Significance: Chronic pain affects 30% of the adult population in the USA and presents with multiple co-morbid psychiatric disorders, including mood alterations and cognitive impairment. Despite the severity of this problem, clinicians often rely on a ?trial and error? approach to find a strategy that provides some measure of relief. This is mainly because most pain treatments were implemented based on clinical observations rather than a mechanistic understanding of chronic pain. One of the pivotal mechanisms that could explain the chronification of pain as well as its resistance to classical treatment is the concept of pain centralization, where initial sensory events following trauma can gradually alter the central nervous system (CNS), resulting in amplified pain and/or aberrant pain that exists without peripheral sensitization. However, most of the research in this area focuses on cellular mechanisms and overlooks the extracellular matrix (ECM) in which these cells function. The proposed research aims to delineate the role of brain ECM components in pain-related cellular and structural plasticity, thereby expanding our knowledge of the effects of chronic pain on the brain. Innovation: The proposed study is multimodal in nature and incorporates techniques related to animal behavior, cell physiology, biochemistry, cell culture, pharmacology, and microscopy. For instance, ECM rigidity will be assessed by using structural (microarchitectural analysis following scanning electron microscopy and physical rigidity using atomic force microscopy) as well as biochemical analyses (immunohistochemistry and protein quantification). Similarly, the role of specific ECM components will be evaluated both in vivo (pharmacology) and in vitro (using a unique decellularized brain substrate for neuronal culture). Upon the completion of the proposed studies, the developed toolset can be a useful asset in studying brain areas outside the hippocampus. Participation of underrepresented minorities in the biomedical/behavioral sciences: Consistent with the NIH?s mission of training and graduating students from groups nationally underrepresented in biomedical research, the current proposal specifically targets the diverse student body of Queens College, CUNY. Queens College boasts high levels of ethnic and socioeconomic diversity and Dr. Tajerian is committed to mentoring the many undergraduate and graduate students in her department. She has extensive mentorship experience both at McGill at Stanford universities, and her current laboratory members include students from diverse backgrounds. Dr. Tajerian is also part of the MARC-U*STAR mentoring program. Maximizing Access to Research Careers is an Undergraduate Student Training program in Academic Research. It is the first NIH program specifically focused on directing under-represented minority students toward graduate school and biomedical research careers. Timeline and developmental objectives: The proposed timeline for the outlined experiments is 3 years. Data collected for the duration of this grant, in addition to the acquired technical expertise, will be instrumental in the acquisition of R01 level funding in the field of brain extracellular matrix alterations in chronic pain.
Chronic pain is associated with altered affect and cognition and paralleled by neuroplastic changes in limbic areas, including the hippocampus. While most findings focus on cellular plasticity, we have recently shown a key role for the hippocampal extracellular matrix (ECM) in regulating pain and memory following injury: paradigm- shifting findings that require a deeper understanding of the exact mechanisms by which ECM dysregulation governs neuronal morphology and physiology. Our goal is to delineate the role of brain ECM in regulating glia- neuron interactions following peripheral injury, thereby offering new therapeutic targets that could modulate already-established central nervous system alterations present in chronic pain.
