Area:
neuronal network dysfunction in AD
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High-probability grants
According to our matching algorithm, Gustavo A. Rodriguez is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2014 |
Rodriguez, Gustavo A |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Effects of Apoe On Neuronal Network Dynamics Using Multi-Electrode Arrays
DESCRIPTION (provided by applicant): Apolipoprotein E (apoE) is a lipoprotein-associated glycoprotein synthesized in the CNS by glial cells, responsible for lipid transport within the brai. It has also been linked to a variety of CNS functions, including: neurodevelopment, inflammation, and synaptic plasticity. Importantly, APOE is the strongest genetic risk factor for the development of Alzheimer's disease (AD); it affects processes early in disease development and is known to influence normal brain function in the absence of AD pathology. There are three common human alleles: APOE-?2, APOE-?3, and APOE-?4. Compared to non-?4 carriers, a single copy of the ?4 allele confers an increased risk of 2- to 3-fold, while two ?4 alleles dramatically increase AD risk by 12-fold. At present, the mechanisms underlying apoE4-associated AD risk are unknown. My overarching hypothesis is that APOE genotype affects normal brain function before AD pathogenesis, specifically by affecting the development and network activity of organized neuronal populations in the brain. The objective of this research proposal is to investigate: 1) whether APOE genotype affects the functional development of neuronal networks in vitro; and 2) how apoE affects activity-induced network dynamics and excitatory neurotransmission. To test these objectives, I will first assess the formation and functional properties of neuronal networks in culture using multi-electrode arrays (MEA) (Aim 1). The MEA allows simultaneous measurement of electrical activity at 59 sites in a neuronal culture system. Cortical tissue will be harvested from APOE Targeted Replacement (TR) mice, a knock-in model expressing human APOE in place of murine APOE, and cultured onto MEAs for repeated electrophysiological recording as neuronal networks develop. This in vitro model allows me to test the contribution of each apoE isoform on neuronal networks, effectively reducing confounds present in other cell-based systems. I hypothesize that apoE4 may negatively impact the development of neuronal networks and cause overall decreased network activity compared to apoE2 or apoE3. Next, I will assess the influence of APOE genotype on activity-induced excitation and neuronal network dynamics using chemical Long-Term Potentiation (cLTP) (Aim 2). MEAs allow simple pharmacologic manipulation of apoE levels and signaling during cLTP to mechanistically determine the role apoE isoforms and its receptors play in activity-induced network dynamics. I hypothesize that apoE4 negatively affects cLTP-induced network dynamics. This interdisciplinary proposal represents a novel approach to understanding how APOE genotype contributes to large scale network formation and neuronal population activity. If my hypotheses are correct, then the information gained by these studies will be critical for the development of preventative therapeutics that compensate for apoE4-related brain changes.
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0.954 |
2020 — 2021 |
Rodriguez, Gustavo A |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Impaired Spatial Decoding and Neural Population Code Rescaling in Ad Mice @ Columbia University Health Sciences
Impaired spatial decoding and neural population code rescaling in AD mice Project Summary: Considerable evidence exists to support the notion that amyloid beta (A?) and tau pathology impair neuronal circuit integrity and function in Alzheimer?s disease (AD). Unfortunately, few studies have tested the direct influence of AD pathology on spatial computation within affected neuronal populations, resulting in an information gap at the neuronal network level. Moreover, in vivo experiments that examine large scale, neuronal network activity in mouse models of A? and tau pathology are lacking. In this proposal, I test the overarching hypothesis that A? and tau associated neuronal network dysfunction impairs task-relevant, spatial information encoding in large populations of neurons within the EC-HIPP circuit, and that combating this aberrant activity can restore order and improve spatial information processing in AD mice. In Aim 1, I will test the hypothesis that oligomeric forms of A? and tau disturb spatial information content encoded within large populations of neurons in the entorhinal cortex ? hippocampal (EC-HIPP) circuit. I will also test if these oligomeric peptides alter the number of neurons recruited into the population code responsible for memory encoding in a spatial learning and memory task. In Aims 2 & 3, I will leverage the predictive power of machine learning to decipher the neural code for spatial information processing in EC-HIPP population activity. Specifically, my goals in Aim 2 will be to examine the individual and combined impact of A? and tau pathologies on features of spatial information encoding in the EC-Tau/hAPP mouse line. In Aim 3, I will employ chemogenetics using a novel DREADDs ligand to combat aberrant neuronal activity in AD mouse models, with the ultimate goal of improving spatial information processing in neuronal networks burdened with pathology. Excitatory neurons will be specifically targeted in an effort to better understand their contribution to impaired spatial information processing in AD mouse models. The proposed research aims are designed to bridge an information gap between AD-related cognitive impairment and the underlying circuit pathology. This Mentored Research Scientist Development (K01) Award will afford me the opportunity to accomplish this major goal while enriching my technical skillset and expanding my knowledge of AD pathophysiology. In addition, the integrated training and mentorship that I will receive will help me develop additional expertise in machine learning for spatial decoding analyses. Together, the proposed studies and career development plan will ensure that I achieve my long-term career goal of launching a competitive, independent research career at a major research university.
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1 |