The brain is very energetically expensive, estimated to consume approximately 8 to 10 times the amount of energy per weight compared to average tissue.
In fact, the brain consumes approximately 20% of the body’s fuel intake but represents only about 2 to 2.5% of the mass.
Although a large percentage of this energy consumption is driven by electrical activity, the brain also likely has high resting metabolic rates because severe limitation of brain electrical activity doesn’t have a huge effect on decreasing fuel consumption [1].
In effect, the brain remains a prominent fuel-guzzler even when its neurons are not firing signals called neurotransmitters to each other.
The human brain generally has a very small safety factor with respect to fuel supply. In fact, when blood glucose levels drop by only ~2-fold, severe neurological consequences proceed. As a result, even brief interruptions in blood flow that restrict delivery of glucose and oxygen rapidly lead to severe neurological impairment.
When a brain cell passes a signal to another neuron, it does so via a synapse, or a small gap between them.
Essentially what happens is that first, the pre-synaptic neuron sends a bunch of vesicles to the end of its tail, closest to the synapse. These vesicles then engulf neurotransmitters from within the neuron, acting sort of like 'envelopes' that hold messages in need of being mailed.
These filled 'envelopes' are then transferred to the very edge of the neuron, where they ‘anchor’ and fuse to the membrane, releasing their neurotransmitters into the synaptic gap. Once here, these transmitters connect to receptors on the 'post-synaptic' cell, thereby continuing the message through the neuron.
It’s already known that the steps involved in transporting a message across neurons requires a substantial amount of the brain's energy [2].
Nerve ends (terminals) closest to the synapse cannot store sufficient energy molecules, which means they must synthesize them on their own to conduct electrical messages in the brain.
This helps to explain why the vast amount of fuel is needed.
So, it makes sense that an active brain consumes a lot of energy. But what happens to this system when neural firing goes silent? Why does the brain continue to guzzle up massive amounts of fuel?
This has been one of the great mysteries of human neuroscience: why in the world does a largely inactive organ continue to require so much power?
New research in this area
To figure this out, researchers designed several experiments on nerve terminals, which compared the metabolic state of the synapse when active and when inactive. Even when nerve terminals were not firing, the authors found synaptic vesicles had high metabolic energy demands.
The pump that is responsible for pushing protons out of the vesicle and thereby sucking neurotransmitters in never seems to be at complete rest and in fact, requires a steady stream of energy to work.
Research indicates that this pump tends to be leaky.
Therefore, synaptic vesicles are continuously leaking out protons via their pumps, even if they are already full of neurotransmitters and if the neuron is inactive [3].
These data have profound implications with respect to how energy balances across synapses in the brain are achieved and whether different neuronal populations might be more susceptible than others to pre-synaptic metabolic compromise due to the total load created by these pools of synaptic vesicles [3].
With the immeasurable number of synapses in the human brain and the presence of hundreds of synaptic vesicles at each of these nerve terminals, this hidden metabolic cost of quickly returning synapses in a “prepared” state comes at the cost of massive fuel expenditure, which most likely plays a prominent role in the brain’s metabolic demands and metabolic vulnerability.
Research in the future will differentiate how different types of neurons may be affected by such high metabolic burdens because they might not all respond in the same way.
Some neurons may be more vulnerable to energy loss and figuring out why could allow preservation of these messengers, even when deprived of oxygen or sugar.
This data gives us a more in-depth understanding on why the human brain is so vulnerable to the intermission or weakening of its fuel supply. If there was a way to safely lower this energy drain and thus slow brain metabolism, the clinical impact could be extremely beneficial.
References:
1. Laureys, S. and N.D. Schiff, Coma and consciousness: paradigms (re)framed by neuroimaging. Neuroimage, 2012. 61(2): p. 478-91.
2. Schotten, S., et al., Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate. Elife, 2015. 4: p. e05531.
3. Pulido, C. and T.A. Ryan, Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals. Sci Adv, 2021. 7(49): p. eabi9027.
