Learning II

Eric Kandel gave the final lecture in our neuroscience course on the topic of learning and memory. In the lecture he described some molecular mechanisms behind the development of long term potentiation.

Here is a very important slide from the lecture. This slide depicts the current leading thought behind how long-term potentiation takes place (LTP). I remember that one time from my childhood, I remember my first plane ride, or the kid who bullied me all thanks to long term potentiation. LTP makes me who I am today. It is responsible for my conscious recall of facts, places, names, etc... Explicit memory. 

Quickly, in the bottom left corner a depolarizing excitatory stimulus activates NMDA receptors. Post synaptic intracellular calcium levels rise, and calcium dependent kinases are activated leading to increased levels of cAMP. The residual calcium makes the neuron more excitable for the time being, but in a short while the unbound intracellular calcium is either pumped out or sequestered, this is short term memory. But how do the big events get registered, the ones I will never forget, first kiss, first football season, first day of high school, college, work etc? Its not too different... Back in the neuron lets say instead of having all that calcium sequestered, the calcium containing neuron is repeatedly stimulated. Now the levels of calcium become so high that the levels of cAMP become elevated. Next in line in this molecular mousetrap is that protein kinase A which finally has the strength to fully dissociate from its regulatory subunit and remain activated. PKA in turn activates MAPK pathway, and the both of them make their merry way into the nucleus. Inside the nucleus (from Latin, nux, kernel, nut or inner part), cAMP response element binding protein or CREB for short is altered by these newly entered enzymes. CREB1 increases transcription and CREB2 decreases transcription of certain genes. CREB2 is silenced, CREB1 is freed and the initiation new protein synthesis can now occur. What are these new "memory" proteins?  New receptors, neuroligins, neurexins, etc... essentially things that make the connection between the two neurons more substantial. 

So Dr. Kandel brought up the interesting point that with new protein synthesis, there are physical changes in the brain when LTP occurs. If for some reason I remembered his talk, his words would have affected my memory, or ultimately the structure of my brain. Yes, the physical structure of my brain is altered, however insignificant, my brain would have weaker or stronger connectivities. Life has taught me that certain instances where my brain has been restructured have been more significant than others if you catch my drift.

Its interesting to speculate on the ramifications of his point because I believe personality is a very subtle and sensitive biological phenomenon. To the extent that aspects of my personality are learned, I have the responsibility to guard and culture my brain's connections in a responsible fashion. Which brings up another interesting point that was made in lecture. Here's another slide:

The slide proposes a mechanism for behavior disorders. I can not tell you how relieved I am that there is a molecular mechanism (pysch needs it badly, talk for another day). In the top row, labeled A, we have schizophrenia. Many are hard at work developing the pathogenesis of this disorder, there is a dopamine, serotonin, glutamate, and now a gene regulation hypothesis. Probably multifactorial, its a way to explain the behavior associated with this disorder. But take in row B there is normal behavior contrasted with that of a behavior associated with PTSD. This would be the first look into a molecular explanation of how a negative behavior is learned, reinforcing on a molecular scale. I'm just spitballing here, but it could be a justification for CBT. 

After lecture I had some questions, I asked:

What about CREB2 -/-?

How do you believe memory and creativity or intelligence overlap?

Why is learning in the critical period (time when a child where everything is easy) different than learning as an adult?

Answers:

CREB2 knockouts display quicker learning but reach a ceiling in their capacity. I gathered that there are too many other moving parts to look for a silver bullet. 

Memory does not map intelligence or creativity very well. He cited an anecdote of an artist who could not add six and six, yet was capable of creating stimulating visual art. I'm beginning to understand that intelligence, and most importantly creativity, is probably some sort of meta-cognitive function. I can't understand how I remember my name, so I'll save explaining why Chopin choose C# minor for another day. 

Learning language, music, mathematics, basically anything, is far easier as a child because the synaptic connections are looser, more susceptible to influence. What a double edged sword! 

Is there a way back? My belief is that there is, it just hasn't been found. The more I listen and learn the more it becomes apparent that we need to increase our appetite for risk. What a pleasure it is to learn of others labors and discoveries, but it is also wonderful to suppose what a breakthrough in that field could do for humanity. Research into subtle phenomena that make us human are poorly represented in animal models. In the name of science we decerebrate cats, inject poison into the veins of primates, and quite literally play God with the genome of mice. All for good reason I'm sure, but are we so much removed? Responsible but experimental and exploratory research should take place on willing and consenting humans. Our understanding of biology will necessitate a greater confrontation of the certain unavoidable truth that we are as much animal as human.