs. In India things are very formal in a way that they are not here at Auburn. You have formal relationship with teachers and mentors." In fact, he is enthusiastic about the work in other labs – at the College of Veterinary Medicine, in Biological Sciences. He enthusiastically references the research supervised by the late dean of the College of Sciences and Mathematics, Marie Wooten. "Her research was very good! She has found a gene which she claims is being increased in the Alzheimer's disease. So that is one of the pathophysiological factors of the disease."

Students often reference Auburn's collaborative atmosphere, although Manuj is experiencing it more closely than most, since he divides his time between two separate labs.

And for the times when he is not in the lab, he has recently taken on a new role as vice president of the Graduate Student Council. In 2010, he served as a volunteer at the council's annual Graduate Research Forum, which allows graduate students to practice presenting their work in a conference environment and compete for monetary awards. "It was the first time I was involved in those kinds of things, so I was enjoying all those things," he says.

There is a variety of experiences available at Auburn University for graduate students, and many ways for them to both lead and serve. In his capacity as a researcher and as a Graduate Student Council officer, it seems that Manuj is set for both.

Last Updated: Oct. 17, 2011

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