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BIOL 4315/6315 Neuroscience Tue Th - NEURO Midterm I Review Tue Th
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00:01 this is mid term one review for section one and I showed this slide
00:09 you guys in the very first lecture I said I'm going to show the
00:13 to you subsequently throughout the course until end of the course. When you
00:18 look at the slide you had one or less understood. Standing up the
00:25 and neurons, neurons and neuronal circuits hopefully you have more understanding of what
00:30 talking about. We discussed neurons as units that communicate with each other that
00:36 influenced by glial cells that perform circuits form networks and circuits. Networks formed
00:43 have a C. N. It's just cerebrum, cerebellum. Brain
00:49 spinal cord and spinal nerves going out the periphery. Very complex connectivity that's
00:57 between different parts of the brain, we know, are responsible for processing
01:02 executing different functions. So in prehistoric these were the brain tra pronation is
01:08 the first neuro surgeries. Imhotep started the brain anatomy but had a very
01:15 access to human body. The Hippocrates changed the thinking of the Egyptians
01:23 heart was the most important organ and the fact that the brain is the
01:28 important organ of the body in renaissance and various vesalius because it was allowed
01:33 actually again do science and even dissections the brain revealed these massive ventricles and
01:40 the ventricular localization of the brain Something to do with ventricles and the
01:46 there or the gasses, they didn't exactly had to do with the control
01:50 the brain function is also distinguishing between matter. White man matter fact that
01:57 matters softer. You know. Gray contains Selma's cell bodies and white matters
02:03 and it's the inter connectivity, the ated fibers, Renada cart was treating
02:09 human body like that uh fluid mechanical and was still insisting that nerves were
02:18 that pineal gland was important but that was some pipeline communication to the periphery
02:25 the brain. Uh that was coming the pineal gland. So the nerves
02:31 still treated as pipes I think. I am was the phrase that is
02:36 famous by renada cart, Luigi. then using the static rotating generator,
02:42 generator, shocks the nerve and the leg and shocks the muscle and the
02:47 leg and the contract. And so shocks the nerve again and the muscle
02:52 . And so he says now definitively nerves are electrical wires. Until we
02:58 a certain anatomy of the occipital, frontal lobes separated by central circus,
03:06 , temporal lobe, cerebellum. We the cerebrum, cerebellum brain stem a
03:12 of the brain, the spinal cord the peripheral nervous system disseminating into the
03:17 from the spinal nerves. There we about the spinal nerve anatomy and we
03:23 about it twice. So we described dorsal ganglion south of the sensory cells
03:28 will carry information dorsal spinal cord, neurons that come out eventually will carry
03:33 information to the muscles for the contraction we'll review it one more time today
03:38 we speak about the reflex arch, there was an intense to really try
03:43 determine what parts of the brain are for what functions. And because you
03:48 only observe the brain or you could observe the brain on the outside.
03:52 was a speculation by monologist that you read the book by its cover,
03:57 was a round speculation, but in theory, they subdivided the brain into
04:02 regions that are responsible for innate or faculties. And they said that if
04:06 regions are active or they're somehow uh anatomically in the brain tissue, that's
04:14 to be reflected on the shape of skull as well. So the chronology
04:19 dominates but also localization of function is very important. And these studies for
04:26 of function that definitively show what parts the brain and responsible for what functions
04:30 from the function loss of function. in this case paul Broca found that
04:37 patients that have missing part of the , which is called Broca's area have
04:42 aphasia, later vernon. This area that have died manager missing this part
04:48 the brain have receptive aphasia. And it was very clear that even for
04:54 , you need multiple areas of the to process language. In other
04:58 if you just damage the speaking part the brain, it doesn't affect the
05:04 and comprehending part of the brain that also important for language. So multiple
05:10 in the brain multiple networks and multiple participate in for example language we also
05:18 the economic uh amnesia, aphasia and aphasia. Then this study with Phineas
05:26 in this case would reveal to us that there are certain parts of the
05:30 that are responsible for motor functions that certain parts of the brain responsible for
05:35 for producing speech or listening speech. then there are certain parts of the
05:40 that don't seem to really affect some these major basic sensory and motor capabilities
05:46 we have. And the case of gauge showed that damage to the frontal
05:51 of the brain caused a significant psychological memory and also behavioral uncontrollable aggressive behaviors
06:04 is part of the executive function of to control yourself and how to control
06:09 with others. So we then started scientists started thinking there are parts of
06:13 brain that are responsible for those other like that. Executive function. Emotional
06:19 , aggression and so on. At same time there were also the beginning
06:24 the cortical stimulations. And if you different parts of the brain you also
06:28 see the motor cortex will end up moving in our if you stimulate the
06:34 cortex but other parts of the brain provoke emotions. And so we know
06:39 emotions and memories. They also have distributed seats within the C.
06:44 S. We talked about Charles Darwin we said that what he observed in
06:51 islands was to islands. A few that are located in very close proximity
06:57 each other. But they had different and environments. And because of that
07:03 species of the animals, turtles, , Sticklebacks, fish lived there and
07:11 , they had slight adjustments to that environment that helped them survive and
07:16 And those adjustments were either in the of the beak or shape people with
07:21 or something else. Uh And in there's external environments where we live and
07:28 determine a lot of our brain structure the brain networks that we have.
07:32 so in rodents you will see these large olfactory bulbs large relatively to the
07:38 size of the brain. And that because rodents sniff around and that's how
07:42 find food their mates and they also around with a whisker. So there's
07:48 large part of the brain that is to somatic sensory cortex where you have
07:53 barrel cortex that's very well developed anatomically large part of the brain that processes
08:00 from whisking. We don't with Really. So you would imagine that
08:07 part of the brain that is found rodents is probably not as developed in
08:12 . Okay. Or maybe not even existent in some instances because we as
08:18 . Non human primates and humans. don't sniff around too much. So
08:22 olfactory bulb will be smaller, it's important sense for us. Olfaction but
08:27 is not the major sense. Were by vision a lot. And so
08:32 parts of the brain will be dedicated vision. Of the sophisticated visual cortical
08:38 that's dedicated and anatomy and function that's to processing visual information. So there
08:47 two different uh uh two different theories coming out at the same time when
08:55 microscopes were becoming better and could resolve the level of a single self and
09:01 when the stains were becoming available. once you you're able to stay in
09:06 neuron because otherwise the brain tissue is , we were able to stay in
09:10 neuron and observe it with enough of optical resolution. You could then reconstruct
09:15 morphological structures of these neurons and neuron held that there are all discrete units
09:22 communicate with each other. And particular held that it's a continuous sensation with
09:27 side of plasma continuity surrounding thousands or of the nuclei that are all different
09:32 . So golden that goldie stay. was a mentor to a Monica hall
09:37 Monica holiday, extensive work in drawing different circuits and postulating and how they
09:44 . And Charles Sherington helped coined this of the synapses, a special space
09:52 contact between two neurons. And started describing it in his work um ra
09:58 Hall was very forward thinking And apart your own doctrine, he also thought
10:03 plasticity and he also thought of some of a directionality or architecture in the
10:09 and these networks. That's something we at in the last couple of
10:13 Especially when we talked about forward propagating back propagating back propagating action potential ceremony
10:21 said that these inputs are coming into den dries and Selma's output here and
10:27 accent of this arrow that interconnect and synapses here and that these connections are
10:33 . That's what he postulated. Another that was very useful is nestle
10:38 But unlike Golgi stain, which stains fraction of neurons and when golgi stain
10:43 those neurons reveals the precise mythology of South's. Golgi stain stains all of
10:49 south neurons and we and does not the process size morphology but rather reveals
10:54 total uh side architecture uh side of . The density is the layering of
11:03 south as you find it throughout the , convenient broad menus, these missile
11:09 to very carefully describe the cyber architecture the human brain with different functional areas
11:17 determined by observing variations in the structure the cells and the packing density of
11:23 cells in the in the sizes and of the things that would comprise the
11:30 in the brain. Now to see cells, we can see them with
11:36 light microscope. Uh to see single like spines, you can still use
11:43 like microscope More advanced version of it a con focal microscope. But to
11:49 organ Alice and to visualize the details the synopsis. You need electron microscope
11:55 resolve about 0.1 nanometers because the synopsis 20 nanometers and in space and electrical
12:03 are separated by three nanometers. You in the second section and it's important
12:09 study these dendritic spines. And we that these dendritic spines are the most
12:14 elements. Some of them have longer shapes, others have smaller narrow
12:20 . Some of them will have three synaptic inputs coming in. Others will
12:25 one. And it is very important the brain has this plastic communication.
12:31 synaptic synaptic communication and where a lot inputs are coming in are coming into
12:36 dendritic spines. So electron microscope allows to visualize these details that you see
12:43 in the pre synaptic side with the being the neurotransmitter vesicles and the post
12:49 side here with post synaptic densities. We also discussed this technique that we
12:55 talked about in the last couple of when I talk to you about the
12:59 clamp or wholesale patch clamp recordings inside recording outside of recordings. This is
13:05 wholesale patch clamp recording. It's done infrared microscopy. So you have an
13:10 camera with a set of mirrors that you to visualize neurons and record electrical
13:17 from these neurons without using stains. these are some important advancements, advancements
13:25 the current view of modern neuroscience from to clinical is from a single molecule
13:32 , studying the function of a single receptor multi educated sodium channel single synapse
13:39 may contain a variety of different protein , enzymes and their transmitters. Cell
13:47 cell networks of south and in the setting, non invasively positron emission tomography
13:55 be used to image activity, functional of the brain. In this
14:00 these hot heat maps show up because cells that are active and performing a
14:07 task that will be consuming a lot energy and it will be metabolically more
14:12 than the South. They're not performing not when the brain is not focused
14:16 a particular task. This is looking words exhibit a low listening towards temporal
14:23 Nicholas area speaking words broke this motor cortex thinking of words, you
14:30 see that the map redistributes itself because engages other parts of the brain that
14:36 not looking that are not listening but thinking about the words And I always
14:42 that the ultimate for 21st century is we could get this clinical level of
14:50 which is not a high resolution so can resolve things that a centimeter,
14:56 that millimeter if you use additional tools are powerful with these imaging techniques but
15:02 want to be able on the clinical to actually see what a single synapse
15:06 cell is doing isolated network and the function of the brand. I think
15:13 is the holy grail of neuroscience to able to understand that. And if
15:17 can do it non invasively with pet or M. R. I.
15:23 that would be really tremendous. That's that is up to you guys.
15:28 reality can also reshape these brain And we also talked about the fact
15:34 each function is observed by more than neural pathway. An example of that
15:41 speech areas. So if you lose area you don't lose all of the
15:47 for speech is just expression for Okay, so damaged doesn't mean you
15:56 all of the language abilities. You not comprehend speech very well. So
16:01 have multiple parts and multiple pathways and lobes and multiple organs in the brain
16:08 are responsible for the same functions such speech language, auditory motor and so
16:16 . These are different careers that can pursued in there since and will not
16:21 for questions on that in the And this pretty much concluded very easy
16:28 lectures and few chapters on history of . Pretty much so if you guys
16:36 mind, I'm gonna move into the lecture. Next two lectures where we
16:44 about neurons and glia and we pointed that neurons are similar to other cells
16:49 they also have certain specific things to . We talked about the micro rays
16:55 are a great way to understand the of genes that may be changing?
16:59 part of the pathology that can be expressed or under express. Talked about
17:05 brain drains a lot of energy. it has a lot of 80 P
17:09 . A lot of 80 P. a lot of a. T.
17:12 . The possibility of bi layer should viewed as a dynamic fluid mosaic model
17:18 which you have the lateral diffusion and of proteins and trans membrane elements.
17:24 underneath there you have the sight of elements. So we pointed out three
17:29 of micro tubules, neuro filaments and filaments as the three major site of
17:35 elements. We talked about how you micro tubular highways and the axons and
17:41 the micro filaments that are comprised of molecules are the smallest elements and the
17:46 dynamic elements and therefore when you stay for larger side of skeletal elements here
17:52 yellow, you'll see them closer and core of the south to the nucleus
17:57 the smaller active molecules will be distributed the edges in the outer edges of
18:02 south shaping the outer um plasma membrane the structure of the plasma membrane.
18:10 we talked about Alzheimer's disease. But of that, I actually showed you
18:14 different slide. I showed you this instead and we discussed several things where
18:22 started introducing clinical language a little What is the symptom, what is
18:26 cellular mechanism or the pathology on a level? You know what when does
18:32 disease occur? Is it a genetic ? You know, is it a
18:36 ? And then we pointed out two pathologies intracellular early neural liberally tangle formation
18:43 impairment of the plasma transport. Actually transport. Extra cellular information of
18:51 Amyloid plaques. Let's start impeding on function of the south. On the
18:56 of the south and actually cause these to produce fewer action potential. So
19:01 actually starts affecting the action initial segment the action potentials are produced and on
19:07 gross anatomical scale, severe advanced stages Alzheimer's disease result in a severe loss
19:16 particular gray matter and shrinkage of the that is illustrated here. So,
19:24 we discussed certain elements of the synapse but then we moved and talked a
19:29 bit about Kinison and diamond is important exa plasma transport. We also talked
19:38 retrograde transport of the sectional transport either from the film into the first retrograde
19:45 the nerve endings into the films can used for staining the circuits revealing the
19:51 . And we mentioned of horseradish peroxide and viruses can be taken advantage of
19:57 tagged viruses can be tagged with stains be tagged with fluorescent stains that will
20:03 help you trace the connectivity from a part of the brain into, into
20:09 network of the selma's where these nerve may be projecting to. We talked
20:15 how important the structure is of the the dendritic spines. And we also
20:24 about how dendritic spines have their own normal complexes in their own mitochondria and
20:32 which makes them somewhat biochemical independent. completely but have some independence and activity
20:39 the level of the spine itself like translational activity or energy activity on
20:46 And these dendritic spines are very important the wood expands when most of the
20:51 excitatory glutamate synopsis or inhibitory Gaba synapses the C. N. S.
20:57 form on the dendritic spines. And very important that the dendritic spines process
21:01 simplest correctly integrate that information in the and then respond accordingly. Here we
21:08 another disease in this case it was genetic disorder, talked about fragile X
21:14 that's down under the umbrella of autism disorders. And we just really focused
21:19 this case on the pathology, pathology the symptomology of mental segregation and the
21:25 of abnormal and good explain formations. so in this case we didn't go
21:31 the details but it's a genetic mutation causes a lack of a certain protein
21:37 and that protein is important in precise development of dendrites and their expanse.
21:43 positioning their densities in the in the of this normal development and this genetic
21:51 . You could have significant impairment in structure that we could experience that is
21:56 and um and other pathologies and other ease. So neurons have four functional
22:04 inputs, integrated unit which is the conduct all units and outputs. It's
22:09 little bit different for things like pseudo solar cells for example. They will
22:14 the peripheral axon and central axles. don't have a damn drive really.
22:21 And the integrated unit is still it's with the south. And then we
22:30 that once we got good at staining we wanted to see either different subtypes
22:36 neurons and just by staining. And saw that morphological lee, they're very
22:41 . So we then where on the of how can we really precisely determine
22:46 subtypes of neurons? And one way do that is by exposing their
22:50 their complete processes. Again this is bipolar cell, This is our pseudo
22:55 . Polar cell, brussel root, , south motor neuron, spinal cord
23:02 parameter cell of the hippocampus which we excitatory projection sound which is multipolar.
23:08 very beautiful park in the salad Up synapses it can receive. And then
23:17 talked about the fact that we can cells based on the morphology whether their
23:22 cells with the excited to inhibitory what frequencies or what patterns of action
23:30 they produce and what inter cellular markets have and this is all plays into
23:37 different subtypes of the cells we spend a bit of time on this
23:44 And yesterday when I did a review reviewed this diagram and then I had
23:49 question asking me so what are important on this diagram? So I hope
23:56 do this once today. The important in this diagram is that this is
24:03 circuit and then it's a circuit of and excited to ourselves. And the
24:09 important things are that the diversity, cellular subtype diversity comes from the inhibitory
24:17 and those are inhibitor into neurons and inhibitor into neurons that release, gather
24:23 inhibitor into neurons controlled excited to So the other important thing is excited
24:29 ourselves. The parameter projection cells will this information outside the surface. Okay
24:37 inter neurons the diversity is the inter morphological E. And the location wise
24:46 cells are not that much different from other. Um The other thing is
24:51 some cells may look alike exactly. number two and number four they will
24:57 in the same layer. Just parameter , they will look the same or
25:02 they will have their axles which are yellow caps targeting the same areas and
25:07 excitatory cells. But number two and four. The only way you can
25:12 them is based on the self specific and number two will contain a certain
25:19 like P. D. And number may not. So you are not
25:23 for knowing the names of these different whether it's PV cell per evolvement and
25:31 or alarm sell you're responsible for understanding concepts that the diversity is an inhibitory
25:39 . Their local the projection excitatory cells that information out inhibitory cells can control
25:46 these excitatory cells project out because they inhibit activity here and that you need
25:55 basically sell sell specific markers eroded to the subtyping of the cells that you
26:04 in different parts of the brain. this type of activities that you're seeing
26:11 , what we call canonical circuits or behaviors of the circuit. Because you
26:17 have this type of interactions also in parts of the brain. Like new
26:21 cortex will give it ourselves locally will controlling the output of the excited to
26:27 cells Uh and excited themselves are pretty . There's only just really two subtypes
26:35 they can be distinguished just by their markers. South one through 21 that
26:52 labeled. They're all in the only ourselves are the parameter ourselves. And
27:00 you can't label phenomenal sauce on the I cannot help you. The parameter
27:07 look like pyramids. So you should able to do it now. But
27:15 interneuron is coming very different shape. if I wasn't clear again these are
27:21 only excited for ourselves with the criminal . This is the only difference is
27:26 marker And they're flying by 21 different middle layer but they're going to types
27:38 themselves. Which is yeah. So once we know these cells, we
27:49 know that these cells produce different subsets voltage gated sodium and potassium channels that
27:55 talked about later. So therefore they be able to produce different patterns of
28:00 potential frequency ation. So the diversity you see here that there's one through
28:06 subtypes of inhibitory neurons, you'll find very diverse subset of inhibitory neurons in
28:12 New York Cortex. And this These different dialects and frequencies in the
28:18 of action potential firing comes from the cells. So you can think of
28:24 excitatory styles, projection styles are pretty and they have a pretty steady code
28:30 firing in a certain frequency pup pup pup pup pup pup but they get
28:36 by all of these different inter neurons that changes how the projection cell now
28:42 those outputs out. Uh We talked little bit about electrophysiology so this is
28:48 setup for things that you would record a patch clamp mode and other
28:54 Talked about glial cells. So pointed radial glial cells that are important for
29:01 and for the migration of neurons in early development. And we distinguish between
29:08 cells in the peripheral responsible for my illegal Deandra sides responsible for the myelin
29:14 in the cns and the peripheral Schwann would also be myelin ating projections from
29:20 brain stem cranial nerves like the facial will be Schwann cells and everything inside
29:26 cranium. Sir, balance cerebral will uh illegal deandra sides. We talked
29:34 uh de my elimination disorders and we out as a so this is an
29:42 . We are as a politic infection causes the Myelin nation and also degeneration
29:48 inflammation in the brain. What we about Charcot Marie tooth disease, which
29:55 a developmental disorder and the periphery lack Myelin Nation on the periphery. And
30:03 talked about multiple sclerosis, which is autoimmune disorder and that is demolish nation
30:11 the CNS accent. And we also talking about models and what is a
30:17 model in this case, we just talked about the shiver mayes and it
30:23 a good model because you have demolished and you have the shivering tremors that
30:29 be representing the human condition. And is a good model to study a
30:37 you're seeking for novel therapeutic treatments or cure for diseases like this shark got
30:44 to his disease would mostly a fact gate and cause bodily deformities because improper
30:53 from the nerves into the muscles causes cause it causes improper muscle contractions and
30:58 balance shape around it. So if seen some individuals and some of your
31:05 actually having this. This walk is pretty specific walk that charlotte Marie tooth
31:13 have and that's because typically it wasn't early enough and the only way you
31:18 adjust for it is with the braces there's no medicine or cure too to
31:24 it better. I would use slides this to summarize all of the
31:30 So a couple of students ask well you already explained how to study
31:34 the test, attended the lectures that the notes and watching the videos so
31:39 should be fine. But then somebody well how else can I study for
31:43 test? And I think that diagrams these are perfect, write down everything
31:48 know write down everything you know about little the underside and seeing us a
31:54 tender side if it's the marination of tender side, is that what kind
32:00 disease is it? Is it likely be encephalomyelitis? It's possible in the
32:04 . M. S. Multiple Yes. Uh track with narratives now
32:12 it's Schwann cells it's a new So write down everything about astrocytes controlling
32:19 activity controlling ions from later section potassium brain barrier, blood brain barrier,
32:29 glial cells scavengers repair moving. So yourself that you have these links to
32:36 and some literature and the class supporting and you can re watch these movies
32:41 your own. So these kind of like this diagram and there's a diagram
32:48 the action potential. You can use print it out or you know copied
32:55 digitally and use it for note you can take a lot of
32:59 you can summarize the whole lecture and sides on this slide and you'll see
33:04 happens to radio mobile cells were not . So add it in and the
33:10 real self functions that will help you lot. We talked about blood brain
33:15 and uh we came back and talked blood brain barrier again we said the
33:21 brain barrier's surprised you have these tie in epithelial cells of the astral real
33:28 and parasites. So and potentially even are involved. This is some,
33:33 new science is emerging, murals are be involved in the blood brain barrier
33:39 . And there's some very interesting stuff I was reading about today, a
33:43 that studies how real elements may be certain factors that affect the permeability through
33:50 blood brain barrier. Really cool So blood brain barrier is good because
33:54 is in your blood doesn't go into brain and gets checked by the
33:58 Check bonus with them. But it's a challenge. We described it.
34:03 when you're trying to treat a person through a tablet or injection into the
34:09 trying to treat somebody for neurological you have to consider that this barrier
34:13 become somewhat of a barrier to get medicines into the brain. And so
34:18 there should be a whole logic and behind drugs that are systemic drugs and
34:24 go into organs easily. Like a which you swallow something and the brain
34:30 things have to go into the blood then cross through the blood brain barrier
34:35 order to exert their effect. So also pointed out a couple of things
34:44 COVID. 19 Yeah. Sorry, just it's just three cell subtypes and
34:58 few real parasites of astra sides. and uh we also talked about blood
35:06 barrier when we talked about COVID-19 So the COVID-19 infections, what do
35:11 have to know? You have to that this nasal cavity and the nerve
35:15 , olfactory nerve endings that come They come in through these demonstrations in
35:19 crib reform play. This administration's here the crypt reform formation and this is
35:26 physical point of contact with whatever you inhaling central and especially through your
35:33 And therefore it's also a pathway for virus to get into the brain.
35:39 there is no ace two receptors we you a tense and converting enzyme to
35:45 on the nerve endings. But they're in the effective helium and the supporting
35:51 . So once the virus gets in and you can hang out these two
35:55 you can actually travel in higher uh in the brain. And they're the
36:04 very common way of getting the virus the brain. We care about the
36:08 . Not not just the virus but focused on the brain and the
36:12 Another way is by your email through blood and because if you have
36:18 if you have information you can have compromise to the blood brain barrier.
36:23 the blood brain barrier, those tight become leaky. Uh the control the
36:31 are out of order and they're not any more things that are going from
36:36 blood into the brain. Virus passes as it passes in. It can
36:42 target neurons and glia cause infections of selves and replication. All the good
36:48 that viruses do. We talked about in the periphery the most common main
36:56 are anosmia, loss of smell and , a loss of taste uh in
37:01 C. N. S. So it gets into the brain basically it's
37:05 and vertigo. And the funny thing I had incredibly strong vertigo after finishing
37:14 lecture on monday, it was so . I even I went to sleep
37:22 I was fine but almost thinking was to test myself with Covid. I
37:29 that part. So vertigo and Um you know some people when they
37:37 on the boats, they have the sea sickness, motion, motion sickness
37:45 something is moving. I'm the opposite I'm on the water. Like if
37:51 on the boat doesn't matter it's still weeks and I've done it and it
37:56 affect me. But when I'm on , land is moving. So I
38:04 I was a reptile in the past something like that, you know?
38:08 maybe efficient form of life. So some of the major syndromes that we
38:15 mentioned. William Barson syndrome, I want you to know. But the
38:19 of the matter that major syndromes in cns are pretty bad stroke,
38:24 hemorrhaging, accurate necrotic encephalopathies, bad , you know. So it's very
38:31 things that are emerging about this what it doesn't bring and like I
38:35 sometimes being viewed now as a coagulant off the body and the brain.
38:42 we'll come back and talk about some these things for now, I'd like
38:47 you to know that there is an through the nasal cavity, basically that
38:52 is different types of entries by re direct through the crib reform plate that
38:58 is loss of smell and taste. already got a headache and then on
39:03 cns part more complex things and that needs an ace two receptor to enter
39:09 the brain hang out to the brain . Alright, so after we discussed
39:16 of these good things in neurons and , we started moving into the neuronal
39:22 addressed and talking about this wrestling membrane and even distribution of charge and we
39:29 the circuit. So I said please down all the notes on these three
39:33 subtypes dorsal root ganglion cells, considering polar salts that are half Aaron's carrying
39:38 stimulus information into the spinal cord they , deliver mate, they can activate
39:44 neurons that are multipolar cells to release seal napoleon on the muscles that are
39:48 excited for it. It's a very synapse because there's no inhibitor synapse
39:53 It's only excitatory motor neurons do not an inhibition of muscles. So the
39:59 way that the muscle closing muscles can relaxed is through the inhibition and the
40:03 inter neurons of the spinal cord, are also multipolar cells. And unlike
40:09 inhibitor into neurons in the cns and spinal cord, these inter neurons released
40:14 the inhibitory neurotransmitter and by releasing, , they will inhibit this motor neuron
40:21 there'll be lack of activity from this neuron, therefore allowing for the opposing
40:25 to relax. And this relates to reflex arches we discussed. So
40:30 these three different subtypes of cells and they do for the chemicals we talked
40:37 , sodium potassium, calcium, The pumps. We talked about how
40:43 proteins are built from the amino the building blocks into the tertiary co
40:49 structures and then these subunits come together remembering channels and ions can pass through
40:58 fossa lipid bi layer. You have pass through the channels and so you
41:03 these channels that are selectively selected to selected potassium calcium and so on.
41:09 the channels that we're talking about the membrane potential. Some of them are
41:15 channels like potassium channels. But for action potential. We're talking about the
41:20 that are volt educated. That means channels will be open. The gate
41:26 will be open due to voltage and it will allow more specific flux of
41:32 specific ion because it has a selectivity in this case for the sodium ion
41:39 it will have negatively charged amino acid . Uh specific locations that will allow
41:47 the sodium ion to pass through on law. D equals IR. Conductance
41:54 one over. R. Or eye G times V. In conductance.
42:02 in general in the brain, what have is we have chemistry concentration gradient
42:10 we have electricity because ions have a and concentration gradient will be driving ions
42:19 concentration from high potassium into low potassium . If the potassium channel is open
42:28 not all of this, potassium is to cross over because there's electrical force
42:36 the positive charge of crosses over from side to the right side starts repelling
42:42 the potassium from crossing over. And is the equilibrium potential or equilibrium potential
42:50 for each ion diffusion alone and electrical are equal and opposite to each
42:56 And there's no not bionic movement. for the major ions we said that
43:05 cell extra cellular has a lot of chloride, uh it has the highest
43:11 for calcium on the outside of the versus the inside of the cell.
43:15 it is loaded with potassium inside of cells. So you should know the
43:22 even the molar concentrations. This is outside five versus testament side 100 or
43:29 approximate ratios of these. Because you not need to calculate the equilibrium potentials
43:34 you will need to recognize uh the values for equilibrium potentials for ions.
43:45 I have written in my slide. actually potential slide And also approximate ratios
43:54 their concentrations on the inside versus the of the cell. Just remember the
44:00 environment outside neurons, the sodium chloride a lot of calcium and addressed it's
44:11 channels that are open so potassium is the conductance is compressed to calculate nurturance
44:18 equilibrium potentials, equilibrium potentials are calculated each ion potassium sodium chloride calcium.
44:27 have the calculation for each 1 to or three rtz epilogue of Ireland outside
44:33 iron on the inside. So this for an individual item, liberal potential
44:38 that island which you can calculate. this abbreviated to three or three or
44:45 in 61 54, 61 54. bus and a K one plus fluoride
44:52 one year becomes minus 65 calcium two becomes half of 65 54. And
45:00 one of these ions will have their equilibrium potential values. So you can
45:06 that they're equilibrium potential values shown here they're somewhat different than other slides.
45:14 another slide with Hodgkin and Huxley shows for Uh sodium equilibrium potential for sodium
45:20 positive 52 here. It's calculated positive . And that's why when I ask
45:26 exam questions I want you to go the scales and okay Okay hold on
45:42 . So you calculate learns equation, the individual equilibrium potential values. And
45:50 use Goldman equation to calculate G. . Which is a member of
45:55 Yes. Mhm. Yeah. And equilibrium potential values. But the best
46:10 to study this is and and this slide just shows that to calculate the
46:18 membrane potential you need to incorporate potassium sodium. So it's not equilibrium potential
46:23 one. I'll you also have to into account the permeability ratios and addressing
46:29 potential potassium the membrane is most permeable potassium. Um And this premier abilities
46:37 change as the cell d polarizes and generating the action potential. Yeah you
46:46 need to use ganglion inhibitor into neuron the spinal cord and motor neurons in
46:59 spinal cord. Thank you all this stuff we learned about. Again this
47:15 the differences between the Lawrence equation, potential for what I owe versus membrane
47:25 calculation which is adjusted and ernst equation with the permeability term addition of the
47:32 concentrations we call that this is very that ionic concentrations on the outside and
47:39 inside are controlled and they're controlled in by real cells potassium concentration from its
47:47 physiological $5 million. There is up 10 or 15 $20 million. It
47:53 de polarize the cell, This is number of potential. So if you
47:58 the extra cellular outside potassium and increased of potassium concentration, we can be
48:06 . The sell by 20 million If the selfie polarizes to -45 can
48:11 produce an action potential. So the doesn't allow for this to happen and
48:17 astrocytes come in and slurp up and buffer this potassium through its own extensive
48:25 and also the interconnected networks with other . Mhm roderick Mackinnon. Really cool
48:34 . I encourage you to read his of discovery. Uh he was in
48:40 quest to solve the structure of the channel. So he used the genetic
48:45 directed me to genesis, you use shaker fly model. It's a different
48:51 . Why would you shake a fly ? What is a shaker fly shaker
48:55 model actually is a model of a like behavior because the flies are shaking
49:01 they have a mutation in the sodium potassium channel. So these gene mutations
49:08 affect different parts of the channel, amino acids that you find in the
49:14 flies. They have amino acid sequences can be conserved in humans. And
49:22 means that roderick Mackinnon was using site me to genesis. He was using
49:29 . So toxins was using electrophysiology was to see who communicates different parts of
49:35 channel, fine binds different substances, different parts of this channel, how's
49:40 going to affect the flux of ions the conductors through that channel And that
49:45 start applying the three dimensional structure of channel. And he was not happy
49:52 that completely. So he used another , extra crystallography in order to visualize
49:58 challenge. So just a great example somebody on the quest to solve solve
50:08 problem or solve the structure of the using different techniques. Now action potentials
50:18 we discussed uh very important because they're fast potentials. We talked about the
50:28 forces. Remember the driving forces is difference between voltage and equilibrium potential forgiven
50:35 . So if you're recording potassium currents are situations in which you're gonna have
50:42 conductance G times V or C. . Like in this instance there is
50:50 difference between minus 80 and 20 million minus 20 million volts. So there's
50:56 driving force here and there is a for potassium and the current is higher
51:03 than zero But at -80 which is reversal potential for potassium also call it
51:11 . In my diagram this reversal potential is zero gear because the equilibrium potential
51:20 of minus 80 and Vienna's of minus . So this is zero. Although
51:25 channels open and there's conduct us through channels, there's no net movement of
51:30 . So there is no current flux in one direction or the other and
51:35 overall current zero. So this is driving force. Now remember that at
51:44 the cell is most permeable to potassium phase sodium falling phase potassium again,
51:52 you're having difficult time understanding these reversal , I would encourage you to go
52:01 this power point diagram that you have look at it this way that these
52:07 all of your equilibrium potentials for ions membrane potential of minus 65 action potential
52:15 minus 45 million balls. This is . M. Measured in billables reversal
52:20 sodium positive 55 Equilibrium or reversal potentials calcium positive 1, 20. If
52:29 have a strong enough equalization with a deep polarization you will open voltage gated
52:35 channels as you open voltage gated sodium , it will be more globalization.
52:39 voltage sodium channels open more equalization and at this level here has a very
52:46 driving force. It's the difference between . N. A. And where
52:50 number of potentials at the moment. sodium ions are flocks. Ng sodium
52:55 are opening and sodium tries to drive DM into its equilibrium potential value.
53:01 as you learn a sinner sodium channels , it also closed And also as
53:08 membrane potential D polarizes the driving force decreases at this level here, the
53:15 force for potassium is huge because it's difference between the and the deliberate potential
53:21 potassium and potassium channels are now open potassium takes over and drives this member
53:27 potential that then gets restored to distrusting and potential values with redistribution of charge
53:34 in part by the slow and Ak . So uh this is I think
53:46 good way to start thinking about driving . Just looking at this diagram.
53:55 other important concepts that we discussed was number of equivalent surface. So I
54:00 you should know what the resistor or with the battery. You should know
54:06 the cell has these resistive capacitive So it has capacitors and neurons are
54:13 good capacitors that can store a lot charge, separate the charge and these
54:19 the palms here you will have the conductance. Is potassium moving from inside
54:25 cells to the outside, each eye each conductor having its own battery because
54:29 battery is the electro motive force. that charge the charge on the positive
54:35 the negative and it depends on the of the ion and which side is
54:41 on two. So, recall that have these resistant capacitive properties that the
54:48 cells will have higher resistance and the cells will have larger capacitance ability to
54:56 it more charge. We looked at ivy plots which are basically um current
55:05 plots, We discussed them quite extensive and maybe two lectures ago.
55:13 so if you are somewhat confused about , please review that lecture but you
55:20 know that there are some I. . Plots that are linear, some
55:24 plots that are non linear that are these ivy plots represent overall member and
55:30 of the cell. And each one these ivy plots can also represent a
55:33 channel, a sodium channel, potassium . And that the overall number of
55:39 of the cell will very much depend the types of the channels and the
55:43 of the voltage current relationships that they generate depending on the types of the
55:49 they expressed. Uh This is again reminding that at lest the cell is
55:57 permeable to potassium during the rising The cell is most permeable to sodium
56:04 the permeability for chloride doesn't change The chloride doesn't play into the dynamics
56:08 action potential. March. And if want to run this calculation without chloride
56:15 with chloride, you'll see that this contributes maybe a change of one or
56:20 million volts and the membrane potential. , it's largely determined by sodium and
56:25 with the small input from chloride voltage . The thing that you have to
56:32 about voltage clamp is not the But the fact that voltage clamp is
56:36 technique that allows you to clamp the , your whole the voltage is desired
56:42 and that allows you to isolate individual or individual passion clams without that you
56:49 do it. So you need to the V. In order to record
56:55 R. You don't know there are neurons and you can know that
57:02 Which is the current. So you to control the voltage. From previous
57:08 . You were injecting current i in voltage by knowing the R.
57:15 Equals Ir. So you have to on two sides of the equation.
57:20 voltage plant, you know, on voltage clamp side of the equation.
57:26 this voltage clamp technique was used by and Huxley to tease out the dynamics
57:32 the kinetics of inward sodium and outward currents. Again, without this voltage
57:39 , you cannot visualize how the cell in different holding potentials. You just
57:46 the potential injecting the current but you're clamping. So they saw that there's
57:53 sodium inward turn followed by outward and potassium current. And at the rising
58:03 of the action potential is a summer currents flowing through all of the sodium
58:11 that are on that path of the . That piece of the membrane.
58:15 can see sodium channels open and close quickly. But they open fast potassium
58:22 . This is the same stimulus potassium channels take some time to
58:27 So they're basically delayed in opening but once they open their prolonged the opening
58:33 prolonged and the flux of potassium is through these channels. So they have
58:39 kinetics sodium is responsible for inward flux the deep polarization and you have potassium
58:47 during the re polarizing portion of the potential, sodium channels have a specific
59:05 and we talked about this voltage sensor s. four and this voltage sensor
59:11 keeping the gates flows that is drawn the negative charge that is accumulated on
59:16 inside of the plasma membrane. That's subunits subunits, six trans member eight
59:24 . You have the for loop between five and 6. Um these are
59:30 gated channels. That means that a in voltage from -65 to -45 -40
59:38 what is going to cause these channels open. They're gonna open their gates
59:44 of the change in the voltage change the voltage again will happen because they
59:49 synaptic inputs that are coming into the that are d polarizing the south.
59:55 if they de polarize the sound, going to be now less of a
59:59 charge on the inside of the plasma . This voltage sensor is drawn by
60:04 charge and when there's a reduction in negative charge on the inside of the
60:08 membrane, this voltage sensor gets repelled starts shifting upward. There is an
60:18 amina assets inside the protein channel that positively charged residues and they start reacting
60:29 the accumulation of positive charge here and they shift upwards the cause of protein
60:36 change and the podium opens the gates that same conformational change that causes the
60:43 of the gates also promotes the second . sodium channels have two gates.
60:49 you do polarize it, you cause shift in the Baltic sensor and you
60:55 the activation gate so now the channel open. But as soon as you
61:01 this conformational change that encourages this swing for this ball and chain to swing
61:10 inactivate the channel. So number three channel is inactivated. That's why sodium
61:15 closed quickly. Basically the same voltage that slides up and opens the gates
61:21 causes the closing up in activation Now the only way that you can
61:26 the inactivation gate is you have to the voltage sensor back down and the
61:31 way you can do it is if build up enough negative charge on the
61:34 side of the membrane, which means have to hyper polarize it again to
61:38 resting membrane potential level of minus 65 volts. And as you hyper polarize
61:44 , this voltage sensor start sliding This confirmation all change now removes the
61:52 and chain in activation gate or causes inactivation and encourages the closure of the
62:01 gates. So sodium channels have two basically one is activation, one is
62:07 activation and this is how it's regulated then activation is the reason why sodium
62:13 close very quickly and why sodium never its own equilibrium potential during the rising
62:19 of the action potential patch clamp techniques looked into different patch plan techniques please
62:27 this. You can be cell attached out will expose the inside off the
62:33 channel to the outside environment which is experimentalist environment. Or the Outside out
62:40 expose the outside of this protein channel the outside experimental environment. Toshio Narahashi
62:48 , great story of tetrodotoxin toxin. Simpson story? Uh Cartoon entered the
62:57 is a specific blocker for voltage gated channels and it will block these
63:07 But there's other blockers like tetra methyl that will block potassium channels. So
63:12 talked about substances in nature, biological chemical synthesized substances that can affect different
63:19 and by having the combination of different . You can start deducing three dimensional
63:26 structure by deducing where they bind and they affect the structure of these
63:31 And we talked about the fact that are also called antagonists and something that
63:38 the channel. There are the substances can encourage the channel to open.
63:41 called agonists or activate that channel There agonists I. D. Plots again
63:48 reviewed here and once again this is linear plot and this is a rectifying
63:55 . Uh This channels voltage gated sodium also has a binding side for
64:02 So we stressed in the slide lidocaine a local anesthetic that will block the
64:07 from the peripheral nerve endings indicating the or from your teeth. For example
64:14 talked about Besides this very large So if you find some small presence
64:20 some chan on a small patch of member in neuron and mammalian brain,
64:24 complex system. You may want to into some simple, more simple system
64:29 the frog who sides that are very over express a channel. Study it's
64:35 and go back to a more complex because now you can maybe better isolate
64:42 the currents that you're seeing that will specifically from that channel. When we
64:47 about the fact that once neurons receive of the inputs excited during inputs,
64:53 produce action potential interaction initial segment. is where the action potential happens.
64:59 reason why it happens there is because has a lot of voltage gated sodium
65:03 , potassium channels action potential that is propagating. The purpose of this forward
65:10 action potential is to cause deep external terminal release the neurotransmitter. So
65:17 action potential gets regenerated and loads of that are also loaded with voltage gated
65:23 and potassium channels that produce action potential the external terminals. In addition to
65:30 potassium voltage gated channels will also have numbers of voltage gated calcium channels which
65:36 necessary for vesicles fusion and vesicles So there's a strategy of where channels
65:43 being placed, you will want to up the accident initial segment with these
65:48 because that's what produces the spike and not just one spike. It's actually
65:55 spikes. We have high threshold channels maybe 1.2 that require a lot of
66:02 high levels of low threshold and maybe . And this illustrates that one
66:09 even in one area, acts an segment co expresses two different subtypes of
66:16 educated sodium channels and the one that low threshold which is located further away
66:21 the selma, is the one that the forward propagating spike and the one
66:26 is high threshold which is closer to selma, initiates the back propagating
66:32 The forward propagating spike is on the of 100 million bowls. The back
66:36 spike is on the order of a million holes. So if the function
66:40 the forward propagating spike is to release , the function of the back propagating
66:50 , the function of the dark propagating is to make sure that there's tuning
66:55 the activity. Because if these networks talking to the cell and they have
67:00 way of knowing that the cell produces action potential because it sends an action
67:05 down to downstream the axon and excite other self. But these inputs have
67:11 way of knowing there was some electrical in the cell unless they receive this
67:16 propagating spike, they receive this back spike at the right time, very
67:22 time inputs coming in and the cell it becomes meaningful. And those networks
67:28 are communicating to these neurons are going be strengthened that they're going to be
67:32 efficient. And if the cell is all of these inputs and stay silent
67:37 like you're talking to a person and person stay silent for five minutes so
67:41 think they don't want to have a and you walk away. So eventually
67:45 ones that don't communicate they don't react the inputs are not strengthening. And
67:51 this is part of the plasticity plasticity learning. This is really plasticity
67:57 Your synopsis is learning and memory is cellular substrates of learning and memory and
68:02 need these things to be happening very . Pre synaptic signaling, post synaptic
68:08 and information that travels and informs the that yes I've been activated. There's
68:15 challenge of the day here we'll come and talk about this concept on the
68:19 section of this course. So you're responsible for the challenge of the
68:24 And the very last concept that plays the previous concept is the fact that
68:31 cells can express the same channel in locations and if it does so that
68:37 these cells are gonna have slightly different properties. Different I. D.
68:43 different way of firing action potentials and cells will express these channels just in
68:49 accents And each neuron subtype that we're at these 21 subtypes in Hippocampus they
68:56 express up to 12 up to Welcome to the party up to
69:02 Up to 20 different voltage gated sodium , voltage gated channels. It can
69:10 sodium potassium calcium. And these different will have different I. V.
69:18 . And these different I. Curves will account for the ability especially
69:22 inhibit their internals to produce very complex patterns of the actual potential. So
69:28 think maybe there was a question in audience but I'm gonna stop here and
69:35 actually have to save this lecture and be happy to take questions after I
69:41 the recording. If you don't mind on zoom or anybody in class and
69:47 I missed your question you want to up and ask me, you're welcome
69:50 this one. Good luck on the
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