Researchers have discovered more about how brain cells convert motivation into energy and signalling to store memories. This discovery may be used to produce drugs for people with memory loss or impaired memory or for people with ADHD.
A well-functioning memory requires energy and motivation.
Energy is required to activate the brain cells, but motivation also plays an important part in the equation. For example, people with depression, mood swings or schizophrenia have more difficulty in remembering because they are not as motivated to do so. People with these disorders are also not very good at concentrating.
Now researchers from the University of Copenhagen and other researchers have mapped the biochemical link between energy, motivation and memory.
The link between these factors may improve our understanding of how the brain stores memories and what goes wrong when this does not happen.
“The brain needs energy and motivation to create well-functioning memory. In this research project, we elucidated how motivation is transformed into energy in the brain and how energy affects memory biochemically,” explains Hajime Hirase, Professor, Center for Translational Neuromedicine, University of Copenhagen.
The research results have been published in Nature Communications.
Drugs can enhance memory
The new discovery may influence the future development of drugs to counteract difficulty in concentrating or to treat people with memory loss or impaired memory.
These may include cases of attention-deficit/hyperactivity disorder (ADHD), in which people have difficulty in storing new knowledge, such as in connection with education or work.
Another possibility is that researchers can develop drugs that generally enhance people’s memory.
“The more we know about how energy is used to store information in the brain, the better we can understand how to pharmaceutically enhance memory,” says Hajime Hirase.
Glial cells orchestrate the brain’s memory
Three components determine how well the brain functions: neurons, blood and the energy it supplies, and glial cells.
The neurons are the electrically active parts of the brain. Blood supplies the whole brain with the energy to function.
The glial cells play a major role in mediating energy metabolism in the whole brain, and one of the latest theories in this field is that the glial cells convert glucose into lactate, which the neurons need to function. The glial cells thus link the energy provided by the blood and the activity of the neurons.
In addition, the glial cells store glucose in the form of glycogen, thereby representing the brain’s only cellular energy store, which can be readily mobilized when needed. The brain does not have fatty tissue like other parts of the body.
“In a study 4 years ago, we were the first to visualize where glycogen is stored in glial cells, but it remains a mystery how the cells reactivate the stored energy,” explains Hajime Hirase.
Adrenaline and noradrenaline convert glycogen to energy and memory
Glycogen is not exclusive to the brain and is present in the rest of the body. For example, the liver uses adrenaline and glucagon to initiate the conversion of glycogen to energy.
The brain has only a tiny amount of adrenaline but has its own kind of adrenaline in the form of noradrenaline, which, like adrenaline, is activated by external stimuli, such as a shock.
In the new study, the researchers from the University of Copenhagen investigated how noradrenaline activates the glial cells and how vigilance plays a role in activating noradrenaline and thus memory formation.
“Memory can be categorized into short-term memory and long-term memory. The process of converting the former to the latter is called memory consolidation, and glial cells play a role in this,” says Hajime Hirase.
Gave mice shocks to study memory
The researchers gave mice one of two types of shock: a facial air puff or a foot shock.
Before delivering a foot shock, the researchers gave the mice a sound cue.
Both kinds of shocks can release noradrenaline in the brain, but in evolutionary terms the motivation to remember the sound cue is greater when linked to the unpleasant foot shock rather than the gentle facial air puff.
The researchers had inserted a glass cranial window into the skulls of the mice to monitor the activity of glial cells in the brain using a two-photon microscope.
“Our rationale was that the mice would not remember the mild shock to the same extent as the unpleasant foot shock and that the noradrenaline activation of the glial cells would therefore differ,” explains Hajime Hirase.
Biochemical difference in activating noradrenaline
The research results showed that stronger stimuli resulted in greater activity of noradrenaline in the brain and thus more pronounced activation of glial cells.
The experiment also showed that the mice required three shocks before they connected the sound cue with the electric shock. Once the mouse had remembered this, the sound cue alone was enough to trigger a stronger response.
The researchers also investigated how noradrenaline activates glial cells. This can happen in two ways:
• increasing the concentration of calcium in the glial cells; and
• elevating the concentration of cyclic adenosine monophosphate (cAMP), the signalling messenger in the glial cells that is also essential in converting glycogen into energy.
The experiments showed that the facial air puff increased the levels of noradrenaline in glial cells by increasing calcium levels, and the electrical foot shock caused a greater increase in noradrenaline by increasing both calcium levels and cAMP levels.
Thus, cAMP appears to play an important role throughout the signalling pathways that ultimately lead to memory consolidation.
“This phenomenon helps to explain what happens in the brain as we form memories. It also enables us to better understand what goes wrong when we are unable to do this in connection with memory loss. In the future, we will delve deeper into understanding this mechanism so that we can figure out how we might be able to manipulate it,” says Hajime Hirase.
“Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance” has been published in Nature Communications. In 2019, the Novo Nordisk Foundation awarded a grant to Hajime Hirase for the project Visualization of Glycogen Dynamics and Identification of Underlying Mechanisms in Brain Plasticity.
