Shining New Light on Failing Memory in Alzheimer's Disease

New faculty member Christine Ann Denny, PhD, recently received an Early Independence Award from the NIH and is taking on one of neuroscience’s most formidable problems—memory in Alzheimer’s disease—with some of the field’s latest “gee-whiz” technologies. We recently spoke with Dr. Denny in her office in the Department of Psychiatry.

What is it about Alzheimer’s that intrigues you?

If you talk to patients with Alzheimer’s disease, they typically have strong childhood memories but often cannot remember that they told you the same story an hour ago. I want to understand what distinguishes older memory traces from newer ones and how memory becomes impaired in normal aging and in Alzheimer’s disease.

In my previous research, I engineered a mouse line that allows for the indelible labeling of a memory trace. We looked at how memory traces are formed and retrieved under a number of conditions, such as in response to stress. We found specific memory deficits in stressed mice and determined where in the brain the memory traces were being improperly formed and retrieved.

With this mouse line that we’ve created, we are able to address a number of memory-related questions that we weren't able to until now. For example, in Alzheimer’s disease, is the brain encoding a memory correctly but failing to retrieve it correctly, or are both encoding and retrieval impaired? If a memory trace is encoded correctly, but not retrieved correctly, are there treatments that would enable the brain to better access the memory? With these mice, we can begin to tackle these short- and long-term memory questions.

The overall goal of my lab is to understand how memories are formed and retrieved under normal and diseased conditions. Only then, can we begin to restore or improve the memory deficits in Alzheimer’s disease.

Part of what makes your study possible is the mouse you developed, in which you can identify the cells that create a new memory and the cells that are used to retrieve memories. How does that work?

Whenever you, or a mouse, learn or experience something, a gene called Arc turns on. Basically, I engineered a mouse that allows me to permanently label cells expressing the gene Arc during a given experience. I can label these cells with a fluorescent tag and then identify which cells were active during learning and see whether they are later activated during recall of that experience. In this genetic design, you can tag any memory or experience that the mouse undergoes.

In my previous studies, I looked at neurons that encode fear memories. The fluorescent green neurons correspond to the encoding of the initial fearful memory; the red neurons are the cells that were active during recall of that fearful memory. The co-labeled yellow neurons—neurons expressing both green and red fluorescent proteins—are what we consider to be a memory trace. These cells have participated in the encoding and retrieval of a particular memory. We have found that if an animal expresses strong fear and, therefore, has a strong memory, there are many co-labeled cells. If an animal weakly remembers the fearful memory, we find a significantly smaller number of co-labeled cells.

What’s unique about this mouse is that the neurons retain the fluorescent label until the mouse dies. In similar mouse models, the fluorescent label eventually disappears, and researchers are unable to assess what happens many months after a mouse first learns something or after a disease has set in. Now with these Arc mice, we can label a memory trace in an Alzheimer’s disease model and wait months, or even more than a year, to see how that long-term memory trace differs from a short-term memory trace.

You’re also using another new, exciting technology—optogenetics—to turn specific memories on and off. What is that telling you?

In optogenetics, one can genetically engineer neurons to produce a protein that can be activated by light. Shining light onto the protein can turn the neuron on or off, depending on the type of protein. In our optogenetics studies, we can specifically turn on or off the neurons that constitute a memory trace. In our previous studies on stress and memory, we were able to partially block retrieval of a fear memory by optogenetically inhibiting the corresponding memory trace.

Now in the lab, using optogenetics, we’ll be able to identify the neurons necessary for memory retrieval and determine whether stimulating those neurons improves memory in mice with Alzheimer’s.

The NIH grant you just received is known as the “Skip-the-Postdoc” grant, and only 15 researchers received one this year. How does this grant help your lab?

I received my PhD in 2012 from Columbia’s biological sciences department, and now I’m an assistant professor in the psychiatry department, with my own lab. It’s a pretty amazing award.

If I had not received this award, I most likely would have been a postdoc for a number of years. At that point, I would have needed to obtain independent funding and then go on the job market. It is an especially difficult time right now to obtain funding and an independent position, so I feel extremely blessed.

In terms of lab growth, a former Barnard student who worked in my lab is now my technician. I have two other undergraduates and a high school student working in the lab. The high school student came through a summer program, BRAINYAC (Brain Research Apprenticeships In New York At Columbia), which pairs high school students with labs, and he’s staying on during the school year. I have also hired a postdoctoral fellow who will start in the spring. Coincidentally, she is also a Barnard graduate —she completed her PhD at UCLA.