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BIOL 4315 & 6315 Neuroscience Mon-Wed 1-2.30 PM - NEUROSCIENCE MIDTERM I Review
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00:02 Welcome to neuroscience. Midterm one If you recall this is a slide
00:07 I showed you early on and the was depicting a lot of information that
00:12 will be studying over the course of semester and in particular neurons synaptic transmission
00:23 neurons different centers, nuclei parts of C. N. S. That
00:28 responsible for different functions as well as cellular subtypes. So when we talked
00:37 history we said the entrepreneur nations were the original neurosurgery is to alleviate
00:45 pain or fluid build up inside the or something that could be done following
00:50 hemorrhaging of the brain. Imhotep was person that was studying initially the anatomy
00:57 looking at the traumatic brain injuries and to describe the anatomy of the brain
01:02 ancient Egypt. But the Egyptians believed heart is the most important organ of
01:07 brain. There's a difference here in Greece where ancient Greeks start believing that
01:13 brain is the major controlling organ of body and with the renaissance times will
01:18 start seeing the glimpses of anatomy. vesalius describes this ventricles here that are
01:25 in the center of the brain and predominant view of the brain is based
01:31 this ventricular localization of brain function. he also distinguishes between gray and white
01:38 , certain properties of gray and white and how different uh potentially different functions
01:46 these different parts of gray or white . Let me pause this for just
01:54 um we studied that basically uh since understood some of these concepts about
02:04 I may have failed to suppress some but talked about renada cart I think
02:12 I am soon the fluid mechanical model the body. The discovery that nerves
02:20 our channels but they can generate electricity our current generators and conductors. We
02:28 about major subdivisions of the C. . S. Cerebrum, cerebellum,
02:33 , spinal cord, peripheral nerves coming of here, major divisions of the
02:41 and to the frontal, parietal, temporal cerebellum and brainstem regions and from
02:48 spinal nerves. We actually talked about different subtypes. Later when we discuss
02:53 reflex arch of the dorsal root ganglion , the sensory component and the motor
02:59 as the motor component. Then we the chronology which was basically trying to
03:05 different brain functions in different parts of brain but they were looking for the
03:10 of these functions based on the surface the skull which was wrong and correct
03:15 of doing that. And finally with area localization of function came into light
03:23 broke. This area is responsible for aphasia Wernicke s area for receptive aphasia
03:29 we also discussed the gnomic and global and this gauge was a very famous
03:35 because she showed that a significant brain cannot necessarily affect vision. Of course
03:43 lost. I but he still has hearing but it can affect your
03:51 it can affect your control, your control and these examples. You're also
03:56 there's multiple areas that are involved in activity processing our brains develop on the
04:05 and the reflection of what develops on outside. How we develop on the
04:08 is very much based on this environment allows us to survive and procreate.
04:16 talked about Ramona ca hall, the theory, there's this neuron doctrine
04:21 believing ramon alcohol using golgi stain by mentor, believing that units neurons are
04:29 units, Charles, Sherington corning the synapse ra Monica hall, predicting that
04:37 flows into cells. Get processed into and get out, put it through
04:42 black axons onto the adjacent neurons. he initiated this belief the theory that
04:48 connections are plastic. They can change theory of elasticity. Nestle stain is
04:55 to stay in all of the south it's a really good way to define
04:59 cider, architectural arrangement and obedient Use them for these side architect tonic
05:05 to describe essentially different functional areas and functional areas. In part would be
05:12 by observing variations in the structure of or structure connectivity influences function. We
05:19 about live microscopes not being able to space between neurons, which is synapse
05:24 20 nanometers, but electron microscope being to do so and being able to
05:30 us different aspect neurons such as uh red ink spines. Uh You don't
05:38 . Please make sure you're muted. We these days we don't need to
05:46 and basically don't need to use We can use infrared microscopy to visualize
05:54 neurons and target them with micro And later we talked about how you
06:00 record using micro electrodes and the types reporting you can do like patch clamp
06:05 later in the course and the current at different parts of the brain responsible
06:10 different functions and experimental level. We a view all the way from a
06:14 molecule single cell, single dendritic spine cell networks, the macroscopic views.
06:21 in a clinical setting we're trying to the problems in the brain potentially in
06:28 activity of the brain. And by at the functional imaging um such as
06:33 emission tomography and there are different disciplines stamp from neuroscience. So this concludes
06:42 review of the history of the I've never seen the chart if there
06:50 any questions. Okay, I don't there's any questions. So I'm gonna
07:00 on to our next topic and actually next topic since we introduced the book
07:09 started talking about neurons and glia neuronal . I said, well, you
07:14 what it's really important for you to about Covid 19 because covid 19 infections
07:21 still present. A lot of us lived through Covid 19 infections experienced some
07:27 these symptoms that we've discussed. And was really important for me to point
07:32 that there are multiple ways by which virus can get in to the
07:41 And in particular we talked about Vira virus and blood can with a significant
07:48 load can reach. The brain virus also enter through the nasal cavity and
07:54 crib reform formation and through the openings in the skull that provide all the
08:03 receptor nerve endings to project right there the upper nasal cavity. And so
08:10 is a pathway to get into the directly through the nose into the olfactory
08:17 here that we'll discuss in the second Great reform plate and the olfactory
08:23 Now also there is a barrier blood barrier between the brain and the blood
08:29 with hypoxia damage. So if you infection in the lungs and you have
08:34 access to oxygen with hypoxia, you blood brain barrier and allow for further
08:41 . An entry of the virus of virus has to enter and hang on
08:47 these two receptors, neuronal tissues in brain. These two receptors are found
08:52 the body. The angiotensin converting enzyme receptors involved in blood pressure regulation.
09:00 so if you look at the afi here, the olfactory epithelium see that
09:06 olfactory receptor neurons and orange actually don't these through receptors but the other cells
09:15 spectacular cells so other cells in the epithelium but not the olfactory receptor neurons
09:23 these two receptors and so the entry the epithelium of this virus can infect
09:30 cells and these cells and how these receptors and are infected. The trans
09:35 means and other means can in fact a factor receptor neurons causing loss of
09:44 also known as anosmia. So the brain barrier as we discuss consists of
09:52 yourselves and also in the brain side have the astra acidic and feed processes
09:57 provide for one of the checkpoints into brain. This is compromised. The
10:03 junctions are compromised. If endothelial cells contains two receptors and glial cells get
10:10 with the virus, then there's another of transferring a virus into the
10:16 breaching the blood brain barrier or the infections a variety of different real cells
10:22 we discussed and we'll come back and about a little bit. Then we
10:26 about how there are different outcomes basically the C. N. S versus
10:32 . N. S. In the nervous system. The two major symptoms
10:38 an Austrian Negussie, a loss of , loss of taste and in the
10:43 . M. S. Most common and vertigo. But the major symptoms
10:48 the CMS which will focus here meningitis, acute necrotic and the
10:54 So information of the brain infection by virus can lead to encephalopathy can lead
11:01 neuronal degeneration and also emerging as it tied to the blood system. So
11:07 me a smell loss of smell and see is loss of taste. So
11:13 on the peripheral level you see mostly sensory dysfunction in the central level.
11:18 see that it can lead to breakage blood brain barrier apoptosis, accurate necrotic
11:26 emerging cerebral edema swelling, uh neural in the brain and neuro degeneration or
11:34 death. So these are some of key things that I'd like for you
11:38 know in this particular section. Let see if there is any questions on
11:48 not. And I'm moving on to and Greer and neurons and Greer We
11:58 about others about 10% of all of cells in the brain and neurons and
12:03 a lot of abundance as we all counting 90% of all the other
12:10 Some of the neuronal features are like cell features and then some others are
12:15 . Dendrites and spines. Excellent initial . Excellent initial segment two here Axon
12:22 for accident, initial segment and you some organelles, cell fundamental organ other
12:29 . But you also have the great eines which are pretty unique to
12:32 And then you have these axons that insulated where the conductors of action potentials
12:38 take place and the synapses that are specialized places of communication between the pre
12:44 external terminal and the synaptic receptors and pot synaptic neuron some basic genetic things
12:52 we are all well familiar with the micro race. We talked about how
12:59 they be used in detecting increased expression decreased expression in groups of genes and
13:06 rates could be designed to track thousands genes. And you could compare normal
13:11 versus diseased brains or normal brains versus conditioned brains and so on. Basic
13:19 . Also finding other um cells neurons a lot of energy. So eight
13:25 will be produced by mitochondria and situated the specific regions in the south.
13:33 gave a lot of emphasis to this of fluid mosaic model of the
13:39 Asthma membrane, which is a possible bi layer made up of the hydra
13:44 heads and hydrophobic fatty acid tails and formation of these possibilities violators, insertion
13:52 the cholesterol molecules, trans membrane trans membrane channels, membrane associated
13:58 glycoprotein, carbohydrates. They're all fluids this possible lipid bi layer. They
14:06 move within this possible lipid bi They can be inserted, they can
14:13 internalized. There's a lot of movement plasticity in the plasma membrane supporting the
14:20 underlying structure of the outer membrane boundaries the side of skeletal elements. We
14:26 . Micro tubules is the largest elements are involved and um external transport in
14:32 , cellular transport in general, micro highways, neuro filaments and the medium
14:39 filaments and microfilm is comprised of the molecules that are found in the outermost
14:46 of the architecture morphology of the plasma . Most mobile smallest units ready to
14:55 arise to extend their chains or deep arise and make them shorter as it
15:00 be And the side of skeletal elements underneath the plasma membrane. The structure
15:06 the plasma membrane can also rearrange the area can be increased or decreased.
15:13 this is very important because we discussed uh slide on the fact that if
15:25 have Alzheimer's disease, we talked about of Alzheimer's disease and we related that
15:34 the side of skeletal elements that we're . And in particular we talked about
15:40 things and the stores about the diseases particular, we talked about several diseases
15:46 they said you always have to think . Is it a developmental diseases?
15:52 a middle aged person diseases it caused trauma is caused by infection. Do
15:57 know the causes of these diseases? is it likely to express itself?
16:03 this is most likely to be most and prevalent? And what age population
16:10 a genetic component to that disease? so when we talk about Alzheimer's
16:15 it's prevalent and older population it has tangles and the tangles will start impeding
16:25 the plaza make and cellular transport and functions inside the cells inside the cells
16:31 the cells. And the formation of beta amyloid plaques and the formation aggregation
16:38 this abnormally cleaved protein. The formation these plaques can start physically impinging on
16:45 surrounding structure of neurons and synaptic communication advanced stages that we said that their
16:54 stages and we talked about some symptomology Alzheimers disease, loss of short term
17:00 , disorientation early stages. Advanced stages just loss of the ability to function
17:07 and the body and severe alzheimer's and gross level will present itself with a
17:13 growth philosophy, neuronal tissue and shrinkage the gray matter in particular. So
17:20 is the slide that goes along with uh following lecture to replace the
17:27 this following slide to replace the slide talked about synaptic transmission so that the
17:35 of the external terminal you will have vesicles that contain neurotransmitters that will buy
17:42 the pot synaptic receptors. There are types of transport and terra grade mediated
17:48 connection and retrograde mediated by dining. There is uh axl plasma transport that
17:56 slow and there is actual plasma transport is fast. And in some instances
18:03 can take advantage of these different modes travel by certain substances retrograde versus interrogated
18:13 in particular retrograde transport, horseradish These herpes virus rabies virus can
18:21 We travel from the periphery into the . So that's a really good tool
18:28 use these to understand for example what of the skin muscle or other part
18:36 the brain that's communicated that's connected to where the soma as that are coming
18:42 talking to this with their axons and if you inject it, it will
18:46 retrograde lee taken up, talked about importance of dendritic spines as the most
18:53 units and somewhat biochemical independent by containing polarized somo complexes and containing mitochondria under
19:02 spines that come in different shapes. precise arrangements of these spines is very
19:08 for normal development. And here we that there are some mental retardation in
19:17 fragile X syndrome and fragile X. you have is essentially a uh abnormal
19:29 of dendritic spines. The shape of pines and the distribution of these spines
19:36 what you also have is mental So we talked about fragile X syndrome
19:45 and we talked about the genetic We talked about how to develop mental
19:52 , how it falls under the umbrella autism spectrum disorders broadly. And if
19:57 have these abnormal expires, that's where lot of excitatory glutamate synapses are
20:03 a lot of inhibitors synopses are formed well and these spines are abnormal.
20:10 means the connectivity, the communication, processing, it's going to be
20:15 The neurons leading to this mental developmental , fragile X syndrome. General neurons
20:23 four units that input and integrated to on the output regions. Can then
20:29 classifying neurons based on their different What are some other properties. Well
20:34 of them look differently more theologically. you can classify neurons based on
20:40 When we talk about bipolar cell. about sudo, you know polar cell
20:45 unit polar cells ganglion cells or dorsal which is dorsal root, ganglion cell
20:51 there's a lot of multipolar cells. is a motor neuron, a spinal
20:55 and you need to know what types neurotransmitters the cell's release and whether the
21:01 inhibitory. And this is the parameter of the Hippocampus which we also
21:06 And you can see that some of cells like Kenji Salad, the cerebellum
21:10 contain up to 150,000 synopses to all this information has to be integrated very
21:16 within the cell body to decide whether axle is going to produce an action
21:21 and communicated to the interconnected cell So these action potentials will be communicated
21:28 certain different patterns. So some of cells we talked about are distinguished by
21:34 fact that their projection cells to project interconnect different areas of the brain into
21:39 are located locally. Cells are can some classified based on excitation glutamate cells
21:48 inhibition, Galba cells. Um They contain cell specific markers for certain
21:55 neuro peptides, calcium binding proteins and molecules that they express. Because different
22:01 subtypes express a slightly different subset of . In the end when we look
22:07 circuit like hippocampal circuit, we talked three predominant layers start already adam pyramidal
22:14 orients and we talked about that on excited projection sells the parameter cells we
22:21 have three different subtypes of cells live three different layers. Ready Adam medaglia
22:27 and some of them contain Calvin din their C. B. Plus
22:31 B. Positive and others do not co dependent. So the C.
22:35 minus, they do not express Calvin . And this was the three
22:39 If you make the excitatory cells will information from this area of the hippocampus
22:45 the interconnected regions. And here the shows that within the same hippocampal circuit
22:52 have About 21 different subtypes of inhibitory although there is a lesser number of
22:59 cells overall only 10-20% of the total population of these networks. These cellular
23:05 are dominated by the presence of the pyramidal cells but these inhibitory cells that
23:11 in at least 21 different subtypes that be distinguished based on their morphology and
23:17 location based on the E cielo Which is the synopsis the synoptic projections
23:24 they're formed in the prom. It'll where they are formed in the pyramidal
23:28 or where they are formed in the item layer on the dendrites of the
23:33 cells and finally by their specific cellular . So having all of this information
23:41 morphology of the cell connectivity with the cells or not. Whether the excitatory
23:48 projection sells all of these inhibitory cells inter neurons are staying locally and controlling
23:56 network activity and processing local network And if we look that the cells
24:03 receive the same stimulus but they will very different output of the action potentials
24:09 if we look in different circuits and which is the cortex we recall is
24:14 parameter cells will pretty much have one of dialect that they speak and as
24:21 as the frequency of action potentials and pattern of action potentials that they
24:26 And so the variety and this dialect the patterns and the frequencies of action
24:32 firing comes from the inhibitory into So parameter cells will be speaking pretty
24:40 the same dialect of action potentials and of these inhibitory into neurons will be
24:46 different dialects. And because of the of these dialects were able to process
24:52 lot of different information in the And later we talked that these action
24:56 patterns and these dialects are produced in certain way because these cells will express
25:03 voltage gated sodium channels with certain voltage . V. Voltage current properties.
25:10 . And that they're all going to slightly different channel kinetics in these vault
25:19 channels that will account for the ability some of the cells to produce very
25:25 rates, continuous rates of action potentials other cells producing much slower firing rates
25:33 the action potentials. We can study again using electrophysiology using patch climb
25:40 And this concluded our section on We next moved to glia. We
25:45 about several types of glia. The way to review this is to actually
25:50 at this diagram here talked about micro that's involved in neuronal repair following damage
25:58 is involved in cytokine and inflammation. about illegal emphasize in the cns are
26:05 for my elimination exercise. Are responsible synaptic genesis, synaptic transmission, control
26:12 neurotransmitters around the neuronal synopsis as well control of extra cellular ionic concentrations and
26:22 their empty to the blood brain barrier cells here we talk to this pluripotent
26:28 and the last type of cell that didn't mention. This radial glial cells
26:33 are involved in guiding neurons is they're and their processes are outgrowing and positioning
26:40 in their final destination as the brains developing. So if in C.
26:46 . S. We have my elimination liquid undersides in the P.
26:50 S. We have my elimination by cells, liquid undersides. One process
26:56 make one segment of Myelin and the . N. S. One Schwann
27:01 will become a single segment of Myelin these segments are separated by nodes of
27:08 . Later you learn that these nodes ranveer contained identities of both educated sodium
27:14 potassium channels and that's where the action gets regenerated as it is traveling down
27:20 axon to the axon terminal. We about the Myelin Nation and we talked
27:27 how there are several different proteins and interactions and uh certain levels of these
27:34 that control myelin compaction or normal Myelin and that if there is and follow
27:41 for example which can be caused by infection and which causes inflammation and d
27:49 Nation uh this is one way to myelin but we then focused on to
27:57 disorders. Multiple sclerosis, the currents which is typically in the 30 plus
28:02 of age which is in this We discuss uh mutations and chromosome 18
28:09 , certain symptomology, electrolysis and convulsions spasms in the muscles and the animal
28:17 by which it was reproduced what we've humans and partly recovered with the Myelin
28:24 using gene therapy and multiple sclerosis and immune disorders of the cNS axons violating
28:32 charlotte married to is A PMS disordered in the P. M.
28:38 Due to chromosome 17 gene duplication that's during early development muscles and the bones
28:47 growing and forming and can cause impaired bodily deformities by over expression of this
28:56 myelin protein in 22. And so um this is a good overview of
29:04 of the glial cells have already And one more time remember that astrocytes
29:09 play a very important role in controlling blood brain barrier. So this concludes
29:17 neurons and glia section. And let see there is uh do we need
29:25 know anatomy of the soma um Like nucleus and the major organelles Golgi and
29:33 plasma in particular. And I think just very basic biology. It doesn't
29:38 to know it. Um And some the features maybe there are more important
29:42 us that we emphasize. There's something neuronal specific like spines for example.
29:48 why there's an importance of normal densities spatial distribution of these dendritic spines along
29:57 axon dendritic access so that there is processing and normal development of brain
30:05 Um And all of the cognitive and abilities illegal then decides well illegal undersides
30:16 here. There you go. So formed the smiling sheets. Myelin units
30:27 the accents of nodes. Alright, neurons produce different action potentials. We
30:35 a variety of real cells. We the my elimination. So this that
30:41 talking about and then we want them resting membrane potential. Started talking about
30:45 number and potential. Before that. said, okay we need to understand
30:49 of the basic circuits and how things . So we use this as a
30:56 stretch jerk, knee jerk reflex, root ganglion cells. Remember the pseudo
31:03 neurons are going to excite modern neurons are multi polar, going to release
31:09 Seattle, calling on the muscles and a muscular contraction but for this muscle
31:15 contract properly during the stimulus sensory stimulation a mallet here, as we
31:21 you also need to make sure that opposing muscle and the hamstring flexor muscle
31:25 relaxed and the same sensory nerves can the inhibitory interneuron which will release inhibitor
31:32 rising. It's also a multipolar. we'll make sure that this motor neuron
31:36 not active and the muscle remains And so this is a very simple
31:42 . Eventually one synapse can cause a of the muscle. For the reflex
31:46 be effective, you have to involve synapses in them. It's still pretty
31:52 reflex, arch. It's all important understand all these three different cellular subtypes
31:58 mythology and neurotransmitters to release whether they're or inhibitory. So neurons have plasma
32:06 and plasma membranes are not permeable to and instead they will have channels specific
32:13 channels embedded in plasma membranes and there's to be a separation of charge between
32:18 outside of the plasma membrane inside of cell approximately, it says minus 60
32:22 minus 75. This resting membrane potential slightly different cellular subtypes. Now,
32:30 happens is that we have a lot sodium chloride on the outside, potassium
32:34 dominating on the inside. There's also lot of calcium on the outside compared
32:39 the inside. It's 10,000 times more on the outside and the inside of
32:44 cell. And calcium doesn't contribute that to change in neuronal potential because overall
32:51 isn't that much the concentration of calcium million 120 Of flora 145 of sodium
33:00 the outside. But it will contribute a lot of changes in the inter
33:03 functions and calcium can serve as a messenger and a lot of the cellular
33:10 calcium is bound up and buffering in to all of the specific channels,
33:16 potassium or calcium channels will also have pumps and A. K. Pumps
33:20 will use a TP to pump sodium potassium against the concentration grading. These
33:25 are made up of amino acids that bound with peptide bonds strong into um
33:35 tides. Secondary structures coiled tertiary ordinary structures to the trans membrane protein
33:44 channels and these channels of specific to ions and specificity is based on molecular
33:51 and chemical interactions. So it's based the size of the size of the
33:56 of hydration and also on the interactions the charged amino acid residues that will
34:05 sodium sodium challenge potassium potassium channels clog calcium calcium channels. So um now
34:18 law V. Equals ir conductance is inverse of resistance. Therefore you can
34:25 current equals G. V. We about that if you just had simply
34:32 gradient or chemical gradient, you had lot of sodium fluoride on one side
34:35 the plasma membrane and nothing on that you open these channels then if there
34:41 nothing else just chemical gradient, then will have this equal distribution of he's
34:48 and chloride on either side of the membrane. However, we know that
34:53 have a charge and cat ions are by Catto negative and repelled by positive
35:00 node and an ions are attracted by ode and repelled by cat toad.
35:08 what happens in reality is the separation charges at the level of the plasma
35:13 . And if you have a lot the concentration of potassium and that potassium
35:18 flexing from one inside to the there's now enough of the positive charge
35:24 up on the outside of the plasma that it starts actually repelling this
35:30 This force now is an electrical force addition to the chemical gradient driving in
35:35 direction. Now you have an equal electrical force repelling that charge in the
35:40 direction. And when the two forces equal to each other, that's where
35:44 have an equilibrium potential value, Librium for a given ion. And so
35:53 talked about equilibrium potential values for each based on their concentrations outside versus inside
36:00 the ratios and these concentrations outside versus and that we would use marist equation
36:06 calculate equilibrium potential for individual ions. 2.3 R. T over zf log
36:14 ion on the outside versus I on the inside of himself, which can
36:19 abbreviated collapsed here from unavailing catalonians into 54 million balls mon available and I
36:28 to minus 61.54 million balls and Duyvil cat tien into 30.77 million balls and
36:37 the log of concentration of each ion outside inside sodium outside, inside,
36:43 inside castle inside inside. So each of these ions and they will have
36:48 respective ionic concentration values. So you not need to have a calculator.
36:55 not gonna need to calculate but you're have to recognize the correct delineation,
37:03 arrangement. For the example chloride You should say that's the chloride that
37:09 be facility more potassium because the Value is -1. You should also
37:14 what R. T. And F. R. And you don't
37:19 to do the calculations but you need recognize different variables of this equation which
37:25 us to calculate ionic equilibrium potential values order to calculate member and potential
37:31 We use a different equation. The equation. Goldman equation still takes a
37:36 of our T. Over f 61.54 of one log but in this case
37:47 adding concentration of potassium outside versus inside sodium concentration outside versus inside. Before
37:57 we're introducing this term permeability and we that arresting number of potential potassium channels
38:04 leaking and open and potassium is leaking of the cells and therefore membrane potential
38:13 dominated by P. K. Permeability for potassium 40 times more so than
38:20 and the overall number and potential VM is much closer two potassium um equilibrium
38:31 than it is to sodium. It close to chloride. It is but
38:36 so you know at the wrestling number potential chloride is really not flexing.
38:40 channels are not open. So it dictated mostly by potassium. This is
38:46 main differences between the nourished equation and golden immigration that we see. Mm
38:59 jumping forward to to formula snow ernst Goldman equation here recall that that means
39:10 concentrations of ions don't need to change much as much as the permeability concentrations
39:17 ions change a little bit during sodium action and potassium action potential dynamics but
39:25 doesn't change that much which changes a is permeability. And by changing the
39:31 for potassium or sodium, you can very much the membrane potential value if
39:37 permissible, the potassium is going to dominant by potassium is going to be
39:43 to the equilibrium potential values for If it is permeability amount of the
39:47 and is dominated by sodium channels open sodium conductance is that means that permeability
39:54 going to be higher for sodium and membrane potential is going to be closer
39:59 the equilibrium potential value for sodium and , to prevent these abnormal extra cellular
40:06 concentration changes. We call upon aside selves and this shows that if you
40:13 the extra cellular potassium concentration here and the memory potential will de polarize significantly
40:21 will reach actually the threshold for action firing, making cells fire to avoid
40:27 drastic increases in local extra cellular Janek situations we have the astro sides real
40:35 that will slurp up these abnormally high ionic concentrations and will spatially buffer through
40:43 own very widely distributed spatially processes and within the interconnected cell networks and other
40:52 side. So they will very quickly try to buffer and prevent the abnormal
40:59 of ions like potassium and abnormal concentrations uh neurotransmitters as well. We discussed
41:08 Mackinnon as a person that used multiple basically to get to the answer to
41:15 this uh this potassium channel structure, just solid but to visualize this potassium
41:22 structure. And particularly he talked about shaker flies and side directed me to
41:28 or genetic mutations. He discovered this loop or the selectivity filter. We
41:35 that a lot of the sequences of acids and these proteins are conserved across
41:41 and understanding the structure of potassium channel the fly is just as important.
41:46 parts of that channel can be identical humans and human function. So would
41:53 eventually use this electrophysiology to see how mutations affect the flexes of ions through
42:01 channels. He used toxins to see different binding sides for toxins are important
42:09 not and where these toxins might be and that helped him deduce the three
42:14 structure of the channel. Eventually he to X ray crystallography visualized using X
42:21 , visualized actual production, general So what a quest, What a
42:27 quest to answer a question and the different techniques and skill sets and almost
42:39 become just a tool to get to ultimate answer that you were searching for
42:48 potentials. Rising phase, overshoot. face. Undershoot easy right rising face
42:56 following phase potassium undershoot potassium still But then going back to the resting
43:03 potential with the house on the pumps record these action potentials intracellular or extra
43:10 early. These action potentials. The can depend on the strength of the
43:16 and part the frequency of action potentials the strength of the stimulus until as
43:21 discuss certain cells will reach the maximum rates that are lower frequencies and other
43:28 can produce very fast trains of action . So the driving force we discussed
43:35 driving force is the difference between the potential and equilibrium potential for an ion
43:43 the greater is the difference the greater going to be the current for that
43:48 island. Okay, so when concerns driving force and the conductance and potassium
43:55 dominating, address, sodium is dominating the conductance is a dominating at the
44:00 phase, potassium again is dominating and phase and the resting membrane potential.
44:07 the best actually uh talk about uh always suggest that it is best to
44:19 this diagram as a real great study for the question since you may get
44:24 action potentials. And if you understand that's labeled here for example. RMP
44:30 membrane potential D. Polarizing inputs, polarizing polarizing inputs. Action potential threshold
44:38 there's opening of both educated sodium influx of sodium that goes through the
44:43 feedback loop more sodium, more more sodium, more deep polarization,
44:48 striving has a huge driving force here negative potentials which is the difference between
44:53 . N. A. And M. The membrane potential. And
44:58 the number of potential becomes more deep driving force for sodium reduces And the
45:03 force for potassium where equilibrium potential potassium here is a huge one. These
45:08 potential so deep polarized. And the reason why sodium never drives a number
45:13 potential all the way to its equilibrium reversal potential values is because of the
45:20 and the closure and activation of the channels. At this point, potassium
45:24 over potassium tries to drive remembering into own reversal potential values and the resting
45:30 potential gets rebuilt slowly with an Ak . You have the absolute refractory period
45:36 you have the relative refractory period as discussed as well. Okay, so
45:42 back to that other portion on the is here, we talked about how
46:03 understood the action potential recordings were recording voltage but we want to record the
46:09 and if we want to record the we can control the voltage and voltage
46:13 allows us to clamp or command the potential a different number of potential values
46:18 to isolate individual currents allowed Hodgkin and to isolate inward currents and describe them
46:26 fast opening and fast and activating or and the outward potassium current As uh
46:33 in opening, that prolonged in their . And they showed that for
46:38 what positive 52, you would actually seen any inward current coming from sodium
46:44 that's where the Librium potential value for is. This voltage clamp was necessary
46:50 experimentally demonstrate what was allowed to be by nursed equation as far as the
46:55 potentials. It also allowed us to individual current sodium and potassium currents.
47:01 you stood later, the sodium channels made up of four subunits, six
47:05 membrane segments. Each subunit as four voltage sensor between five and six.
47:11 have the selectivity filter the poor loop as for that has a voltage sensor
47:17 positively charged. The negative potentials of plasma membrane, that negative positively charged
47:25 acids inside this protein are attracted by charged membrane and it keeps the channel
47:32 but with deep polarization, with excitatory inputs coming in with deep polarization.
47:39 voltage sensor is going to actually slide because there's going to be less of
47:45 negative charge and more of a positive now on the inside and that is
47:50 to start repelling this voltage sensor. it's this. This basically channel will
47:56 the change in voltage that's where they to as voltage gated channels. And
48:02 the sensor slides up the gates of voltage gated sodium channels open. We
48:06 that voltage gated sodium channels as you polarizing will open very quickly. But
48:11 soon as that voltage sensor slides up channel, it also causes the inactivation
48:18 inactivation gates closing the channel and very Stopping the conductance is through these voltage
48:25 sodium channels. Now to deon activate to remove the inactivation gates. And
48:31 only way you can deactivate is that you release this deep polarization from -40
48:37 to resting membrane potential online in 65 then allows for that sensor to slide
48:43 down into its resting membrane potential position it is sliding down, it's gonna
48:49 activate move this ball and chain and the closure of the channels. Channel
48:55 to be closed open, inactivated Dean , closed open, inactivated Dean
49:03 closed open in this cycle. And the reason why the membrane potential during
49:10 potential doesn't reach the equilibrium potential value sodium. We talked about these really
49:16 techniques using micro electrodes and patch pipettes study different channels and different patches of
49:24 plasma membrane and several techniques that we as a cell attached recordings and also
49:31 inside out patch clamp recording which allows to expose the inside of the protein
49:40 of interest to the outside experimental environment the outside out recordings which exposed the
49:47 of the protein. The outside selling of the protein to the experimental
49:53 And we talked about toxins. We about TTX in particular. No it's
50:00 the slightest coming up blank. But talked about several uh important uh concepts
50:11 . Let me check one more time this is coming up. I may
50:18 skipped a few of these slides in recording but we talked about how there's
50:26 equivalent circuits and I want you to symbols for capacitor, what's a good
50:32 ? The pump um variable conductors or and each one of them containing their
50:40 batteries and the polarity of the battery the charge separation across plasma number and
50:48 ions. This is a capacitor charges lot of stores a lot of
50:52 And we talked about numbering property says resistant and capacitive properties. This is
50:59 I. V. Plot where positive amperes of current is outward current negative
51:05 convention nanogram paces inward current and this I for current and V for voltage
51:11 membrane potential. So small neurons will small neurons, small radios will have
51:17 input resistance, large cells, large will have large capacity to be a
51:23 capacity. I have to have a of numbering area store a lot of
51:27 charge up and discharge pretty quickly. so this is a good capacitor in
51:31 membrane permeability will change and switch so the cells and most permeability of potassium
51:39 during the action potential sells the most volta sodium and just by changing the
51:44 not much of the outside inside concentration you can have a significant alteration in
51:49 member and potential voltage. You know talked about voltage clamp the techniques to
51:55 these currents. Hodgkin and Huxley inward outward conductance is the kinetics of sodium
52:02 . The two gates open and activated closed patch clamp recordings and some
52:09 This is where we stopped where we about tetrodotoxin which is found in puffer
52:15 . It's found in some other organisms well. It's made by microorganisms that
52:24 live in the organs of these Saxon toxins. Found clams, mussels
52:32 cry toxin, Colombian frog. They target different parts of the channel activation
52:37 inactivation. But Toshio Narahashi demonstrated Tetrodotoxin a selective sodium channel antagonist. It's
52:46 reversible sodium channel antagonist but it's a sodium channel antagonist. So he said
52:52 to T. X. Blocks action by blocking the influx of sodium.
52:57 doesn't the fact that outward potassium conductance talked about. Tetra methyl ammonium is
53:02 matter of substance that is a specific or an antagonist for these channels or
53:08 that blocks is an antagonist blocker. ? So tetrodotoxin Saxon toxin,
53:16 We also talked about how lidocaine this S six trans membrane subunit of wealthy
53:22 sodium channel the lidocaine has a binding here and that's a common local anesthetic
53:28 was also used as local anesthetic in 60 that's as low binding affinity devolved
53:33 sodium channels. That's not what it's for now. Illicit drug Tetra Soleimani
53:39 specific to potassium. We talked about you measure these I. V.
53:45 and how I wanted you to recognize oneK I. V. Curves in
53:51 case from the acetylcholine receptor channel, also for potassium channels and for sodium
53:57 . I urge you to review these is a pretty impressions from the last
54:00 lectures or so talked about how some are linear and others are rectifying and
54:06 subtypes of cells will have collections. can express 12, 10, 9
54:12 types of voltage gated channels and these gated channels. The conductance is will
54:17 on the changes and voltages that will different curves. Therefore accounting for the
54:22 dialects that they can produce and different of action potentials that they can
54:27 Some of these cells are rectifying, means that they conduct more current.
54:32 direction over the other direction, talked how you can over express different channels
54:40 you can over express these channels because the small patches of the membrane that
54:46 you're doing the recordings, you may have one or two channels and you
54:50 not be able to pick up the very well from noise. So in
54:54 to amplify that signal, you can express it in simpler system like Prague
55:00 sides for example, there are large one millimeter and study the kinetics and
55:05 in this channel. And when you you understand the different sub tribes of
55:10 gated sodium channel also have different properties how they are opening, how long
55:15 stay open and so on. And very insightful. And then you can
55:19 that information back into more complex systems neurons, mammalian neurons, more complex
55:26 . So now what we talked about how this action potential is made.
55:32 once the action potential is generated it generated at the axon initial hillock
55:39 Okay. And this is a very area. And so this area will
55:44 high densities of voltage gated sodium potassium channels, nose of ranveer which
55:51 breaks in between the myelin segments will contain high densities of voltage gated sodium
55:56 potassium channels. Where action potentials will regenerated at each node around here and
56:03 that the amplitude of that action potential going to be the same and constant
56:07 its propagation down the axon and when reaches external terminal is going to be
56:12 same as when it was generated. axon. And a lot of this
56:16 area here the neurons will be receiving trade inputs on their gun rights,
56:22 their inputs. There could be hundreds of them could be simultaneous, could
56:26 separated by a few milliseconds and ramon predicted that there's this principle of dynamic
56:33 . So he was making the he says of all the inputs are
56:36 to come into the dendrites and some and the action potentials are going to
56:40 produced and communicated down the axles. this is directionality from selma to access
56:46 this is input processing and then the only gets communicated in that direction.
56:51 is called principal of dynamic polarization by alcohol. So if the cells project
56:58 the distal done rides, they have have very strong inputs and a lot
57:02 inputs activating in order for this accident segment to get deep polarized. And
57:07 the D polarizing stimulus will reach the initial segment, we talked about how
57:12 have inhibitory inputs that are very close the soma and excited. The inputs
57:17 are common commonly further away located more away from the soma and the excellent
57:23 hill log here we have two types local educated sodium channels. You have
57:28 threshold and low threshold and maybe 1.6 so once this deep polarization reaches this
57:35 it's N A V 1.6, they're a little bit further away from Soma
57:40 they are low threshold. They're the that are going to generate the forward
57:44 action potential and that forward action potential action potential is going to cause a
57:50 release effect terminal And as that there's also going to be now enough
57:58 enough of the threshold to open high and maybe 1.2 channels going to generate
58:04 propagating action potential. This back propagating potential is going to spread back into
58:10 soma and back into the den It's in the way challenging this principle
58:15 dynamic polarization. Where the forward propagating communicating synaptic information, neuronal transmission,
58:23 transmission and back propagating action potential is information back into the soma. Into
58:29 den rights. And so what is significance of that? And the significance
58:35 that is that the uh back propagating potentials are very important for learning and
58:49 . Very important for plasticity. And is happening is this is communication between
58:56 and there's certain spike timing that is , neurons communicate in a very fast
59:03 . And that means that if this prison optical is trying to excite the
59:08 and the cell response within a few and says this back propagating action
59:13 It helps to sell bind the pre synaptic activity. It helps to sell
59:20 plasticity in these active synopses based on spike timing, there's this concept of
59:27 timing dependent plasticity. So the back action potential is very important in plasticity
59:33 synaptic plasticity. Dendritic plasticity and spike dependent plasticity and forward propagating action potential
59:40 going to cause the release of the and synaptic communication that we will address
59:47 the next section of this course. this actually concludes our review of the
59:56 . Gonna check chat. Should we the ratios you should remember the approximate
60:09 of the four ions that we discussed potassium chloride calcium is the driving force
60:17 potential always sodium. The initial rising of the action potential is always
60:23 sodium will always happen highest driving force addressing memory and potential, the neuronal
60:29 of potential is far away from the potential for that ion as we
60:35 Um and then the following phase will dominated by potassium. So the driving
60:41 is going to be the highest for . Especially with these deep polarized membrane
60:49 . What are the circle symbols I'm sorry I don't um I'm not
60:58 what so called symbols you're referring Um Sorry if I didn't see this
61:05 . Do axon initial segments also contain levels of acetylcholine receptor channel.
61:11 Now they're specifically I want you to and know that axon initial segments and
61:18 over on beer contain identities of both sodium channels and potassium channels and that's
61:24 they're strategically positioned in the best way um regenerate the action potentials in the
61:32 . Over here. The circles and capacities background the circles of the capacities
61:41 . I think you're referring to the for the pump. N.
61:46 K. T. P pump if not mistaken. So there's a conductance
61:51 resistance for each channel then there's the . The pump shows arrows for ions
62:01 against concentration gradients and then the which is a charge storage across inside
62:10 outside of the number. Okay, , we're just on time of finishing
62:22 review, as I mentioned, if can use some of these tools to
62:28 the diagrams for action potential, do sample exam take some sample questions from
62:36 book at the end of each Review the sections that you may have
62:43 with understanding. Review those lectures on points and good luck to you on
62:52 . So you have a whole weekend study and wishing you luck take
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