Thalamic Control of Memory in Alzheimer's Disease
Memory fails early in Alzheimer's disease because the entorhinal cortex, a brain area first affected by the disease, cannot properly communicate with the hippocampus, the second brain area affected by the disease. However, there is another brain region, the thalamus, that communicates with the hippocampus but is not affected at early stages. Here we lay the groundwork for possibly stimulating the thalamus to compensate for entorhinal-hippocampal miscommunication, by first deciphering the structure and function of the "wiring diagram" between thalamus and hippocampus, and then examining how this functional connectivity changes in Alzheimer's disease. This will provide a better understanding of the role of the thalamus in normal memory, and set the stage for future work aimed at precisely tuning these thalamic inputs to enhance memory in patients with early stage Alzheimer's disease.
Our goal is to provide proof-of-principle evidence that brain stimulation of an alternative memory pathway can overcome the damage caused by Alzheimer's disease and treat cognitive deficits. Memory fails in early Alzheimer's disease due to miscommunication between two brain areas, the entorhinal cortex and hippocampus, but the thalamus, another brain area, also communicates with the hippocampus and is not affected. Using optogenetics, a technique to render specific brain cells sensitive to light, we will first decipher the "wiring diagram" between the thalamus and hippocampus in mice genetically engineered to have Alzheimer’s disease. We will then strengthen the connections between thalamus and hippocampus using special light stimulation patterns and measure their ability to improve memory in the Alzheimer’s mice. This work is innovative because the role of the thalamus in Alzheimer's disease has received very little attention, and we are using precise techniques like optogenetics to provide unprecedented access to the functional architecture of the thalamo-hippocampal network. Regardless of outcome, these experiments will provide vital new information on memory circuit dysfunction in Alzheimer’s disease. It is our hope that this work, if successful, will lead to more sophisticated memory neurostimulation trials in human Alzheimer’s patients.
About the Researcher
Dr. Masurkar is an Assistant Professor of Neurology at NYU Langone Health. He earned his BS in Electrical Engineering at MIT, focusing on the mathematical description of information processing in electrical circuits. Looking to apply this to biomedical problems, during his MD/PhD at Yale University he studied odor processing in the rodent olfactory bulb by applying a variety of in vitro and in vivo imaging and electrophysiology techniques. This was followed by neurology residency at Columbia University, where he developed a clinical interest in Alzheimer disease (AD). He remained at Columbia to pursue this clinical interest with a fellowship in behavioral neurology and neuropsychiatry. Simultaneously, he obtained postdoctoral scientific training, applying optogenetics and multiphoton microscopy to functionally interrogate memory circuits relate to AD. Now at NYU, he combines clinical practice in dementia and translational research program in AD that utilizes a two-pronged approach. At the bench, his team uses AD mouse models to study the differential vulnerability of neural circuits to early AD and their relationship to early cognitive and behavioral symptoms. The approach combines a variety of molecular, histological, imaging, and electrophysiological techniques. Second, as Clinical Core Director of the NYU Alzheimer’s Disease Center, he leverages its longitudinal clinical study of human subjects and its associated brain bank to translate his bench findings and explore analogous structure-function relationships in human AD.
As an electrical engineering undergraduate interested in medicine, I took a course that was designed to teach engineers about the physiology of nerves. The main experiment was to dissect a frog's sciatic nerve, and study its responses to electrical stimulation using the same principles of circuit operations that we learned in our more theoretical classes. My eyes widening with each nerve impulse visualized on my oscilloscope, I realized that this was a remarkable synthesis of my two passions - engineering and biology. This planted the seed for me to think about the brain as a computer, and neurological diseases as dysfunctions of microscopic electrical circuits. Fast-forward nearly twenty years, after interweaving engineering, neuroscience, and clinical neurology during my training, and I run my research program on Alzheimer disease on this essential principle. With this unique background, I hope to bring a fresh perspective on the difficult problems that face this field. Our project is a perfect example of this, as we apply our microcircuit understanding of memory to propose a novel brain stimulation paradigm. We are greatly appreciative of BrightFocus Foundation donors for their support that allows us to take innovative directions and build towards better treatments for our patients that suffer from this terrible disease.
First published on: July 2, 2019
Last modified on: August 7, 2019