Imagine building a house. A clearly defined budget is crucial to planning and coordinating the many moving parts that go into turning a blueprint into a building. By the end of project planning, the cost of each room, every door handle, and even the font of the address letters is known.
Now imagine trying to build a house without any of these numbers. At best, you have some guesses. It’s impossible. Without a blueprint, there can be no progress.
This is a situation similar to the longstanding limitations holding up the field of brain energetics, the study of how the brain produces, distributes, and consumes energy. But the recently announced Simons Collaboration on Brain Energetics ( SCOBE ) will uncover those vital figures as it investigates how energy constraints shape neural computation, from molecules to circuits to behavior.
Investigators in 26 labs across the US and Europe will work to answer many long-pondered questions in neuro-energetics that, until now, have not received the same amount of attention as more traditional neuroscience questions such as those about the structure and function of neural circuits.
“There are lots of really cool energetics questions, but most of them are completely unanswered,” says Professor Anna Devor (BME), the Boston University College of Engineering researcher who is co-leading the collaboration with a colleague at Stanford University, Professor Tom Clandinin. “For example, nobody understands how the brain’s computational principles are constrained by the availability of energetic resources and how that works.”
The collaboration is looking to provide the first quantification of energy costs of computation across spatial scales, from the subcellular to the systems level, revealing how activity of neural networks in the brain are aligned and coordinated to optimize computation within the constraints of the energy budget.
“Energetics is everything,” Devor says. “Our basic brain activity cannot happen unless the brain utilizes ATP—a nucleoside triphosphate, the ‘energy currency’ of the brain—and we don’t really understand and don’t have a quantitative account of how much ATP different types of computations in the brain utilize.”
Adding to the complexity of this endeavor, the brain changes how it produces energy during periods of cognitive engagement. “It starts consuming more sugar than what is needed for the reaction of burning it down to water and CO2, a process that requires oxygen and relies on super-efficient cells’ power stations—mitochondria,” Devor says. “When neurons are actively solving a task and energy demands go up, a higher fraction of energy is being derived from inefficient mitochondria-independent processes known as glycolysis. Why? This is unclear and very puzzling.”
Devor outlined two possible explanations for this conundrum. Although glycolysis produces less ATP per molecule of sugar compared to mitochondria, it runs faster. So perhaps we trade the efficiency for speed, and at the end of the day that trade-off delivers a higher yield. “Or it’s possible that the extra sugar is consumed by non-neural cells of the brain called glia that have the ability to store sugar as glycogen and may be able to support neurons energetically when the going gets tough,” says Devor. “These ideas are not new, but testing it experimentally requires new research tools and quantitative models. Our SCOBE consortium is perfectly positioned to deliver both.”
A related critical question is what signals the metabolic dial that tunes up glycolysis in a cognitively engaged brain? Devor points to the neuromodulatory systems in the brain that control our alertness and arousal. For example, the brain uses a neuromodulatory transmitter norepinephrine, a cousin of adrenalin, to promote alertness and cognitive acuity. “There’s a reason to believe that the same neurotransmitter upregulates glycolysis to rapidly increase the energy production,” says Devor. “This has not been proven experimentally, but we are on it!”
The implications of finally understanding the rules of energy delivery and consumption within the brain could be vast.
In our brains, both sugar and oxygen arrive with blood. Therefore, an interruption of blood flow, even as small as stoppages in single capillaries, can be quite harmful for neurons. Unfortunately, capillary dysfunction and microstrokes are common in neurodegenerative diseases and aging. At the same time, some studies have shown a remarkable return of cellular functions in neurons following a long period of blood flow interruption. This suggests that scientists are missing something fundamental about how the brain can cope with oxygen deprivation, Devor says.
Better understanding of the residual metabolism that allows preservation of the brain’s integrity during blood flow interruption could have implications for emergency medicine, particularly in how doctors approach resuscitation after cardiac arrest.
“The thing which is really needed is just basic understanding of how metabolism works [in the brain],” Devor says. “And that would really be helpful for all sorts of things.”
Over the next ten years, Devor’s BU lab will receive $3.2 million from the foundation for the research. The large and multidisciplinary team and the funding window—double the length of a typical NIH R01 grant—allows the team “to be more adventurous, think bold, draw lessons from invertebrates, perform data driven modeling and model-inspired experiments,” Devor says. “This is very powerful.”
The Simons Foundation is also providing their computational resources to the team, “which actually is a very big deal,” Devor says. “For a large-scale, cross-institutional, cross-disciplinary collaboration, sharing the data is not a trivial task. In particular, when it’s high-resolution, high-speed imaging data where the file size grows very big very fast. For example, BU has top-of-the-line neurophotonic imaging tools, and we would like to share our data with partner labs in Norway and Austria. The Simons Foundation’s resources are making this possible.”
“We feel very fortunate and are very grateful to the Foundation,” Devor adds. “This is a dream come true! From the initial call for proposals in November 2022, this project has been evolving over the last three-plus years. At this point, we are definitely ready to hit the ground running.”