Researchers identify protein responsible for ‘enhancing’ learning and memory.


Just as some people seem built to run marathons and have an easier time going for miles without tiring, others are born with a knack for memorizing things, from times tables to trivia facts. These two skills, running and memorizing, are not so different as it turns out.  A multi-centre study led by Salk researchers have discovered that physical and mental activities rely on a single metabolic protein that controls the flow of blood and nutrients throughout the body. The new study could point to potential treatments in regenerative and developmental medicine as well as ways to address defects in learning and memory.  The opensource study is published in the journal Cell Metabolism.

This is all about getting energy where it’s needed to ‘the power plants’ in the body, the team explain.  The heart and muscles need a surge of energy to carry out exercise and neurons need a surge of energy to form new memories.

Energy for muscles and brains, the team discovered, is controlled by a single protein called estrogen-related receptor gamma (ERRγ). The group has previously studied the role of ERRγ in the heart and skeletal muscles. In 2011, they discovered that promoting ERRγ activity in the muscle of sedentary mice increased blood supply to their muscles and doubled their running capacity. ERRγ, they went on to show, turns on a whole host of muscle genes that convert fat to energy.

Thus, ERRγ became known as a master metabolic switch that energized muscle to enhance performance. Although previous studies had also shown that ERRγ was active in the brain, the medical community didn’t understand why as the brain burns sugar and ERRγ was previously shown to only burn fat. So the team decided to look more closely at what the protein was doing in brain cells.

By looking at isolated neurons in the current study the team found that, as in muscle, ERRγ activates dozens of metabolic genes in brain cells. Unexpectedly, this activation related to sugar instead of fat. Neurons that lacked ERRγ could not ramp up energy production and thus had a compromised performance.  The team assumed that ERRγ did the same thing throughout the body.  However, they learned that it’s different in the brain with the data findings showing that ERRγ turns on fat-burning pathways in muscles and sugar-burning pathways in the brain.

The team observed that ERRγ in live mice was most active in the hippocampus, an area of the brain that is active in producing new brain cells, is involved in learning and memory and is known to require lots of energy. They wondered whether ERRγ had a direct role in learning and memory. By studying mice lacking ERRγ in the brain, the researchers found a link.  While mice without the protein had normal vision, movement and balance, they were slower at learning how to swim through a water maze, and poor at remembering the maze on subsequent trials, compared to mice with normal levels of ERRγ.

What the current study has shown is that mice that missing ERRγ are basically very slow learners. Varying levels of ERRγ could also be at the root of differences between how individual humans learn state the team.  Everyone can learn, but some people learn and memorize more efficiently than others, and the researchers theorise that this could be linked to changes in brain metabolism.

The team explain that a better understanding of the metabolism of neurons could help point the way to improved treatments for learning and attention disorders. And possibly, revving up levels of ERRγ could even enhance learning, just as it enhances muscle function.

Source:  The Salk Institute for Biological Studies

 

Neurons utilize mitochondrial oxidative phosphorylation (OxPhos) to generate energy essential for survival, function, and behavioral output. Unlike most cells that burn both fat and sugar, neurons only burn sugar. Despite its importance, how neurons meet the increased energy demands of complex behaviors such as learning and memory is poorly understood. Here we show that the estrogen-related receptor gamma (ERRγ) orchestrates the expression of a distinct neural gene network promoting mitochondrial oxidative metabolism that reflects the extraordinary neuronal dependence on glucose. ERRγ−/− neurons exhibit decreased metabolic capacity. Impairment of long-term potentiation (LTP) in ERRγ−/− hippocampal slices can be fully rescued by the mitochondrial OxPhos substrate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ in cerebral cortex and hippocampus exhibit defects in spatial learning and memory. These findings implicate neuronal ERRγ in the metabolic adaptations required for memory formation.  Dependence of Hippocampal Function on ERRγ-Regulated Mitochondrial Metabolism.  Evans et al 2015.

Neurons utilize mitochondrial oxidative phosphorylation (OxPhos) to generate energy essential for survival, function, and behavioral output. Unlike most cells that burn both fat and sugar, neurons only burn sugar. Despite its importance, how neurons meet the increased energy demands of complex behaviors such as learning and memory is poorly understood. Here we show that the estrogen-related receptor gamma (ERRγ) orchestrates the expression of a distinct neural gene network promoting mitochondrial oxidative metabolism that reflects the extraordinary neuronal dependence on glucose. ERRγ−/− neurons exhibit decreased metabolic capacity. Impairment of long-term potentiation (LTP) in ERRγ−/− hippocampal slices can be fully rescued by the mitochondrial OxPhos substrate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ in cerebral cortex and hippocampus exhibit defects in spatial learning and memory. These findings implicate neuronal ERRγ in the metabolic adaptations required for memory formation. Dependence of Hippocampal Function on ERRγ-Regulated Mitochondrial Metabolism. Evans et al 2015.

 

 

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