 Welcome back to the lectures and animal physiology in the NPTEL. So, we are in section 5 with the nervous system. So, today is the lecture 7th. So, as of now in a nervous system, if I just have to have a recap, we have started with the structure of neurons. We have talked about the supporting cells, the real cells and their structure and function. We talked about malination and then we talked about the overall architecture of the nervous system, the central nervous system, peripheral nervous system. Then we talked about the reflex circuits, talked about the higher brain functions like memory and learning and we talked about the two learning models, long term potentiation, long term depression, one of which is based on Hebbian learning model and then regarding Alzheimer's disease and dementia. So, today what we will start is, we will talk about few other diseases all the central nervous system, which has helped us to learn a whole lot about the way our nervous system functions. It is very interesting that most of these informations what has been gathered in last 100 years are mostly or mostly have evolved from clinical 1940s when this part of the hippocampus or the hippocampus was removed from the epilepsy patient that leads to the loss of memory like this person never acquired any further memory and that set the tone to understand hippocampus and the energy storage mechanisms followed in the hippocampus for next almost now 70 years and it is still continuing and it is continuing at the molecular level with enormous understanding and intense applications of electrophysiological techniques into it whereas, that was the beginning of long term potentiation which was in 1970s followed by 1970s, 1980s when the long term depression model it was given by Masao Ito and afterward people like Teras Sajnowski in Salk Institute and few other people who have done significant of work and India national center for biological sciences professor Sumantra Chatterjee he is doing a lot of work on amygdala and some really groundbreaking works have been done all over the world to understand how our emotional memories are being stored and are being carried forward and in that process while explaining the long term depression we kind of I kind of highlighted the fact that you know there are neurons whose threshold to respond reduces because of long term depression just as opposite to the long term potentiation phenomena whose threshold increases here the neurons thresholds decreases because most likely because of it has a different kind of neurotransmitter profile and it is on it is membrane the channels densities may be totally different as compared to the neurons in the other regions of the brain. So, with this let us talk about one of few other diseases we will be talking briefly about epilepsy again relevant to hippocampus we will talk about Parkinson's disease and therapies and then we will be talking about spinal cord damage futuristic therapies these are the aspects what we will be dealing in these three topics what we will try to do in this lecture or in the subsequent lecture will wind up these or at least my objective is that you people should be aware about the state of art across the world where we are that will help you to kind of you know go through any kind of research papers or the findings and should be able to see that how far we have progressed coming to epilepsy. So, the first one what really is epilepsy in the last class I explained you that epileptic patients all of a sudden gets about it is kind of about when they the first symptoms if I do not know how many of you have seen an epileptic patient they like you know like this likewise and then they fail down like the whole body starts shivering and then they fail down and you will see some time from their mouth you know some kind of you know saliva started coming in and they are not aware and just after some time they are all fine they just got up they feel very tired, but then they have no idea what happened few minutes back because that part of the event at that time t is totally washed out they have no idea. So, how that happens it is something all of a sudden thing of a crossing on a road all of a sudden the vehicles start coming from all sides and they collide there is a huge bank and then everything becomes quite and obviously you know you remove the debris and then again the traffic starts moving. So, it is something very similar to that what happens in epilepsy there is a hyper activity in the hippocampal region of the brain. So, it is something like this if this is the structure of the brain here you have the hippocampal region. So, all of a sudden there is an uncontrolled hyper activity here. So, what happens immediately is due to this hyper activity certain hyper activity the impulses are being transmitted all over the place all the connected circuits and as I told you all the circuits are connected all of a sudden all the coordination of the body is kind of lost you are just have no proper signal as if there is a collision on a four way crossing and that collision could be because of what are the possible hypothesis out here could be because of all of a sudden if you break up the problem at the cellular level all of a sudden there is excess secretion of neurotransmitters. So, sorry for the glitch there was some errors in the systems. So, there may be excess secretion of neurotransmitters uncontrolled secretion of neurotransmitters and most of these neurotransmitters which are involved which is believed to be involved is glutamate as I have already mentioned that this is basically most of the hippocampal region are consisting of glutamate ergic neuron and this glutamate ergic neuron all of a sudden secretion lot of glutamate. So, the problem with glutamate is that glutamate may lead to excitotoxicity this is another problem with the glutamate because it has to be removed from it. So, there is a base line up to which a body or the brain can tolerate, but beyond that it becomes toxic and that leads to further complications. So, one of them will be glutamate or somewhere or other there is another aspect to it. So, while talking about the hippocampal region I told you that within the hippocampal region you have glutamate ergic, glutamate ergic, GABA ergic, GABA secreting neuron, glutamate secreting neuron and there is a balance between the numbers there is a proportion in the numbers there are certain numbers. So, may be there are brains which have developmental issues or you know developed in a totally different way their number of the GABA may be much lesser. So, GABA which is an inhibitory neuron which allows some of the chloride and all this kind of ions to move through that may be less. So, that may lead to an hyper activity and excess activity of the glutamate ergic neurons. So, whatsoever be the situation it must have to deal with the neurotransmitters and the ion channels or there may be some mutated ion channels which are formed the one which are conducting all the. So, may be an ion channel problem. So, at the level if you look at it from very simple chemistry perspective or biochemical perspective it will boil down to either neurotransmitters or ion channels. Now, if you go with reference to the first chapter or the second chapter what we covered in the membrane physiology. So, they are all membrane related phenomena and that is why there is intense amount of funds across the world in best of the best places like national institute of health or in UK. There is enormous grant which are given to understand the membrane channels structure and function because these membrane channels are the one which ensures what is entering inside the cell and what is going out and that is the hot target for all the drugs to bind and carry out all the downstream functioning or executing their pharmacological effects. So, with this brief idea about epilepsy we will move on to the next pathological condition which is Parkinson's disease and its therapies. So, Parkinson's disease and its therapies. What exactly is Parkinson's disease? So, in order to understand Parkinson's disease we have to rebuild the circuit, but before I build the circuit let me tell you the problems of Parkinson's patient faces. A Parkinson patient cannot move he sort of heard the motor controls are compromised. In other word they cannot move their hands or their legs or several other parts of the body do not move what exactly that means whenever we see a patient of Parkinson's. So, now if you recollect the circuit of neuromuscular junction. So, what is happening there is a sensory input from your muscle which goes all the way to the spinal cord and from there part of it goes to the brain. From the brain if it is not a reflex circuit of course there are two options either it is a reflex circuit it goes to the brain it goes to the spinal cord from the spinal cord it comes back. So, just for a recap so this is the brain the spinal cord so and this is the target tissue and these are the sensory neurons these are going body out here and if it is a reflex circuit then the motor neuron which are sitting on the spinal cord they come back and tells you. So, this is the classic reflex circuit what we have already talked about now there is a second circuit which needs higher motor controls. So, the motor neurons can be divided into two parts. So, one which I have already mentioned here these are called spinal cord motor neuron spinal cord motor neuron their cell bodies are sitting on the spinal cord and their processes goes out to all the target tissue these are sometimes also called SMN also spinal cord motor neuron. So, they are all sitting all along this ventral ventral root and if you remember when I talked to you about the dorsal and the ventral root just again for a recap. So, the center is the ventral root out here on both sides is the dorsal root where the sensory root or the ascending pathway is being. So, this is the ascending or the dorsal root it is ascending because I told you all the informations are carried like this to the brain on this and this is motor where the signals are being brought back from the brain or directly from the spinal cord like this. So, the ascending and the descending pathways coming back to where I was. So, there are other circuits where basically a signal from say for example, here a sensory signal from another situation this is a sensory ending which is moving all the way here is the ganglion from here along the ascending pathway this signal is moving to the brain. So, for example, here it reaches the motor cortex just for your again recapitulating some of the myelination thing. So, these neurons which are sitting partly outside this says outside the central nervous system are myelinated with Schwann cells and the one which is the part of it which is sitting inside this spinal cord is myelinated with the oligodendrocytes. Now, the from the motor cortex it synapses on another set of motor neurons say for example, it is in the motor cortex these neurons are called higher motor neurons higher motor neurons these higher motor neurons are present in the motor cortex of the brain motor cortex is the region of the brain which regulates the higher motor control or coordinate the higher motor control how it does so higher motor controls. So, the way it works is from the brain from the region of motor cortex which are sitting somewhere out here series series of thousands of motor neurons they send the signal to the lower motor neurons. So, here in the blue you have the lower motor neuron on the ventral ventral cord and that is where they are synapsing or some motor neurons sitting here synapsing and these signal are then being sent to the target tissue and here you have the target tissue fine. So, the way signal is moving is here is a sensory input going all the way to the brain either via inter neuron or directly by synapsing on the higher motor neuron this signal is being transmitted signal moves like this all the way to the brain and from here the signal starts coming down likewise it reaches the target tissue. So, in that process what happens signal reaches here. So, the higher motor neuron commands and this command is being executed by these neurons imagine a situation when selectively some of these higher motor neurons which are present here starts dying just putting its higher m n they start dying and if this happens next thing what you know will happen is this the signal or the electrical impulses which are supposed to be transmitted along this line will be compromised they would not be sent. So, under that situation option is that this person is no more receiving the higher motor inputs and this may lead to unable for this person to move his hand or her legs or you know all other body parts this is the classic symptom of Parkinson's disease and the series of neurons which is starts dying at the motor cortex are specially in a region of the brain called substantial nigra this is the region of the motor cortex motor cortex which is responsible for coordinating the motor control the specific set of neurons which starts dying are called dopaminergic neuron. Now, if you dopaminergic neurons now if you people go back and see the classification of neurotransmitters you will see there is a series one class of neurons or neurotransmitters where serotonin dopamine all the amines you know it is that class of neuron there are population of neurons whose so it is like this is a so this higher higher motor neurons on receiving input from the sensor in neurons secretes dopamine. So, this dopamine is synthesized here these cells are specialized to synthesize dopamine and this dopamine act as a neurotransmitter entities these dopamines travel all along here or make synthesized out here and these one forms synapse on the lower motor neurons out here through dopamine it is the dopamine which is transmitted from here. So, now there is no more dopamine dopamine energic neurons are no more there they starts dying under that situation it is not getting any further signal this is the classic case of Parkinson's disease what are the difference between a Parkinson's patient and an Alzheimer's patient. So, A D Alzheimer's disease and P D Parkinson's disease in Alzheimer's disease the majorly affected region is the hippocampus and in hippocampus whereas in the case of Parkinson's disease it is substantiated nigra of motor cortex first difference the second difference is it leads to dementia or memory loss conscious memory loss dementia or memory loss whereas in the case of Parkinson's no memory loss whereas in the case of Alzheimer's disease motor control is intact there is no problem in the motor control motor control is motor control is compromised. These are the very very fundamental difference of these two different kind of diseases which happens in the brain and if you look at it what I wish to highlight here is that whenever you think of a brain think you know there is a mass of neuron all over the place. But if you just think little bit in depth you think of it a disease which is happening here and if for example this is the region of the motor cortex which is all the substantial nigra and all other regions of the brain or say for example let us talk about a disease in amygdala and this is your hippocampus. So, it is the same mass of neurons but the way they succumb to disease is totally different say for example if this one it has two diseases we have discussed Alzheimer's disease and epilepsy it is a totally different kind of way it works and talking about motor cortex we talked about Parkinson's disease and talking about amygdala there are depression and fear psychosis. So, if you look at these neurons what is is there a central way we can put them of course they have all have one common thing they are all electrically active but they have different kind of neurotransmitter profiles molecular at the molecular level at the level of their membranes they are totally different the like the substantial nigra neurons they secrete dopamine which is being transmitted to the lower motor neurons and then the signals are being executed. In the case of hippocampus you have the glutamatergic neuron they secrete glutamate and this glutamate is being then helps in communicating with other neurons. You have the amygdala they have a lot of serotoninargic neuron they secrete serotonin. So, it is the same brain but the fate of different neurons are totally different and what is the most fundamental question one of the very very fundamental question in neural development how the nervous system developed is how a neuron decides that it will become glutamatergic that it will secrete glutamate or it will become dopamine how it will become it will secrete dopamine how it decides that it will become cholinergic that it will secrete acetyl choline how it decides it becomes GABAgic it secrete GABA or serotonin serotoninargic because this question has to be answered in the years to come why is it so because now by this time it is clear to you people that all these different zones are dictated by different set of neurons. So, now when we are assuring into the era of regenerative medicine and tissue engineering where people are pulling out different kind of stem cells which has the protein shield to become any fate. So, for example, from the brain you pick up a set of stem cells and you wanted to look for a therapy how you will what you will do. So, it is something like this say for example, this is the brain and you know a part of the brain or any part of the tissue which could be transformed into say for example, some stem cells are coming out let us call them as neural stem cells. So, these cells will form neurons if they are given the proper conditions they will form neurons and now what will decide that these neurons could become. So, do you have a control mechanism or do we as human race have a control mechanism to tell that you know under these conditions these will become say cholinergic under these conditions they will become say glutamatergic or under these conditions if I grow them in under this condition in a dish. So, what you do essentially is that you take a stem cell population like this and next thing. So, these are the stem cell population and next thing you do you grow these stem cells you divide make these stem cells to divide stem cell division and next thing you do. So, the dream therapies are like this next thing you do you pull out a specific population out of it like this and then you differentiate them differentiating them means you decide what kind of feed they will have will they the first question is could I make from a stem cell population a motor neuron or could I make a pyramidal neuron of the hippocampus could I make a neuron of substantial nigra kind say for example I say say for example here is a patient. So, in future in a distant future this is why our therapies will be. So, if say for example a person suffers from say Parkinson disease. So, this is the zone where the neurons are dying now what will happen distant future is that I know these are he has this kind of a stem cells neural stem cell in neuron stem cells in a seas these neurons neural stem cells will be divided in the lab and then they will be differentiated to form differentiated to form dopaminergic neuron the one which secretes dopaminergic neuron and then these dopaminergic neurons will be transplanted back to that part of the brain where they are dying out transplantation with the hope that these dopaminergic neuron neural newly transplanted dopaminergic neuron will form the same connectivity. So, that is another whole different ball game this is at least what is being dreamt of as the futuristic therapies for mankind if one day and this is going to happen. So, for the generations now the challenge lies here we all now have well characterized stem cells from different parts of the body these cells it could be even a skin cells you know you could have a skin cells and you can make neurons from them from a skin cells you are making neurons now these neurons have to be transformed into say a motor neuron could we do that or I say I want to make from these skin cells say oligodendrocyte could I make that or when I am talking about could I make say for example, a cardiac myocytes since we have already studied about it cardiac myocytes could I make that because skin cells are most easily accessible skin stem cells or maybe some skin cells or could I make say dopaminergic motor neuron I just put dopaminergic or could I make hippocampal neuron even if I could make them could I decide that this will become cholinergic or this will become dopaminergic. So, these are the challenges for next few generations that how far we can control the fate of a cell and then comes the next challenging part what I was trying to highlight in the previous slide that transplanting it back to the brain or specific different parts wherever it is needed and ensure that they form the circuits and this will be these kind of experiment in a future will surely help us to look at neuroscience from a totally different perspective I mean next hundred years for neuroscience is going to be one of the most brilliant time because where all these things will be tried out in some form and already things are being tried out in small animals and kind of in rodents and all these things these are being tried out when this will come to human is a different question I mean it is just a matter of time it is going to happen it is just a matter of time when it is going to happen. But currently what are the possibilities for persons who are suffering from Parkinson's disease so for those who are suffering from Parkinson's disease one of the therapies is called L dopa L dopa therapy what is L dopa therapy. So, this is basically so I told you that it is the dopaminergic neuron which are dying so dopaminergic neurons secretes dopamine which is the neurotransmitter. So, in the lab there is an analog of dopamine which has been synthesized called L dopa and this L dopa is put in the spinal cord in a slow releasing manner. So, that is the L dopa therapy where L dopa is being injected into the system. So, that is the only possible therapy currently existing for the Parkinson's disease patient there is no other therapy currently which is successful. So, while summarizing what all we have covered. So, we started with epilepsy and we talked about the role of excitatory neurotransmitter glutamate and all of a sudden and uncontrolled activity of glutamatergic neurons present in the hippocampus which leads to hyper activity of the hippocampus and thereby leading to a temporary uncontrolled non coordinated fate of the system one. Second we talked about the Parkinson's disease and in that process we talked about the death of the neurons in the higher of the higher motor neurons of substantial nigra and their death leading to not sending signal to the lower motor neurons which are cholinergic in a channel and if you look at the neurotransmitter profile. So, the higher motor neurons from motor cortex in substantial nigra they are communicating with the lower motor neuron with dopamine whereas, the lower motor neurons which are sitting on the ventral horn or the ventral root or the descending root of the spinal cord are communicating with their target tissue with acetylcholine. So, there are two different neurotransmitters which are involved in this process and except just for your interest except in the case of drosophila the small fly where you have the nerve muscle connection and most of the nerve to muscle neurotransmitter involved is acetylcholine except in drosophila where it use glutamate except in drosophila rest all of them use acetylcholine. So, there are two different neurotransmitter which are regulating the whole motor control pathway. So, now if one component of it is starts dying which is the substantial nigra or the higher motor neuron and that leads to something like a Parkinson's disease situation and we talked about the therapy and then we briefly talked about the regenerative medicine where in future probably what will happen or what we dream that mankind dreams of happening is that there will be neurons neural stem cells these will be divided and differentiated to form different kind of neuron dopaminergic this could be cholinergic I mean secreting acetylcholine could be gabargic or secreting gabar or even glutamatergic. So, and those could be transplanted for say Alzheimer's patient or patients with Parkinson's or epilepsy or anywhere where there is and same holds true for situations in other like in the cardiac myocytes or cardiac damage on all these things. So, what we will do in our next class is we will talk about another disease which is amyotropic lateral sclerosis and spinal cord injury because then we will be talking about the diseases of the lower motor neurons and how they are going to be treated. They affect us. Thanks a lot.