The brain is physically intricate and chemically complex and dynamic. We use cutting edge electrochemical technology, fast scan cyclic voltammetry (FSCV) at carbon fiber microelectrodes (CFMs) to make fast, sensitive, selective and minimally invasive recordings of the brain’s chemistry. The CFMs are 5 µm in diameter. Using FSCV, we have pioneered in vivo serotonin and histamine measurements.
Our primary interests are the roles of these neurotransmitters in depression. Depression is the leading cause of disability world-wide and results in over 8 million deaths a year. This order destroys quality of life and poses the greatest economic burden in terms of disability and lost productivity. Antidepressants are prescribed to 1 and 5 Americans, yet these agents do not work for the majority of people who take them.
Serotonin is thought to be involved in the pathology of depression. We detect serotonin and histamine in vivo and in human derived stem cells. By combining these measurements with a variety of other methods such as pharmacology, biochemistry, genetic models, confocal imaging, molecular biology, animal behavior and computational modeling we are tackling important questions. The impact of our work will guide the next generation of antidepressant therapies.
In Vivo Serotonin Measurements: Implications for Depression
Trace metals are thought to act as neurotransmitters but not in the classical sense. For example, Cu(II) is released at the same time as the messenger glutamate during neurotransmission. When released into the synapse Cu(II) stabilizes the quaternary structure of some of the glutamate receptors, thus facilitating glutamate signaling.
The levels of trace metals in our brain can be affected by a variety of factors that can serve to increase or decrease extracellular concentrations. There are theories that reductions in Cu(II) release occur during neurodegenerative diseases, however it is very difficult to test these theories in vivo.
Trace metal electroanalysis is traditionally a slow process that is best achieved at mercury electrodes. In our lab we have discovered that carbon fiber microelectrodes enable an ultra fast adsorption step that results in ppb sensitivity to Cu(II) every 100 ms. With this method, we can analyze metals such as Zn2+, that are traditionally difficult to electroanalyze and we can report formation constants rapidly.
We covalently modify this probe with Cu(II) selective ionophores. This ultra-fast, ultra sensitive and selective probe is now being applied in vivo to test the roles that Cu(II) plays in health and disease.
In Vivo Trace Metal Analysis
The environment plays a significant role in how brains develop and function. We are interested in how the things that we are exposed to, like environmental toxins (heavy metals, pesticides), food additives (artificial sweeteners, emulsifiers), endocrine disruptors (DBP) and disease (HIV) travel through the body and affect the brain’s chemistry. In particular we are interested to know if pre- and post- natal exposure to these risk factors changes serotonin chemistry in the same way we have learned is indicative of depression and ASD.
We collaborate with environmental engineers and neurotoxicologists to design exposure paradigms to heavy metals, pesticides and other environmental risk factors. We are asking two questions. First, by placing electrodes in the periphery and in the brain, we are studying the kinetics of analytes, such as heavy metals, across the blood brain barrier. Second, using behavioral analysis, biochemical assays and mathematical modeling, we are studying how exposure to toxins affects behavior and neurotransmission. Finally our models bring forth hypotheses about how to 'normalize' neurotransmitter levels.