Of Diabetes, MAPK and Memory

In the previous article we saw how MAPK translocated from the cytoplasm to inside the nucleus. In the nucleus, it forms cascade of responses, which end up in transcription of some portions of DNA and forms proteins that strengthens the synapse. This is one example of chemical basis of memory.

There are some diseases where MAPK levels rise. For example, in type 2 diabetes mellitus, a form of diabetes, where the end organ sensitivity of tissues to the effect of insulin decreases. Insulin has many diverse functions, one important function of which being the lowering of blood glucose. Insulin helps glucose to enter into the cells; this is one of many ways it lowers plasma glucose.

In type 2 DM (constituting 90-95% of all diabetics), glucose lowering effect of insulin is not there, as if the cells are refusing to listen to the instructions of this hormone. The cells are now deprived of their regular dose of sugar, and blood sugar level rises. The body senses danger and is driven to the ‘wrong’ conclusion that it is due to the ‘inadequate’ insulin level the glucose is not entering. So, it revs up the production of insulin. Thus, in type 2 DM blood insulin level is raised.

While it is true that insulin’s instructions for glucose entry are no longer obeyed, not all commands of insulin are null and void. Insulin’s command on MAPK is still valid! Insulin plays an important role in mitogenesis, i.e. growth of cells. It does it through MAPK or mitogen activated protein kinase pathway. We just learned that insulin level is increased in type 2 DM, and so does MAPK activity. One nasty effect of enhanced MAPK activity is atherogenesis, which is a fallout of enhanced mitogenesis.

Now that the MAPK activity is raised in type 2 diabetics, can we expect more efficient memory in this disease? Other factors that are relevant here are glucose metabolism and blood flow to the brain. Atherogenesis more commonly affects the lower extremities (in the form of peripheral arterial/vascular disease: PAD or PVD), while upper extremity involvement is uncommon. Again, the entry of glucose into the brain is, largely, independent of insulin action. So it seems enticing to assume that patients with this disease will have better memories. Is it the case actually?

We need to develop better and preferably objective tests to quantify memories, if we are to find the significance of such a finding. Any statistical correlation of memory in patients of Alzheimer’s dementia (or other dementias) or diabetes mellitus along with disease duration and plasma glucose, insulin level, HbA1c and so on with those of normal control subjects need to be searched for. As a matter of fact, insulin enhances cognition not only in normal individuals but also in patients with mild AD, as was seen by Watson and Craft. At the same time, chronic hyperglycemia in diabetes has been associated with impaired cognition. But even today the role of insulin and memory is unsettled and debated.

Last modified: Jan 8, 2009
Reference: 

Watson GS, Craft S. (2004). Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease. Eur J Pharmacol., 97-113

The Cerebellum-Part2

Quite a few of us are acquainted with the fact that in Windows XP, the start menu items that display, when we click the start button, organize themselves continuously (dynamically), as we use them. The programs we use most frequently, are placed on the top; while the least used items settle down at the bottom. A similar hierarchy is followed by the brain too. The tasks we have inherited from our ancestors, phyllogenetically, are kept at the bottom of our memory/program cache while more recent skills are placed at the top. As we go on acquiring new knowledge, they first locate in the cortical areas;- once the task have been mastered, they settle down deeper, into the cerebellum and so on. It seems we have our own stack registers. For example, much of our basic and posture maintenance algorithms are kept in lower brain areas such as the spinal cord, medulla, the midbrain rather than the cerebral cortex. They are old programs, evolution wise, and hence kept in the lower shelves. In early neonates, and in diseases of neuronal pathways e.g. in upper motor neuron lesion, midbrain lesions, spinal cord lesions the functional architecture/hierarchy is lost, as the higher centers are not yet or no longer active.That is, now, the sophisticated programs of the cerebral cortex are no longer working, the phylogenetically/ evolutionarily old programs resurface. Babinski reflex in UMN lesions, Moro's reflex are two examples.

In addition to the above mentioned address lines, there is this real time integration and differentiation that goes on constantly within the brain. The much awed calculus is their regular cup of tea!

To be contd.

Cerebellum: Electronically Speaking

Sometimes journeying into physiology textbooks can be a deja vu in electronics. The other day I was studying the way cerebellum learns from its past 'karma' and memorizes the best setting for an action. I was surprised to find that its learning resembled a lot with the op-amp (operational amplifier) ic's (LM741, for example) and its memorizing resembled to that of the EPROMs (erasable programmable read only memory, a picture of which is shown here on the left).

The cerebellum has one of the largest nerve cells of the body, the Purkinje cells, in addition to other types of cells. Purkinje cells have numerous tree-like branching dendritic processes. They receive two types of electrical connections; from the mossy fibers (about 250000 to 1 million fibers for each Purkinje cell) and climbing fibers (ONLY one for each cell).

The cerebellum fine tunes the movement that accompanies a certain task in the following way. The brain (lateral portions of the cerebellum and the basal ganglia) 'plans the action' even before we start an action. After the task has been executed, the cerebellum calculates the 'error', the difference between the planned trajectory and the achieved output in much the same way a does.

In the figure on the left, the op-amp is configured as a negative feedback, through resistance R2 which feeds a portion of output voltage back into its inverting input (since input is fed into its - terminal) amplifier. This way, the op-amp can have both a fraction of the output and input at the same pin, thereby the gain and other parameter remain 'stable'.


A still better analogy is that of the phase locked loop, the output phase of which 'locks' to the input frequency (diagram on the left). Likewise, the cerebellum too matches its expected action with that of the resulting action. The cerebellum is 'happy' with the performance when the error is minimum. At this moment of bliss, the climbing fibers fire for a long duration and with a characteristic waveform: a spike followed by a long trail. Now the information is written permanently.

Doesn't our experience of programming a 2716 (EPROM) tell a similar story; a peak programming voltage and a normal working voltage? When we wanted to program an EPROM, we needed to give it a high programming voltage in the beginning, followed by a steady 5 voltage thereafter till the EPROM 'learned'.

It doesn't end here. In the cerebral cortex, memory is consolidated in sleep, when it receives a spike voltage: the k-complex in the NREM stage of sleep. It seems that we have a micro, or may be a pico-controller in our brain.

To be contd.

Sleep to Dream and Dream to Discover

Imagine this. You are trying to solve a problem for the last few days. You are too tired to concentrate any more. You go to bed and sleep like a log, just as The Beatles sang. All of a sudden you find the "key" that leads to the solution you wanted, in a dream.

Things like that do happen in real life. Many a inventions in the past were directly or indirectly inspired by dreams. Elias Howe was toiling his brains out trying to figure out how he would make a needle stitch clothes, so that it could be operated by a machine. He was dog tired and went to bed. He had a good night's sleep that day only to be taken prisoner, in his dream, by fierce tribals wielding bizarre lances with holes at the tips. He immediately understood the dream's implication and the sewing machine was born.

Otto Loewi's discoveries about chemical neurotransmitter won him the Nobel Prize in Physiology or Medicine. The discovery appeared in a dream. He immediately jotted it down. But he couldn't decipher his own handwriting the next day. Loewi, disappointed, spent his 'longest day' in his life and went to sleep again. He got another dream. This time he went straight to his laboratory and performed the test according to the dream on a frog. This dream led to the discovery of neurotransmitters, chemicals through which neurons communicate. Acetylcholine was discovered and Loewi became known as the father of Neuroscience.

Kekule, the German chemist, was doubly fortunate for he was rewarded twice in dreams. Firstly, he got the structural formula and valencies of carbon atoms in a dream and secondly he propounded the ring structure of benzene ring, after having dreamed of a snake fidgeting with it's tail and putting it into it's mouth. His dream, while he was traveling in a London bus is well recorded. Serendipity in dreams doesn't end here, for there are many more examples. That is why Kekule once said, 'lets learn to dream'.

The whys and hows of dreams are not clearly understood but it is known that the brain does some housekeeping tasks (consolidation of semantic memories) while we are asleep. Also, it is the dreams in REM sleep that are vivid and remembered upon waking. It (REM or rapid eye movement) is a paradoxical sleep phase since, although the person is sleeping there is increased heart rate, brain activity and breathing. So, we need to sleep tight if we are to stay ahead in the race, and right now I feel I should do justice to myself by giving my fatigued brain it's due. Zzzzzzz....