Changes in brain cell energy affect activity throughout the brain, but the exact mechanisms that link brain energy metabolism with brain activity are not well understood. Nevertheless, the relationship between brain energy and brain activity is central to understanding how brain function is regulated and how metabolism influences ongoing behaviors such as sleep, sensory processing, learning and memory, and cognition. ATP and its core molecule adenosine provide a unique link between energy and brain activity, and may play a key role in translating changes in cell energy directly to changes in brain activity.
The investigators will test the hypothesis that ATP and adenosine link brain energy to brain activity both at the cellular level and the behavioral level by performing a combination of electrophysiological recordings of brain activity, measurements of ATP and adenosine using an enzyme-based sensor, and behavioral testing. These experiments will provide new insight into the evolutionarily important relationship between brain energy and brain activity. In addition, the investigators will mentor undergraduate students as research partners both during the academic year as part of their academic courseload and support them in doing research full-time during the summer. Undergraduate students will be involved in all aspects of this interdisciplinary proposal, participate in weekly laboratory meetings and attend and present research at several local, regional and national conferences.
Taken together, this project is an ideal use of both research monies and tax dollars: it offers innovative and important research on the relationship between brain metabolism and brain activity, and provides a comprehensive year-round educational and training environment and individualized mentoring for a diverse set of undergraduate students aimed toward a career in scientific research.
" provided new insight into the dynamic relationship between metabolism and brain activity. We focused specifically on adenosine, a molecule that regulates neuronal activity and is also related to brain energy (ATP). Traditionally adenosine has been identified as a molecule released to protect the brain during stressful and pathological conditions, such as a seizure or a stroke. A major aspect of the intellectual merit of this work is that we found further evidence and new conditions whereby adenosine and thus brain activity is regulated dynamically – for example, increased by a decrease in pH under certain conditions, and increased by ketone-based vs. glucose-based metabolism. Ketone-based metabolism predominates during conditions of starvation or when adhering to a high-fat, low-carbohydrate diet and is a normal process in our cells. The increase in adenosine by ketone-based metabolism was predicted as one of our central hypotheses, and we also found that adenosine increased when we developed a metabolic mimic of a ketogenic diet in a brain slice. Importantly, we found that ketone-based metabolism, like adenosine, is neuroprotective; these findings on protection from HIV-related neuronal damage agree with previous research that ketones can reduce brain injury. Based on its emerging multiple roles as a dynamic regulator of neuronal activity, in biochemical process such as DNA methylation, and a central player in cell energy cycles, we now termed adenosine to be a "homeostatic bioenergetic network regulator" in the brain. These findings all contribute to the intellectual merit of the work, and to our ongoing goals of optimizing brain health and understanding the conditions which regulate adenosine and brain activity. Contributing to these "big picture" questions outlined above is part of the broader impacts of this work. Additional broader impacts include our educational contributions and outreach. For example, undergraduate students were involved in all aspects of this interdisciplinary proposal during the academic year and the summer - participating in weekly laboratory meetings, and attending and presenting research at several local, regional and national conferences. One student was awarded a Fulbright. The concepts behind this work were also integrated into teaching objectives, such as assignments focused on metabolism and brain function, and public policies and brain health.
