Default Mode Network write up # 2

I said in my first posting that there is a “default mode network” in the brain, it is active at rest and is related to memory and emotion. Now, how does it get its energy?

What we learnt from the lectures of Profs. Ramakrishnan and Joseph are that glucose undergoes 3 pathways of metabolism.

1.    The normal pathway of glucose metabolism, in presence of O₂, is to oxidize it completely to CO₂ and H₂O. The formula is

C₆H₁₂O₆ (glucose) + 6 O₂ = 6CO₂ + 6 H₂O

It must go through 2 steps (glycolysis and oxidative phosphorylation) and generates 32 ATP (we learnt it as 36 ATP, but recent edition of Harper says it is only 32, the reason being that 2.5 and not 3 ATPs are made during oxidation of NADH in the respiratory chain). Anyhow, remember the ratio 1 glucose to 6 oxygen, the ratio is 1:6, because PET can measure these 2.

2.    The second pathway of glucose metabolism, in anaerobic condition, is to go through the first part of 1 (glycolysis) and stop there because of absence of O₂- unlikely in the brain, this pathway converts pyruvate to lactate. It generates only 2 ATP, 16 times lower than pathway 1, but it is instant energy with no O₂.

As you can see, the first path is what you want for a marathon runner, maximum energy minimal glucose, whereas the second is what you need for a sprinter, instant energy even when O₂ is limiting. In this aspect, brain behaves like muscle, red muscle: thin fibers, more myoglobin, more mitochondria, more oxidative metabolism, no lactic acid accumulation, perform sustained work for a prolonged period without fatigue (slow and steady); white muscle: thick fibers, less myoglobin, less mitochondria, more glycolysis, more lactic acid accumulation, fast strenuous work for a short period (fast but soon fatigue).

3.    The pentose phosphate pathway (PPP). This doesn’t generate ATP, but it produces molecules such as ribose that are required for cell proliferation and NADPH that are required for fatty acid synthesis, antioxidant response.  

Just to evaluate, how efficient is our biological system? if you combust 1 mol of glucose in a calorimeter to CO2 and water, you generate 2870 kJ as heat. On the other hand, 32 ATP gives 32X 51.6 = 1651 kJ or ~58% the energy combustion. Not bad.

Coming back to brain, glucose is the principal energy source for the mammalian brain, but glucose must be transported into the brain as there is a blood brain barrier. To overcome this, you need glucose transporters. There are glucose transport proteins that supply glucose to the brain. Hint: there are 3 glucose transporters GLUT1, GLUT 3 and GLUT 5, there are 3 types of cells in the brain, neurons, astrocytes and microglia.

Another diversion, does the brain need only glucose to function? It can use ketone bodies (acetoacetate and beta hydroxy butyrate) under extreme conditions of starvation. The normal blood glucose is 5.5 mM or 100 mg/dL. If you fast for 48h, the blood glucose goes to 3.6 mM (65 mg/dL) but the free fatty acid and ketone bodies comes to the rescue, if you starve for 7 days ketone bodies are used to maintain glucose at 65 mg/dL. Sad scene you see in TV, children with emancipated body and big head.

Back to PET, brain glucose uptake, oxygen metabolism, and blood flow in humans were measured with PET. At resting-state the molar ratio of glucose to oxygen consumption was found to be of 1:4.1, instead of 1:6, suggesting that some of the glucose is used by other pathways other than complete oxidation to CO₂ and H₂O. Physiological neural activity, however, increased glucose uptake and blood flow much more (51 and 50 percent, respectively) than oxygen consumption (5 percent) and produced a molar ratio for the increases of 1:4.5. Transient increases in neural activity cause a tissue uptake of glucose more than that consumed by oxidative metabolism, it consumes much less energy from glucose than previously believed, suggesting that glucose is used for purposes other than oxidative metabolism.

4.    This brings us to the 4^th pathway of glucose metabolism. It is called “Aerobic Glycolysis or Warburg Effect”. We learnt about little bit but not in detail.

Otto Warburg observed in 1924 that cancer cells metabolize glucose in a manner that is distinct from that of normal tissue. He found that unlike most normal tissues, cancer cells tend to “ferment” glucose into lactate even in the presence of sufficient oxygen to support mitochondrial oxidative phosphorylation (OXPHOS). This may sound counter intuitive, in part because the energy requirements of cell proliferation will be better met by complete catabolism of glucose using mitochondrial OXPHOS to maximize ATP production. 

But, OXPHOS leaves no Carbon for biosynthesis, Glucose you ingest, O₂ you inhale, CO₂ you exhale, H₂O you excrete. To cut it short, the reason that cancer calls do this, cancer cells need to grow also. To produce two viable daughter cells at mitosis, a proliferating cell must replicate all its cellular contents. This imposes a large requirement for Carbon in terms of nucleotides, amino acids, and lipids.

During growth, glucose is used to generate biomass as well as produce ATP. Aerobic glycolysis provides these intermediates that can be used to make macromolecules. Two questions?

Question 1. Why doesn’t this happen in normal tissue?

Answer: Aerobic glycolysis does occur in normal proliferative tissues. But, it doesn’t occur in terminally differentiated tissues, because non-proliferative mammalian cells do not normally take up nutrients from their environment unless stimulated to do so by growth factors. On the other hand, cancer cells overcome this growth factor dependence by acquiring genetic mutations that functionally alter receptor-initiated signaling pathways.

Question 2. What this has to do with brain, it is a terminally differentiated tissue and is not a tumor.

Answer: The brain regions communicate with each other by synaptic transmission. There are two parts to this, maintenance and transmission. The maintenance requires continuous remodeling/re-synthesis of synaptic membrane, proteins, neurotransmitters whereas transmission requires an efficient energetic system. Aerobic glycolysis provides the intermediates for maintenance and recycling of synapses, whereas OXPHOS provides the energy for transmission. At least, that is the current thinking.

Coming back to the brain and PET, aerobic glycolysis is present in the normal adult:

In human brain at rest, aerobic glycolysis accounts for 12–15% of the glucose metabolized. Variations?

Glucose plays an important role regulating the redox state of the brain. This occurs through the operation of the PPP.

Interestingly, aerobic glycolysis is not distributed uniformly at rest. Rather, it exhibits elevated levels in the DMN and adjacent areas. The significance is that aerobic glycolysis is used to remodel and maintain synaptic function for emotion and memory. In my next posting, I will discuss how does it change during development and aging.

In summary, energetic fluctuation in the central nervous system was considered a consequence of neuronal activity. Recent studies imply that changes in cellular metabolic state could be the cause, rather than the result, of neuronal activity.