 Welcome back to the lecture series on amnesty physiology. So, we are in section 5 and in nervous system and today we are on the section 5 lecture 5. So, basically there are almost 8 to 10 allotted lectures for this section. So, we are on the 5th lecture. So, today we will be studying about the brain and the key central processing unit of our body in terms of cognition, thinking process, learning and memory. We will talk about some of the models of memory and the diseases pertaining to that particular memory deficit or dementia or any of our information storage loss. So, to start off with let us look at the geometry of the brain. So, that will help you to kind of understand. So, we are into section 5, I have already mentioned. So, we will be talking about the brain, learning and memory and we talking about diseases pertaining to memory loss. So, before we start let us tell you some stories which may help you. So, back in 1948 sometime in 40s or 40s exactly I do not recollect the year. There was an individual there was a patient you can call who was getting frequent bout of epilepsy. Those of you who does not know epilepsy, epilepsy is a disorder when all of a sudden the brain becomes hyperactive. It is said that some of the one of the theories says that there is a uncontrolled secretion or release of excitatory neurotransmitters like glutamate. It may be a resultant of glutamate excess secretion or glutamate toxicity or something like that. So, all of a sudden the brain become completely hyperactive and the person loses complete control on its peripheral system. Most of the time, epilepsy patient pretty much falls down and after sometime he or she regains consciousness and then they are fine. But, the problem is that you really cannot predict when they will be getting that kind of violent bouts of epilepsy. So, here was a patient or an individual call him x or y whatsoever. So, this individual was a mine worker he was working in the mines in Canada. So, he was getting this frequent bouts of epilepsy and they had to go through every time he had to be admitted to the hospital and you know doctor says to do giving medication and this is 40s and 50s much even before I think the DNA was also not discovered by the time. So, this is fairly early. So, eventually there was one surgery which was performed on him by some of the neurosurgeons. What they did is that they specifically removed a part of the brain was supposed to be the origin of this hyperactivity. So, brain has and will come to that. So, before once I tell you the stories and I will come back to this. Next what happened is that of course, this person did not suffer from epileptic bouts since then, but he never learnt anything from that day. He could never remember anything what he learnt from that day on he could only he lived only on the information which he gathered in the past. So, this was the first you can call it an accidental discovery or you can call it a just a freaking chance that because of one surgery or surgical removal of a specific part of the brain human being came to know as a race we came to know for the first time that this particular part is involved in some form of information acquiring information. It is something like if I had to give a computer analogy it is something like a random access memory. You need it to have a RAM in your computer. So, that you can you know. So, higher the RAM the more you have the ability to download information set all the other things. So, it is almost like a RAM and that sets the tone for series of experiments since 1940s we are into 2013 it is since then it is almost 70 years 73 years. There are series of experiment across the world a good number of scientist who are involved in understanding what is learning what is memory. And in that process several new information have come to known to mankind and in this section and the subsequent section of these lectures will be discussing about some of these discoveries which took place. So, having said this what I will do first of all I will go to the structure of the brain and I will try to show you that part of the brain which was actually removed in that patient. So, that way you will have a visualization of that area. So, going back to the slides. So, if I draw the brain like this. So, this is from the top you are seeing the individual. So, for example, you are lying down and this is the brain stem and this is the spinal cord coming and I am not doing complete because I will be only dealing with the small bugs out here. So, the region which was removed in this patient I am highlighting that region was an organ like this a bilobed structure. And this structure is termed as if you look at the structure shape of this structure if I had to put it like this it is almost like this which for the Greeks this is the Greeks used to call this kind of structure this kind of animals as seahorse. And in Greek seahorse the word in Greek is hippocampus. So, this region of the brain based on this got the name called hippocampus. So, in that particular patient this was the part where there was uncontrolled electrical activity all of a sudden without any time without any prediction or anything. So, what the doctors did is they removed this part they got rid of the surgically removed this part and next what they found this person never gathered any further information. Now, talking about the other parts of the brain. So, if this is the hippocampal region then let me redraw another picture to kind of help you people to appreciate these are the left lobe and the right lobe. And here you have the hippocampal formation likewise the rest of the region which is are called the cortical regions. And within the cortical regions you have several areas the language area which is called Broca's area Warnicke's area you have visual cortex you have areas which are involved in hearing you have areas which are involved in motor control. And especially most of the motor control are on the are in the brain stem regions out somewhere here there are nuclei. So, here the nucleus does not mean the nucleus of a cell it is the aggregation of neurons at a specific point which are controlling. So, there are areas which are controlling your respiration there are areas which are controlling other motor activities then there are areas which are controlling your appetite. And yet there are areas which are not well defined have some role to play with different kind of pains circuits. So, just by removing this small area of the brain with respect to this is a smaller area this patient this individual loses any information gathering area. So, this is your cortical region cortical region. And this is the hippocampal region the neurons which forms the hippocampal region are called the major class of neuron which form hippocampal region are called pyramidal neuron pyramidal neurons. So, why it is called pyramidal neurons because these neurons if you see the structure of these neurons they look like pyramids like this the cell bodies are like this. And these are the axonal processes and these are their dendritic tree here is the nucleus of the cell. So, and apart from it. So, if I kind of you know magnify this image how this looks like in a cross sectional view of this. So, let us move on to the next page to tell you the cross sectional view. So, the cross sectional view of this structure is almost like this. So, what will you see is there are kind of circuits all over the place likewise. There are specific regions and there are and these regions are consist of several circuits and these regions are have different names. Now, come to the namings C A 1 region then you have similar regions which is called C A 2 regions C A 3 regions C A 4 regions. And underneath this is a area called many books you will see it is written as D G D G stands for dented gyros. So, this is the site to architecture of the hippocampal neuron which are mostly consist of. So, if I have to kind of you know blow up on this these mostly they are consist of those pyramidal shape neurons like this with the dendritic processes and likewise. So, these are the and apart from it there are series of interneurons. If you remember interneurons we have talked about the interneurons in the spinal cord circuits there are series of interneurons. And most of these neurons are in the hippocampal region are either glutamaturgic and I will mean tell you what does that mean glutamaturgic or gabargic. So, this means if they are glutamaturgic or gabargic glutamate means. So, if you remember the classification neurotransmitters. So, most of these neurons secretes an excitatory neurotransmitter called glutamate secreting glutamate and gabargic means the secreting gamma amino beta eric acid as neurotransmitter. So, based on the neurotransmitters these are being classified apart from it these. So, another thing remember one more thing well study about the brain none of these regions are kind of isolated they are not isolated regions. So, in other words if for example, let me redraw the brain this is how the brains look like and this is the brain stem. So, and from these spinal cord you are getting all the signals which are coming all the motor neurons which are sorry sensory neurons which are bringing the signals. And then they are all interconnected with multiple kind of connections likewise somewhere they are converging they are all interconnected with neurons. And there are circuit it is imagine you open a radio or you open a computer or you open a supercomputer circuit or you open or you see a IC chip under a micro under a very high end microscope it is a huge circuits and these circuits we call them as neuronal pathways and these pathways are kind of you know linked up with one another. In other words if you remember in the last class I was telling you something and whenever we see an individual say for example, I have to remember something there are several ways by which I can remember an individual say for example, today you are seeing I am putting on a particular shirt color of the shirt have I shaved my facial expression my voice I mean look at it already a sound modality my voice shirt color face visual cues color codes visual cues color codes to into the visual section voice is another section apart from it some other aspect of it. So, a piece of information is being stored is say for example, if somebody has to store in his or her memory the face of an individual or about to know and like you know to remember an individual there are several ways we remember. So, say for example, now let me give you a practical situation. So, for example, you see this individual and you have to remember this individual. So, part will be say for example, you have the visual cortex which is ensuring the visual visual cues about this individual visual cortex. If this person is a speaking is a speaking something. So, that will be stored in some region called you know hearing or hearing region then you have something called a language processing area where language what I am speaking you are processing it language processing. So, in other word what is happening us individual whom you are seeing as a whole all the information. So, for example, if this is information 1 this is set of information 2 this is information 3. So, all the information about an individual if that I called as I t the total information is divided into I 1 plus I 2 plus I 3 plus I 4 likewise and these pieces of information are stored at different parts of the brain all over the brain they are stored. Now, what happens is this. So, say for example, if I call show them at the memory traces about this individual these are the different memory traces for x y z whom you want to recollect. So, now if I had to recollect this individual as a whole what I have to do is either I had to gather all this points and gathering all this point means I had to get this piece of information this piece of information this piece of information. So, I am drawing this piece of information this piece of information about this individual this piece of information this piece of information this piece of information this piece of information and this whole pieces of information then eventually should be able to recollect this individual and this only happens when they we are all connected with each other. So, when he started you know you remember like we also you remember he had a very husky voice or you remember he is or her eyes were like this or on that day he or she was putting on the or specific kind of clothes or specific color. These are those bits and pieces of informations and this is what I was trying to tell you. This falls under the final frontier of human existence understanding the neural code in this circuit. In this huge circuit these falls under the neural coding. How we are being coded? How all these informations are being coded? Neural coding you are neutrally coded. So, we are all neutrally coded. So, coming back where I took the detour. So, talking about the hippocampus. So, I started this with hippocampus while talking about this circuit. So, this circuit what you see out here is getting inputs from other areas. Several other areas it is getting input likewise and some of the inputs which are coming in the form of cholinergic neurons. Cholinergic neurons are the ones. So, I talked about the glutamatergic neurons which are secreting glutamate. I talk about the GABAergic neurons which are secreting GABA. Yet there are series of cholinergic neurons. It has been proved that hippocampus has some of the interneurons which has the ability to secrete acetylcholine. So, cholinergic are the ones which secreting acetylcholine. So, this cholinergic neurons either they may be the interneurons or this is a debatable topic that whether there are cholinergic neurons as it is other than interneurons in the hippocampus or not. But it has been documented in the literature that hippocampus indeed have some cholinergic neurons way in the beginning of it is development. But then the number goes down, but apart from it it gets cholinergic inputs from other parts of the brain. So, another word to put it hippocampus. Hippocampus receives cholinergic inputs from other parts of brain. So, the cholinergic inputs what you see. So, the hippocampus receives cholinergic neurons. So, what I wanted to tell you highlight here something very important that each one of these neurotransmitters decides. So, apart from the time and space we talked about. So, the neurotransmitters have the ability to code different type of signals. So, depending on what kind of neurotransmitters are functioning at a specific regions of the brain our coding pattern kind of changes. So, this is very important for people to understand. So, talking about the coming back to the hippocampal part. So, this was the region which was removed from this particular patient. So, where it all started the structure of the hippocampus and it is having the pyramidal shape neurons and CA1, CA2, CA3, CA4 and the dented gyros region of the brain. So, since we are talking about this thing let me and highlight another part of the aspect of the brain which is very very controversial. We will come to this in depth in the subsequent lecture. This is the part. So, if you people remember in the beginning I told you that the real cells are the dividing cells and the neurons are the non dividing cells. But, I told you that there are certain regions of the brain where indeed the neurons do divide and dented gyros is one of the such hot spot where the neurons are dividing and we will come to the whole controversy across the world among the scientist that do they really divide and do they form functional neurons or not. This is something which is under intense investigation from different groups across the world really what is happening are they dividing are they becoming neurons or not and all that processes. Now, coming back to the circuit what we are talking about. So, next thing was that. So, now we have since we have talked about the geometry of the or the morphology or the structure of the hippocampus hippocampal region of the brain. Now, we will talk about some of the why this region is so very important. So, of course we saw from the patient, but by the same during the same time during there was a psychologist who proposed a model of learning and memory. His name was Donald Hebb people can check it out on the web if you go Donald Hebb and Hebb was a psychologist and he proposed a model for learning and memory. So, what and that was eventually called as learning and memory which was eventually called Hebbian learning rule. So, what exactly is Hebbian learning rule once again Hebbian learning rule. So, Hebbian learning rule states that. So, first of all I have to make you understand this then I will kind of schematically draw it at one point of time. There is a say for example, this hand this is sending some signal and this one is receiving some signal and both of them are equally excited. This is sending a huge train of signals very strong train of signals and this one is receiving one hand is sending signal the other one this imagine this is one object and this is the another object one is sending signal other one is receiving and a very high train of signals after some point even after and both of them are very active if the sender if this one is the sender and this one is the receiver this one which I am moving now is the receiver. If sender stops sending signal to the receiver yet receiver still keeps on receiving signal this may sound bit bizarre. So, think of this situation what is happening. Now, let me put it in terms of schematically if this one is a and this one is b. So, a is the sender and b is the receiver. So, a is training sending a train of signal like this to b very strong train of a very high frequency signal which are reaching to b like this and a and b are both active at some point. So, the precondition is that at one point of time at t point of time both a and b are equally active. So, at t one we made this recording that this one is sending signal and which one which was being received by b after some point of time. So, at t two point of time here is b and here is a is no more sending any signal is a is no more sending any signal yet b is perceiving that it is getting signals like this. In other words say for example, I teach you something very intensely and you are listening to it very intensely I stop teaching I finished my class, but still your brain is processing that information continuously you are remembering the you know some way or other something is getting changed in your circuits. It is slightly bit abstract for 1940s when this whole theory was proposed, but that was the first learning model that is how we learn we regurgitate we say you know in our childhood our parents teaches us you know learn something by heart like you know learn by heart like you say two one the two two the four two three the six two four the eight likewise you know you remember it or there is some poem you continuously you listen to it and you remember it is something like that and this was and that is being said at that time that this is how the information. So, what happens essentially what have said is that in that process there are permanent changes which I am showing in green happens on the receiver side and this is a form of learning which was proposed by learning and memory which was proposed by donald e have this was the first model it was just a model and the whole field of neural network and all these things all those who are from that field knows that these were some of the initial models which are being taught, but then does this model well this is a mathematical model out there does this model has physiological significance that was the question. So, now going back what all we have talked about because I will come to this because that is why I am giving you some discrete pieces of information. So, we talked about this structure and we talked about the patient where this structure was removed and this person could never gather any further information could never remember anything. So, this was proved by that time 1940s and 50s that hippocampal region is involved in learning and memory first set of learning second thing was which was known at that time. So, there was an existing learning model by donald e have and the learning model looks like this when a is intense sending an intense signal with a very high frequency and b is receiving and both a and b are active at that point of time after some point of time in spite of the fact whether a is sending any signal or not b is receiving certain signals. So, in other word there are two possibilities one possibility which comes up was that b request a somewhere or other to send more information it is more of an interactive. So, this loop becomes much often interactive loop now could this be proved in biological system that was a challenge the story from here shifted from 1940s and 50s to 19 late 1960s or somewhere in 1960s there was one study which was done by three individual bliss lomo and collengridge this was one of the very seminal paper bliss lomo and collengridge believe the spelling may have some mistake but kindly corrected so what they did is that they took out hippocampal region from the brain of I think they use guinepig or something like that. So, here is the dissect out an animal basically they sacrifice the animal because when you are taking out the brain you are sacrificing the animal. So, from here you are trying to do they remove the hippocampal region. So, this part was removed likewise. So, already I have told you that there are specific circuits on this part C A 1 region C A 2 region C A 3 region C A 4 region and you have this dented gyros sitting underneath it. So, here you have the C A 1 C A 2 C A 3 circuits C A 4 circuits and they are all interconnected in a complex manner. So, what they did is they placed it in a bath likewise the next slide and redraw the whole thing that will help you to understand C A 1 C A 2 C A 3 C A 4 dented gyros. So, they placed it in a bath where this tissue can live for at least few hours and then they did by the time there was lot of good development in electrophysiology. So, they placed multiple electrodes like this these are the electrodes which are faced and they were making recording. So, this is the amplifier out here very high gain amplifier though at that point also the amplifiers were just kind of in the developing phase because this was the time just after the discovery of the transistors in 1950s and this was the stimulator. So, imagine this part to be your A region in the previous diagram if you go back to the previous diagram where I was showing A and B and imagine this to be the part B and they are connected by a circuit say for example, this is B 1 B 2 B 3 fine. Now, A is sending a train of signals from here to B of course, not only to B this will continue all the way to through this circuit to B 2 and this will continue of course, to B 3 fine. So, these are the train of signal at time t 1 time t 2 this continues say for few minutes or few seconds a very very strong train of signal is to call that as theta burst very high frequency high frequency signal. Then at time t 2 the stimulator stopped sending signal yet it was observed that B 2 is getting some signals. So, do at B 3 is getting some so B 1 B 2 and B 3 all are getting signals why is it. So, now if you go back I was talking about the heavy and learning model this was the study we change the way we think because these are some of the seminal discoveries which helped us to appreciate. So, this was this seminal paper which was published in journal of physiology at that point of time was the first documentation of the heavy and learning model or memory documentation of heavy and learning it was this experiment which helped us to develop the whole field into another level and they term this process as first memory model biological system was termed as long term potentiation what exactly is does that mean and what exactly happens here. So, coming back to again I will refer back to the heavy and learning model because that is the starting of this whole journey. So, if you remember while I was explaining that I told you there are certain signal which is which was believed that B is sending to A that when A is no more sending signal asking A that you send more signal. So, the next idea was in this model in 1970s when during 60s and 70s when this was discovered it was thought that there may be some signals which are send out by B to A telling them telling A that you send more signals. In other word those signals which are being sent from B to A out here what you see which I am putting in black and like I am putting a asterisk mark on those these were termed as retrograde messenger. Now, what are those retrograde messengers till date this is 1970s and 43 years have gone since then we are in 2013 we are not really sure what are the retrograde messengers they are potential molecules which have been implicated in that one of them is the nitric oxide if you remember I was telling you about this molecule in the classification of neurotransmitters then one of the fatty acid arachidic acid which is involved in it possibly and few other molecules, but nobody with certainty can tell which are the retrograde messenger till date and there is intense investigation on the way that what are those retrograde messengers are there at all and if they are who are they and how they are communicating from B to A or from from the receiver to the sender that you react accordingly. Now, what really is long term potential now that is what I was where I stopped. So, what does that mean so at this stage what I will do I will stop with this lecture and in the next lecture we will talk about what are what are long term potential and the other model what is long term depression and we will come to the diseases what will be dealing with thanks a lot.