Improving the Quality of Spatial Information Processing by Combating Dysfunctional Neuronal Activity in Alzheimer’s Disease Mouse Models

Gustavo Rodriguez, PhD
Columbia University (New York, NY)

Mentors

S. Abid Hussaini, PhD
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$200,000
Grant Reference ID:
A2019382F
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern
gustavo rodriguez, male researcher

Machine Learning & Impaired Spatial Decoding in AD Mice

Summary

Complex information processing in the brain is possible due to the combined strength and diverse talents of large numbers of neurons working together. In mouse models of Alzheimer’s disease (AD) pathology, amyloid beta (Aβ) leads to overactive neuron signaling and poor spatial information processing, which may be aggravated by tau build-up. Using sophisticated recording techniques, we will measure the content and quality of spatial information transmitted by large numbers of neurons in brains containing Aβ and tau pathology. Dysfunctional neuronal populations will be selectively targeted to correct their overactive firing patterns, with the overall goal of improving the quality of spatial information carried by large numbers of neurons.

Details

While considerable evidence exists to support the notion that amyloid beta (Aβ) and tau pathology negatively impact spatial learning and memory in Alzheimer’s disease, few studies have tested their direct influence on spatial computation within affected neuronal populations, resulting in an information gap at the neuronal network level. Thus, the overall goal of this project is to bridge this gap by offering a greater functional understanding of Alzheimer’s disease-related cognitive impairment and the underlying pathology.

In this proposal, I will utilize recent advances in machine learning to better understand how early pathological accumulation of Aβ and tau interfere with encoding of spatial information in the entorhinal cortex of aged, transgenic mice. The entorhinal cortex plays a critical role in spatial representation, navigation and learning & memory, and is particularly vulnerable to Alzheimer’s disease pathology. Neuronal recordings will be performed in awake, behaving mice as they navigate several contextually unique environments. Machine learning strategies will then be used to decode features of task-relevant, spatial information from neural ensemble activity in the entorhinal cortex. Dysfunctional neuronal populations will be selectively targeted using chemogenetics to correct abnormal firing patterns, with the aim of improving the quality of spatial information carried by pathology afflicted neuronal networks. This interdisciplinary proposal represents a novel, innovative approach to understanding how Aβ and tau pathology work independently, or perhaps synergistically, to impact spatial computation in the brain.

About the Researcher

Dr. Gustavo A Rodriguez is an Associate Research Scientist in the Taub Institute for Research on Alzheimer’s disease and the Aging Brain at Columbia University Medical Center, New York, NY. His research is focused on understanding how neuronal populations in the entorhinal cortex and hippocampus are affected by amyloid beta (Aβ) and tau pathology, and in turn, whether neuromodulatory approaches can be successfully implemented to correct aberrant neuronal activity in Alzheimer’s disease (AD) mouse models.

Dr. Rodriguez is originally from Houston, TX. He completed his undergraduate education (B.A. Psychology, w/ minor in Philosophy) at Texas State University – San Marcos (2006). His formal neuroscience training began as an undergraduate in the Behavioral Neurobiology Training Program at the University of Texas - San Antonio (2006), followed by a post-baccalaureate fellowship in the Summer Undergraduate Research Program at the University of Texas Health Science Center - San Antonio (2006). He then served as a research assistant in the laboratory of Dr. David A Morilak at the University of Texas Health Science Center - San Antonio (2006 - 09) before applying to graduate programs. Dr. Rodriguez received his PhD (Neuroscience) from Georgetown University in Washington, D.C. (2014) under the mentorship of Dr. G William Rebeck. His thesis research examined the impact of Apolipoprotein E4 (APOE4), a significant genetic risk factor for AD, on AD-related neuropathology and on normal brain function in mouse models. A growing interest in understanding the underlying mechanisms of spatial learning and memory dysfunction in AD led Dr. Rodriguez to pursue postdoctoral training at Columbia University Medical Center under the joint mentorship of Drs. S Abid Hussaini and Karen E Duff. Dr. Rodriguez employs neuromodulatory strategies and in vivo electrophysiology in his research to explore the impact of AD pathology on entorhinal cortex – hippocampal function in transgenic AD mice, and compliments this work with behavioral studies that assess the cognitive impact of modulating neuronal activity, as well as Aβ and tau aggregation, in his mice, with the ultimate goal of informing future studies that drive translational strategies to combat AD dementia.

Personal Story

My career in neuroscience stems from a transformative year during my undergraduate studies. In my senior year, I was exposed to two advanced level philosophy courses that would change my life. These two courses (Philosophy of Mind and Consciousness) examined the “mind-body problem” and were conducted in roundtable discussions of influential philosophical essays. Nearly all my thesis defense papers for these courses were rooted in neuroscience research, which I used to strengthen my logical arguments. It was clear that I had a blossoming interest in neuroscience, and so I was encouraged to seek opportunities to increase my scientific training and exposure to that career path. My early mentors opened an important door for me metaphorically, as I had never even considered a scientific career in neuroscience was possible for me. I did not have extensive academic training in the natural sciences and thus did not show particular strength in those fields, but at that point, I was extremely motivated to understand the neurobiology underlying complex cognitive processes, especially learning & memory. So much of our personal identity is tied to our consciousness, a phenomenon that is enriched by an expansive history of memories. I was hooked. From then on, I made every effort to challenge myself academically and pursue a career in science. My full research experience and academic training demonstrate a commitment to neuroscience research, and specifically to pursuing mechanisms of neuronal network dysfunction in Alzheimer’s disease, which is characterized by significant memory loss.

I am grateful to the BrightFocus Foundation and their generous donors for their support. This funding opportunity will leverage the strengths of three independent labs across two institutions at Columbia University, and will allow me to advance my research training and career development.

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