Food for thought: a virus-like signal for the energetic demands of higher cognitive functions

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To maintain organismal energy balance, energy molecules extracted from the diet or liberated from stored forms must be distributed appropriately throughout the body. By integrating and distributing signals to and from disparate tissues and organs, the brain plays a major role as a command center in organismal energy balance. The brain is also a hungry organ, consuming a disproportionate amount of energy relative to its size. Higher-level cognitive functions like learning and forming memories burn even more energy. Energy imbalance, such as a chronic high-calorie diet, perturbs cognitive functions like learning and memory, but the underlying mechanism is not clear. Metabolic syndromes like obesity are also associated with neurodevelopmental and neurodegenerative disorders. Most studies of organismal energy balance focus on how the brain uses a few known pathways to mediate inter-organ communication, but it is not known how cognitive functions specifically signal the brain’s demand for fuel and mobilize energy from stores in other parts of the body. The proposed studies test an entirely new model in which virus-like particles synthesized during learning/memory activity in brain neurons travel to fat storage tissues and induce mobilization of stored energy. Arc (activity-regulated cytoskeleton-associated protein) was known for decades to be induced by learning/memory activity in neurons, where Arc oligomers promote synaptic activity and plasticity. Arc proteins evolved from a retrovirus and retained the ability to assemble into virus-like capsids that spread from cell to cell. A ground-breaking hypothesis to be tested here proposes that Arc capsids travel from the brain to fat storage cells, where they signal brain activity and trigger release of energy into circulation. Levels of circulating energy feed back onto Arc expression via metabolic control of N6-methyladenosine (m6A) modification of Arc mRNA. Together, these coupled processes are proposed to comprise a homeostatic circuit that integrates the brain’s need for fuel and maintains organismal energy balance. The experimental system addresses the basic features of this circuit from the behavioral to the molecular level, including a conserved requirement for Arc in associative learning and cognitive dysfunction when excess dietary calories overwhelm the system. The planned research will determine properties of Arc required for communication with fat storage cells and how it alters organismal metabolism to supply energy to the brain. Other experiments will identify the key components of diet that alter m6A modification and virus-like Arc assembly and test custom diets designed to ameliorate cognitive dysfunction. This project will establish the mechanistic details of a previously unknown brain–adipose signaling axis and a homeostatic circuit where uncoupling leads to neurodevelopmental and neurodegenerative disease.