Window to the brain

In a flap of skull the size of a pinhead, Martin Paukert, M.D., mounts and seals a thin window onto an anesthetized mouse.

This window will allow Dr. Paukert and his team to monitor, in real time, effects of stimuli to the brain of a conscious mouse while it walks on a tiny treadmill. That’s something that’s not often done, Dr. Paukert said, but that can yield important data.

Dr. Paukert is the principal investigator of a five-year, $2 million grant from The Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation to study brain activity that may take place long before Alzheimer’s disease symptoms are observed.

“The unraveling of the mystery of this terrible illness will emanate from discoveries along the lines of what Dr. Paukert and his colleagues are doing,” said UT Health Science Center President William L. Henrich, M.D., MACP. “You can’t develop a drug, you can’t develop an antibody, you can’t develop something to prevent this unless you know what lies at the very center of the problem. That’s why this work is so important. The consequences of having a neurodegenerative disease are deeply felt by everybody.”

One of the earliest sites of noticeable neurodegeneration is a brain stem structure called the locus coeruleus. This structure has a major influence on the entire central nervous system because it delivers norepinephrine, a neurotransmitter associated with attention or arousal. Initial triggers of Alzheimer’s disease may include less norepinephrine release, and fewer norepinephrine-dependent calcium spikes in cells called astrocytes. While astrocytes are the major support cells for neurons, in Alzheimer’s this relationship appears to be somehow affected, causing the death of neurons.

Using Dr. Paukert’s system, the scientists measure spikes in calcium signaling in the astrocytes, which occur when the mouse walks on a treadmill or, more pronounced, when the mouse follows the movement of the motorized belt of the treadmill. During the measurements, the mouse is conscious and the window to its brain is immobilized under the microscope. Critically, its legs remain free to walk.

“This technique gives us a window into how brain cells engage in a cross-talk and how these communications are determined and interpreted by a certain behavior,” said Dr. Paukert, assistant professor of physiology. “The hope is that we can use these signals as a readout of what is necessary to normalize norepinephrine signaling, and to see whether this intervention slows the progression of Alzheimer’s disease.”

Only a handful of labs around the world are recording these spikes in real time, while the mice are awake, said Manzoor Bhat, Ph.D., professor and chairman of the Department of Physiology.

“The Paukert lab is in its early phases in San Antonio, and funding from The Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation will have a major impact on how quickly they can get the animal models established to address the central questions related to the early onset and progression of Alzheimer’s disease in real time,” Dr. Bhat said. “In the future, this will allow exploration of new avenues for therapeutic intervention.”