S1 E2

S1E2

Dear All,

Hope all of you are doing well, happy and healthy with your families.

As you all are, I am looking forward to tomorrow's video meet. Briefly, the details are: 

Time: Apr 9, 2022 08:30 AM Eastern Daylight Time (US and Canada) = 18:00 IST

https://nih.zoomgov.com/j/16141462900

I started out this post to give a brief intro on how we got here, to those that are new (I intend to send this link to those on the whatsapp groups). Way back in 2003 we thought having a group mail facility would keep us know of each other's whereabouts. And so

 

This was 6years before Brian and Jan came up with whatsapp (incidentally they worked at yahoo before that). Then later, our group transitioned to groups.io when yahoo abandoned groups. We had close to 100 members at one time. Most of us are  from the 70's and 80's, meaning we were at jipmer during that time span. Some of you at the other (whatsapp) groups are either from the 60's or from the next century!

Our mode of meetings initially was personal meetings (in addition to active email exchanges) - when someone from India visits the US or vice versa we used to gather in Philadelphia/DC/Chicago or Chennai/Bangalore and share all the news. And a few grand meetings were organized in Pondy itself, in Chennai, in Bangalore and I think those are the ones. I think the last few were also shared on the internet.

Fast forward to now, as the corona kept us mostly at home and zoom took over, we all got used to working, meeting, teaching, and what not ,everything online. We and other friends have been holding video meetings and these being very convenient to join and see and talk old buddies and classmates, became widely liked. From this group, we had one in January, although our Pharma and Micro friends have been holding such videocons more often. Following that enthusiasm we said let us have a meeting once every three or so months. So tomorrow's is the S1E2 (as they say in TV serials! Ha ha ha - guess who says that).

We would love to see all those seniors and juniors in the whatsapp groups too, to see and be seen. Even those in this group, some of us have met after 40 years in the last meet. It is like living in the past, some felt (although we all have now gray hair on bald heads)!

Please join us at the above link tomorrow - sorry for such a short notice again.

Yours truly,

NageswaraRao aka TNRao

Default Mode Network # 4 Final
Happy New Year 2018

Default Mode Network Posting # 4

Posting # 1: Default Mode Network (DMN) is aerobic glycolysis (AG), AG is defined as glucose utilization more than that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water. AG is present in the normal human brain at rest, it is highest in the regions that relate to memory and emotion. During neuronal activity, i.e., when we see or hear or touch or smell or do a job, the AG decreases in these regions and metabolism increases in those regions that are activated locally by neuronal activity.

Posting # 2: In terms of biochemistry, glucose is the principal energy source of energy for our brain; there are transporters that carry glucose to the brain; to generate energy, 90% of glucose is used by oxidative pathway and 10% of glucose is used by “aerobic glycolysis” since it occurs in presence of oxygen. I said that the brain uses this combination pathway is to preserve some carbon for remodeling and repair of synapses and to protect against oxidative stress. I said also that there are 3 types of brain cells which use these glucose pathways differently and coordinate with each other to achieve the goal of smooth organized brain function.

Here is the metabolic energy organization of the 3 cells that coordinate with each other, they are astrocytes, neurons and oligodendrocytes. Blood flows through the capillary, glucose is taken up by astrocytes; metabolize it by aerobic glycolysis up to pyruvate/lactate and then gives lactate to neurons to oxidize it to CO₂ and H2O. Neurons are rich in mitochondria and astrocytes lack mitochondria to match their role.

Rationale for this organization in the brain, synapse is the site of action, it is the connecting part of one neuron to another, the neuron sends the signal to the receiving neurons by firing a chemical (neurotransmitter). The neuron(s) that receives the signal becomes electrically active and passes the signal to the next neuron. Now the neuron that sent signal must remain in reduced redox state to send the next firing signal, the neuron that received the signal must come back to its original state to receive the next firing signal. Importantly, all these actions occur within milliseconds. It is an energy consuming process. Two points: One, this can’t be done by neuron alone, it requires a second player, to provide instant energy, that is where astrocytes come to play. They convert glucose to lactate and provide instant energy. Neurons take up the lactate and burn it to CO2 and H2O, to provide maximal energy for transmission. Neurons have a sheath of myelin to reduce energy loss, but they can’t do for long distances, so we have node of Ranvier, a way station that provide us an opportunity to generate additional energy, this is where oligodendrocytes come to play, they do similar function to that of astrocytes, provide instant energy and energy bars for neurons to push the transmission further. That is the sum of the game on neurotransmission. The second point is, when you are not attending to physical activity, engaging with the external environment, or carrying on a conversation. Inattention DMN, also consumes energy, that is why you don’t see any difference in blood flow, glucose and oxygen consumption as we age. Take home lesson: quality of glucose consumption rather than the quantity makes all the difference.

Posting # 3: There is a change in the way how the brain metabolizes glucose (AG) as we age. We are using glucose less toward formation of new memory and emotion at older age than when we were younger. If we don’t, what was an asset when we were younger, all the energy spent towards emotion and memory, now is a liability at older age, you don’t want to live in the past, it is good to remember but not live in the past. If our mind starts to live in past and we lose all the contacts, we have developed that defines you as who am I?

Solution: Mindful Meditation, as we age, what can we do to decrease the blood flow to the regions of memory and emotion and increase to the blood flow to the regions that relates to what we are doing. Here are four conscious exercises that are proposed to help us as we age

Meditation

I wish that I had done this as a daily routine, spend half-an-hour each day just close the eyes and focus on the breathing. It is easier said than done but setting aside 30 min each day will change AG over a longer period. Here is the published result: “We found that the main nodes of the default-mode network (medial prefrontal and posterior cingulate cortices) were relatively deactivated in experienced meditators across all meditation types. Furthermore, functional connectivity analysis revealed stronger coupling in experienced meditators between the posterior cingulate, dorsal anterior cingulate, and dorsolateral prefrontal cortices (regions previously implicated in self-monitoring and cognitive control), both at baseline and during meditation. Our findings demonstrate differences in the default-mode network that are consistent with decreased

mind-wandering. As such, these provide a unique understanding of possible neural mechanisms of meditation”.

Exercise. Making physical exercise a part of your daily routine is the next best thing that you can do to maintain the difference in aerobic glycolysis at rest and during activation. It refreshes the brain. When you exercise, I mean simple, turn of TV, focus on your breathing and where your feet are in space as you move. 

During brushing your teeth and taking bath. You can't go a day without brushing your teeth, taking a bath, making this daily task the perfect opportunity to practice mindfulness. Feel your feet on the floor, the brush in your hand, your arm moving up and down. Einstein said he did his best thinking while he was shaving--what he was really doing in those moments was practicing mindfulness! The same is true when you take bath. Focus on what you need to do the whole day, plan your day, what is the app message you want to send to your family? What is the dinner plan? What do I need each member of the family to do for that day, set reminders?   

Evening, men cook and do the dishes. "washing the dishes to wash the dishes". When you give yourself over to the experience, you get the mental refreshment of a mind-body practice and a clean kitchen. For men, if you can cook, that is the best mental relaxation that you can come up with, but what is important is you must love it to do it and not feel it as burden. It's multi-tasking at its best! I have been doing this for the past 30 years.

Default Mode Network # 3

Lay Abstract

This is what happens to our brain as we age

Yellow, Orange, Red lines show that there is no decrease in blood flow or glucose use or oxygen use from 20 to 80 years. But there is a change in how the brain metabolizes glucose (aerobic glycolysis or AG) that is the blue line. We are using glucose less toward formation of new memory and emotion at older age than when we were younger. Now take a careful look at the variation as we age, what was an asset when we were younger becomes a liability when we age. Lower the value is peaceful the mind, at rest. Alzheimer’s disease patients have higher AG values. My dream is to make a rodent model of this AG. My final posting will be how to reduce AG, clue meditation.

Chandru Jr, Biochem 71-74

Below is the details 

Let us get the facts first:

As we get older does the flow of blood to our whole brain decrease?

The answer is NO.

As we get older does our whole brain use less oxygen?

The answer is NO.

As we get older does the glucose uptake decrease in the whole brain?

The answer is NO.

In short, the total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, from 20 to 82 years of age (yellow/orange/red line in the figure).

But, look at the blue line, there is decrease in aerobic glycolysis as we age, is it good or bad? Aerobic glycolysis means emotion and memory, we needed it when we were younger but are not so important when we age. Emotional response is OK when younger, but the society expects us to react with a reasoned response when old. But, you still need aerobic glycolysis to refresh synapses, don’t stop learning. A decrease in aerobic glycolysis gives us the energy to increase the blood flow to focus on the job at hand.  may be a good thing because we are not spending all the energy in emotion and memory as we age, we must be efficient in getting the job done, namely synaptic transmission. That means you are making decisions not based on emotions but based on what is needed for me. Let me remind you also that these measurements are done at rest with eyes closed, ears plugged, there is no sensory input. This is the reaction of your brain. But, look at the figure more carefully, the variations among individuals has become greater as we age. A 70-year-old can have the same aerobic glycolysis as a 30-year-old.  That means, if a 70-year-old has the same emotional reactions as a 30-year-old person, we may call them immature, emotional and unreasonable.

I said in my previous postings that brain uses glucose metabolism for two purposes, synaptic maintenance and growth (aerobic glycolysis); synaptic transmission (oxidative metabolism). In another word, how refreshed our memory and emotion are and how fast we process the information. As we get older, we lose the power to refresh, quality vs. quantity struggle, that is why learning throughout our life is important. 

I guess your question is, what should I do to lower my “aerobic glycolysis”? Finding the balance, quality vs, quantity. That will be my last posting. Before that I should focus on the biochemistry of how the brain does this aerobic glycolysis, who are the players and how do they coordinate? Restless brain to start with. Several recent studies have revealed that high DMN cortical regions exhibit high amounts of AD pathology. Subjects with high AD pathology in these regions have significantly reduced functional correlations within the DMN. This is the main reason for me to get back to brain, a research project, to combine this aerobic glycolysis with Alzheimer’s disease to develop an animal model so treatment can be tested.  

is the PET image of what happens as you age, see the remarkable difference in the way brain uses the glucose.

Yellow color is maximal aerobic glycolysis and red is lower aerobic glycolysis.

Coming back to the subject, when we are young, you want to generate as many synaptic contacts as possible and to grow these synapses, as you get older you want to retain these synaptic connections and if possible develop new synaptic contacts. This is the struggle.

Let us get back to from the beginning, from birth.

This is the profile of brain growth from birth.

Though I want to focus in this posting on aging, I should tell you that adequate nutrition in the first 1000 days has a tremendous effect of the development of the quality and quantity of aerobic glycolysis in the developing brain and therefore gut microbes may play a significant role. These topics have greater societal importance.

There is a question if the changes in aerobic glycolysis that occur with normal aging could be influenced by how we developed the connections during the first 5 years of life. In other words what happens to your brain when we are a senior citizen could come from what happened to us when we were a child?

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.

default mode network #1

Is there a “day dreaming network” in our brain?

The answer is YES, with a caveat.

Scientific term for this is “Default Mode Network”.

The discovery was an unexpected consequence of brain imaging by positron emission tomography or PET (Vijay can enlighten us on this). Some basics: Human brain relies almost entirely on glucose to function. Our brain weighs 2% of body weight, but uses 25% of total body glucose, 20% of total body oxygen, and receives 15% of cardiac output. The brain extracts about 50% of the oxygen and 10% of the glucose from arterial blood. Therefore, you can give positron emitting isotope (C11-Glucose – iv injection), O15-Oxygen (inhalation) and O15-H2O (iv injection) and scan the brain to measure Cerebral Metabolic Rate(CMR) for glucose and oxygen and cerebral blood flow (water). You need a cyclotron to generate positron isotopes, so very specialized facilities can do it. Vijay has one. Raju got one recently, if I’m not mistaken. At NIH, it is popular among summer students (gets paid $300 to 600), I had volunteered once in my late 30s when I was at NIH. They scan the brain with eyes closed, ears plugged to get the baseline. The intensity of the image reflects the brain usage of glucose, oxygen and blood flow. Then, you are asked to do a specific task (multiplication, memory recall, image identification, sound recognition, etc) depending on the investigators interest. The brain is scanned the whole time. The investigator would then calculate the increase in CMR glucose, oxygen and water from the baseline scan. They will then superimpose the increase in activity on the anatomical atlas to derive a functional map of the brain. They can then say which brain region respond to the specific task. An example is shown here (red arrow marks the regions that are activated by a given task).

Some interesting observations: When I was asked to do multiplication tables, in addition to the expected region of increase in blood flow, my language area was also activated suggesting that my brain converts the numbers in to Tamil and then responds as I have learnt multiplication tables in Tamil. Bilingual French Canadians show no difference in pattern. Interestingly, some native Pondicherians can do 3 languages (French, English and Tamil). More than 3, the brain converts to a dominant language, that is my understanding. It is worth testing multilingual Indians to know the limit of the brain.

Coming back to the subject, this was the situation from 1980 to 2000. In 2001, a pioneer in brain PET imaging, Dr. Marcus E. Raichle @ Washington University, St Louis, noticed that there were some brain regions that showed a decrease during the task, it was ignored before then. That meant, to start with at resting state they had increased blood flow and the task decreased the flow and increased the flow to the region of interest. It was not one area but a network of brain areas or regions. He went ahead and tested all the PET images and to his surprise he found that irrespective of the task the same areas showed a decrease. He did a meta-analysis of all the PET studies done by different investigators, this is when he came up with:

This is the map of “Day Dreaming” or “Default Mode Network or DMN”.

What are these brain regions?  They are in front and center of the brain. They belong to what is called “Association neocortices”.

Do these regions exist in mammals? The answer is yes but these regions have rapidly expanded in human brain evolution.

                          Rat                                                  Monkey                                 Human

Does it represent consciousness? NO, the patterns of resting-state functional connectivity appear to transcend levels of consciousness, it is present under anesthesia in humans, is present in monkeys and rats, also during the early stages of sleep in humans.

What does DMN regions represent?  These regions are related to emotion and memory. DMN is active when you are not attending to physical activity or engaging with the external environment or carrying on a conversation.

Caveat, the way I am using daydreaming is contemplating the future, reliving the past, or general rumination. But it could be argued that mind wandering, and daydreaming are conscious cognition. Therefore, it would be misnomer to call it daydreaming. I agree, is it natural-state brain or restless brain or simply DMN?

So, what, there are some regions that are active at rest, what is it implication?

DMN has important implications, consider what if DMN activity is low or high: depression (over regretted pasts, presents, or futures), anxiety (over potential pasts, presents, or futures). Small changes functional connectivity in younger subjects can push them to act violently to become incarcerated juveniles? Does the activity change in development or in aging or in diseases, I will come back to these topics later?

This brings us to the two points of view on brain organization. Since majority of the people respond to a situation in a similar manner, it must be reflexive, driven by momentary demands of the environment (Sherrington 1906). In contrast, his student (T, Graham Brown, 1914) posited the theory that the brain’s operations were mainly intrinsic, involving the acquisition and maintenance of information for interpreting, responding to, and even predicting environmental demands.

What I want to say is that default mode network plays critical role in the organization and expression of preplanned, reflexive behaviors that are critical to our existence in a complex world. You see some people respond in a cool collective manner, but others become impulsive and destructive. It’s all due to DMN.

Don’t lose hope, there are ancient Indian practices that is gaining popularity to address these issues.

But, before that I want to bring back to you the lectures of Profs. Ramakrishnan and Joseph on glucose metabolism and little bit of Prof. Prasanna (fatty acid metabolism). I bought the 29^th edition of Harpers Illustrated Biochemistry (for $2 from Amazon) to refresh my memory, I think we read 11^th or 12^th edition, the current edition is 30^th. Biochemistry of Brain Glucose Metabolism, that is my next posting.

This is Chandru Jr (Biochem 71-74), I haven’t been in touch with the group for a year, sorry. Couple of apologies also, I missed meeting Raju and Bala last month, but I promise to meet you next time, in April? Balu called me the other day, told me to get back to the group and persuaded me to do a write up on another stimulating topic that all can have inputs. Here, I go, my research interest for the past 20 years has been energy (glucose) metabolism in nervous system, 15 years on brain (Alzheimer’s disease) and 5 years on peripheral nervous system (Diabetic neuropathy). I have been “day dreaming about getting back to brain”.  That is my topic, “day dreaming”, is there a network for this in the brain? is it in the back of the brain? why do we need it? how does it work? do we need to preserve it as we age? and importantly how can we preserve it? all from a layman biochemist’s point of view. The primer is next week (hopefully once a week) and will be a word/PDF attachment. Thanks, Balu for getting me back to day dream. 

Chandru

Biochem 71-74

"True Friends are always there"

This shows the number of  messages per month per year since Jipmerian group started. Pushpa, no need to be concerned!
You can see this info always here (scroll down to the bottom): https://groups.yahoo.com/neo/groups/jipmerians/info