Phase II of the COBRE Center for Neuroplasticity will support three subprojects.

Each subproject will be conducted by a highly trained early-career investigator using modern approaches to neuroscience. The three projects all address major neurological or behavioral disorders that are high priority areas of the NIH, including alcoholism, traumatic brain injury, and obesity. While diverse in scope, ranging from animal behavior to the activity of single channels, the goals of these three projects are unified by common technical approaches and a shared commitment to increasing our understanding of nervous system structure and function at the cellular and molecular levels.

1-Epigenetic Control of Transcriptional Dynamics in Longterm Alcohol Neuroadaptation

Subproject 1. PI: Dr. Alfredo Ghezzi.
Epigenetic Control of Transcriptional Dynamics in Longterm Alcohol Neuroadaptation. This project explores the neuroadaptations that lead to alcoholism. A progressive increase in alcohol tolerance, coupled with the emergence of physiological dependence, are thought to contribute to the uncontrolled urge to consume alcohol by influencing the brain reward system. Ghezzi’s project seeks to uncover the molecular mechanisms by which alcohol initiates and perpetuates changes in gene expression, neural physiology, and behavior that drive the alcoholic state. He will test the hypothesis that temporally distinct epigenetic modifications contribute to the dynamics of alcohol neuroadaptations by orchestrating multi-gene transcriptional reprogramming. Specifically, these experiments will explore the role of epigenetic histone modifications in the dynamics of alcohol tolerance in the Drosophila model system. Identification of such mechanisms is crucial for the development of more effective treatments for alcoholism.

Mentor. Dr. Nigel Atkinson will serve as external mentor for Alfredo Ghezzi. Dr. Atkinson belongs to the Department of Neuroscience and the Waggoner Center for Alcohol and Addiction Research at the University of Texas at Austin. He studies molecular mechanisms underlying drug and alcohol tolerance in the model organism Drosophila melanogaster. His highly interdisciplinary research (funded by the NIAAA) combines genetics, electrophysiology, and behavior. As one of Alfredo Ghezzi’s postdoctoral advisors, Dr. Atkinson has provided guidance in the development of his research plan and is fully committed to mentoring his transition to competitive independence.

2-Contribution of Traumatic Brain Injury to Fear Extinction and Avoidance

Subproject 2. PI: Dr. Demetrio Sierra.
Contribution of Traumatic Brain Injury to Fear Extinction and Avoidance. This project explores common mechanisms that contribute to the neurobiology of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Traumatic brain injury affects approximately 4 million civilians and soldiers each year, many of which are diagnosed with mental health conditions like post-traumatic stress disorder. Epidemiological studies of combat veterans show a strong correlation between sustaining TBI and developing PTSD. However, animal studies show conflicting results. To help evaluate the extent to which there is a relationship between TBI and PTSD, a biological link must be examined using reliable brain injury models and appropriate behavioral tests. This project will therefore utilize the Controlled Cortical Impact model of brain injury, and will test its effect on extinction of conditioned fear. Results from this work could lead to the development of novel approaches for treatment of patients with TBI and PTSD.

Mentor. Dr. Anthony E. Kline
Will serve as external mentor for Demetrio Sierra. Dr. Kline’s academic affiliation is with the Department of Physical Medicine & Rehabilitation at the University of Pittsburgh where he serves as Associate Director of Rehabilitation Research at the Safar Center for Resuscitation Research. His investigation focuses on the assessment and development of translatable therapies that facilitate functional recovery following Traumatic Brain Injury. Kline’s research is supported by R01 grants from NINDS and NICHD.

3-Role of Microglial α7nAChR in Diet Induced Brain Inflammation

Subproject 3. PI: Dr. José Colón.
Role of Microglial α7nAChR in Diet Induced Brain Inflammation. This project takes a cellular and molecular approach toward understanding obesity, a demonstrated risk factor for many conditions including diabetes, hypertension, dyslipidemia, stroke, heart disease, several cancers, and arthritis. Obesity has also been shown to be associated with certain mental health conditions, including depression and cognitive impairments that occur in Alzheimer’s disease. The proposed study will utilize α7 nAChR conditional knockout mice developed as part of Colón’s postdoctoral research at NIEHS. Crossing this line with inducible microglia selective Cre recombinase mice (CX3CR1CreER) will result in the production of microglia selective, tamoxifen-inducible α7 nAChR knock-out mice (α7 nAChRmicKO). This mouse model will present Colón with the unique opportunity to dissect the role of α7 nAChR in microglia activation and subsequent neuroinflammation caused by a high fat diet (HFD), without affecting the α7 nAChR found on other cell types such as neurons, astrocytes or peripheral myeloid cells.

Dr. José Colón obtained his graduate education in Pharmacology at the University of Minnesota, He then received postdoctoral training at the National Institute of Environmental Health Sciences. Colón then returned to Puerto Rico and joined the faculty of the UPR School of Pharmacy in 2015. His research combines advanced electrophysiological techniques with morphological and biochemical approaches. His work has appeared in leading journals including the Journal of Neuroscience, Journal of Neurochemistry, and Nature Neuroscience

Mentor. Dr. Jerrel Yakel
José Colón’s first postdoc advisor, will serve as his external mentor. Dr. Yakel leads the Ion Channel Physiology (ICP) group at the National Institute of Environmental Health Sciences (NIEHS; Research Triangle Park, NC). His research focuses on the cys-loop receptor/ ligand-gated ion channel superfamily, with a emphasis on the nicotinic acetylcholine (ACh) receptor channels (nAChRs). He has extensive expertise in the techniques that form the core of José Colón’s project, including patch clamp and two-electrode voltageclamp in combination with a variety of fluorescent imaging techniques. Jerrel Yakel is resolutely committed to advancing Colón’s research career.