Tiffany Mathews - US grants

The rewarding, hyperlocomotive and addictive properties of drugs of abuse are often associated with an elevation in extracellular dopamine (DA) levels. Locomotor stimulating doses of ethanol produce activation of DA cell bodies in the ventral tegmental area, which leads to increased extracellular DA levels in the terminal fields, such as the striatum and nucleus accumbens. Sensitization refers to an augmented locomotor stimulation produced by repeated ethanol injections. It has been assumed that increases in extracellular DA levels occur in parallel with locomotor sensitization to ethanol. But in fact, there is no literature documenting changes in extracellular DA levels after ethanol sensitization. Understanding the DA neurochemistry behind ethanol sensitization is important because the process of behavioral sensitization has been suggested to contribute to the development of addiction. The goal of this research is to evaluate DA dynamics in the nucleus accumbens of C57BI/6J mice at several time intervals after sensitization. Specifically, microdialysis in freely moving mice and voltammetry in brain slices will be employed to examine the function of the DA system in detail. We postulate that DA and locomotor parameters will sensitize in parallel.

[unreadable] DESCRIPTION (provided by candidate): My immediate short-term goal is to obtain a tenure-track faculty position at a Ph.D. granting university. My long-term goal is to lead a neurochemistry research group focusing on the neuroadapations produced by long-term exposure to alcohol. In order to understand the neuroadaptions produced by alcoholism, my laboratory will use two biosensor techniques in vivo microdialysis and in vitro voltammetry to evaluate the neurotransmitter dopamine. Approximately, 20 million people within the United States endure alcohol abuse, which leads to about $200 billion dollars lost per year. This proposal has two aims (1) to understand the interaction between brain derived neurotrophic factor (BDNF) and dopamine in the brain by using mice that have a 50% reduction in BDNF levels (BDNF) and (2) to evaluate the effects of chronic alcohol exposure on the dopamine system in control and BDNF. The ultimate objective is to determine if an imbalance between BDNF and dopamine may lead to abuse of alcohol or protect the brain from expressing biochemical adaptions associated with the addiction process. Most drugs of abuse; like ethanol, have the ability to elevate extracellular dopamine levels in brain areas such as the caudate-putamen and nucleus accumbens. This dopamine release is thought to play an important role in the stimulant properties of drugs of abuse. Recent evidence shows that BDNF is able to modulate dopamine neurotransmission, but the most direct evidence illustrates BDNF's control over the dopamine D3 receptor. Using in vivo microdialysis, extracellular dopamine levels will be evaluated in the presence or absence of dopamine D3 receptor agonist in control and BDNF mice. Next, in vitro voltammetry experiments will examine the effect of reduced levels of BDNF on dopamine release, uptake and the dopamine D3 receptor. We hypothesize BDNF mice will have low BDNF levels and a low functioning dopamine system, resulting in a tendency to drink greater amounts of alcohol. The second goal is to evaluate the dopamine system in BDNF and control mice three days after a chronic alcohol regiment. We hypothesize that chronic ethanol will decrease endogenous BDNF and DA levels. Using the in vivo microdialysis and in vitro voltammetry we will characterize the dopamine system following 3 days of ethanol withdrawal. The impact of this research is to improve our knowledge of the molecular mechanism of alcohol abuse in an effort to develop better treatments and/or therapeutics. [unreadable] [unreadable] [unreadable]

Professors Squire Booker, Tiffany Mathews, and colleagues at Pennsylvania State University host the REU Site: Catalysis and Motion. This site is funded by the REU Site Programs of the Division of Chemistry and Division of Biological Infrastructure. Its provides research experiences for 9 undergraduate students for 10 weeks during the summer months.  The motivation for the program is the recognition that hands-on research experience at an early stage has an enduring impact on students' careers. Participation in hands-on research encourages students to pursue advanced degrees and careers in science, technology, engineering and mathematics (STEM). Early participation in research is also critical to inspire undergraduate students to take on global scientific challenges such as the growing energy crisis and the environment, clean water, infection, antibiotic resistance and other health crises, and agriculture and food production for an increasing population. Students are recruited nationwide, with a strong emphasis on students from underrepresented and underserved groups. Each student is supervised by a faculty mentor, and the program structure provides opportunities for cross-collaboration with students and faculty in other research groups in the department and across the university. Students work daily on their research projects; attend weekly research seminars; participate in professional development workshops and outreach events; and deliver research presentations. Interactions with professional industrial chemists, including site visits to companies and seminars, give students career information and inspiration. Formative and summative assessment is conducted, and students' careers are tracked during and after their participation. The goal is to help, inspire, and retain undergraduate students in scientific careers by providing them with a strong educational, mentoring, and research training experiences.

Many of the leading global scientific challenges require a deeper understanding of both biological and chemical catalysis, and the subsequent or parallel ability to evolve new and better catalysts for an increasing demand for clean, renewable and sustainable energy, food, clean air, pharmaceuticals, diagnostic tools for healthcare, and consumer products and other necessities. Moreover, the ability to manipulate or regulate biological catalysts within human cells is the foundation of current therapeutics for a multitude of diseases. Students are recruited to work in the following areas: 1) Understanding Macromolecular Catalysis, which focuses on understanding how protein enzymes, protein metalloenzymes, and RNA enzymes catalyze reactions with rate enhancements and high stereoselectivities and regioselectivities; 2) Dynamics of Biological Processes, which focuses on understanding how protein movement or "dynamics" relates to enzyme catalysis and the regulation of enzyme catalysis, molecular motors, and the movement or "trafficking" of various types of macromolecules and small molecules within the cell; 3) and New Insights into Chemical Catalysis, which involves the synthesis and characterization of chemical catalysts for a variety of processes, including the generation of new fuel sources and target-oriented organic synthesis.