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00:00 um This is lecture 11 of neuroscience its neuro transmission to and last lecture

00:09 discussed that there are two synopses, types of the synapses in the

00:16 n.s. Give Me 1 2nd. have chemical synopsis and we have electrical

00:25 . Chemical synopsis is chemical neuro transmission fusion, neurotransmitter release and binding of

00:32 chemical neurotransmitters to the post synaptic receptors evoke a post synaptic response, electrical

00:39 gap junctions are formed when you have of the membranes of neurons to neurons

00:45 close in proximity about three nanometers apart each other. And if they express

00:50 gap junction proteins that connects on proteins will form the gap junctions. Gap

00:56 are permeable to ions. They're also to small molecules such as secondary messengers

01:04 as cyclic GMP. Gap junctions will able to feel immediately what the Jason

01:11 that is connected to these gap junctions experiencing. So the response is instantaneous

01:17 chemical synaptic transmission. There is a from vesicles fusion release of neurotransmitter binding

01:24 the receptor and boston attic response. may have anywhere between 5 to 20

01:30 , delay. Gap junctions are instantaneous gap junctions will be found in glia

01:38 astra sites will take advantage of that they're buffering spatially buffering increases in local

01:44 of ions. They can Transported in the cells through these gap junctions connectivity

01:51 . And they're also gap junctions are expressed in neurons and the neurons.

01:56 very important so that you can engage number of neurons by stimulating one and

02:01 one neuron is interconnected to another few through gap junctions therefore you would only

02:08 to activate one neuron for all the 10 neurons to feel some sort of

02:13 level of activation. Only a fraction the stimulus that you see in sal

02:18 here, this large response electrical membrane , only a fraction of that will

02:24 translated through the gap junctions. But this is a really good tool in

02:29 to engage and synchronize larger populations of which is necessary in order to perform

02:36 tasks that we uh performing every day talked about neuro muscular junction and there

02:44 certain features of neuromuscular junctions that we out. So neuro muscular junction here

02:50 we talked about is the skeletal biceps triceps, hamstrings and we also

02:57 about the neuron or nerve to the junction to the cardiac muscle.

03:04 and the cardiac muscle and this cardiac acetylcholine was reducing the contraction of the

03:11 muscle was slowing down the heart That was Okelo, his discovery originally

03:16 he discovered acetylcholine now in the that same molecule acetylcholine has an excitatory

03:26 response on the muscles and it's the molecule acetylcholine but in heart it's acting

03:33 Mascarenas. Acetylcholine receptors. And then neuro muscular junction here it's acting through

03:39 acetylcholine receptors. Now these axons that from motor neurons in the spinal cord

03:47 ratify and form these large synopses that called end plates, motor end

03:54 motor employed region that will contain these large synapses with synapses will have

04:00 Each vesicles will contain 2000 to 4000 molecules. When there is an action

04:07 here at the motor neuron, it release the packet of these acetylcholine

04:13 2000 to 4000. Acetylcholine will activate optical in nicotine acetylcholine receptors. These

04:22 receptors will generate and played potential. very large pasta fanatic potential that's always

04:31 the size of 70 million balls. very large deep polarization through acetylcholine receptor

04:38 is going to be sufficient enough to volt educated sodium channels and voltage gated

04:44 channels in the muscle fiber and cause contraction of the muscle by muscle producing

04:50 action potential. So, it's a reliable synapse. That action potential in

04:55 synapse means release of neurotransmitters. It'll means employed potential and means contraction of

05:03 muscle fiber. So this is what have for the neuro muscular junction and

05:14 only excitatory, it uses acetylcholine. , there is no inhibition here.

05:23 nothing that can inhibit the muscle once signal from motor neuron goes out into

05:27 muscle and it's an action potential, will contract unless there is some pathological

05:34 with the muscle or with the release Americans narratives that once you have this

05:41 membrane potential of about -65 syllables. have a threshold for action potential -45

05:50 volts. This is VM. And this is resting membrane potential.

06:01 , when in the neuro muscular junction produce the employee potential, that template

06:07 is always going to measure. This potential is abbreviated E P P.

06:15 the post synaptic response. So if recall to acetylcholine molecules have to buy

06:23 this receptor. Okay, and when buy into this receptor, sodium ions

06:30 going to influx And positive charge coming , it's going to cause this massive

06:37 polarization that will measure approximately 70 million in size. And so because these

06:47 always have the quanta of 2000 to molecules that combine to 1000 or 2000

06:56 receptors and activate 1000 to 2000. will always have this complete potential on

07:02 of which you will always be able evoke a very long cardiac action

07:09 So it's a very reliable synapse. only excitatory. And so the connectivity

07:17 between the motor neuron motor neuron and cells is only excitation by sid alkaline

07:30 binding to these nicotine IQ acetylcholine Okay, so these nicotine acetylcholine receptors

07:39 ligand gated receptor channels that will allow the influx of sodium for this deep

07:47 . They will also allow for the of potassium causing this ripple polarization during

07:55 athlete potential. Okay, so now is a neuro muscular junction and it's

08:02 different situation. It's a different situation the central nervous system synopsis and I

08:12 that everyone on zoom can see what's the board really well. If I

08:20 sharing for example, I think you have a larger screen so you can

08:25 your screen larger and hopefully take a of it and inverted and the power

08:35 or something along these lines. So let's continue on uh neuro muscular

08:45 And so the initial deep polarization is a single coding receptor channels and then

08:51 action potential gets produced by these voltage sodium and calcium channels that are not

08:57 here. And we're not going to the dynamics of the action potential in

09:02 muscle for the purposes of this we talked about different neurotransmitter systems and

09:08 said that there are different types of and there are certain distinguishing features of

09:18 neurotransmitters and maybe I can save this uh raise part of the screen over

09:27 to add more information. Let's So we talked about amino assets and

09:42 talked about the means and we talked peptides, amino acids are the major

09:48 glutamate inhibitory gaba neurotransmitters in the glycerine inhibitory neurotransmitter in the spinal cord

09:56 neurons gliding in the cns is also co factor for glutamate ergic signaling of

10:03 signaling and we'll get to that in next lecture. So amines are acetylcholine

10:11 epinephrine, histamine, norepinephrine I any an amine serotonin. And if you

10:19 about glutamate, you can think about plus excitatory post synaptic response generating action

10:27 . If you think about gaba you about inhibition inhibits the cell membrane it

10:34 polarizes. It makes neuron less likely fire. When you think about the

10:39 you can think about them a little differently. They're regulating other features of

10:45 C. N. S. And features are related to our state of

10:50 our state of alertness. Our moods distinct dysfunctions in these systems can result

11:00 specific neurological disorders. So in Parkinson's and lot of motor cortical disorders who

11:09 have dough opening dysfunctions, Opening dysfunctions also be present and addictive disorders and

11:16 also implicated in schizophrenia dopamine receptor of . When you're talking about serotonin,

11:23 talking about regulation of mood and appetite when you're talking about dysfunctions and serotonin

11:31 , you're talking about depression, anxiety post traumatic stress syndrome disorder. And

11:43 you're talking about norepinephrine, you're talking adrenaline of the nervous system. So

11:48 there is a threat coming at you levels of North of northern africa are

11:53 to go up. A lot of substances are regulated during the day dependent

11:59 the external stimulus. So once again somebody is approaching you in an aggressive

12:04 and threatening you you're gonna engage your is called fight or flight response,

12:10 either gonna fight or you're gonna fly of the situation and to do that

12:15 need to engage the systems you have synchronize neurons. You have to do

12:20 split second really milliseconds to do And you would engage systems like norepinephrine

12:28 epinephrine which are the stimulatory systems. systems that mediate that fight or flight

12:34 and dopamine for example is a reward too. So when when you have

12:40 rewarding dopamine you get a shot of . So it's not just disorders,

12:44 also regular normal behaviors that are regulated by these systems and some of them

12:51 regulated by external stimuli. Some of are regulated by the day cycles are

12:56 diurnal or circadian rhythms. So some go up at night and go down

13:02 the morning and vice versa. Uh know from other courses of the stress

13:09 the cortisol, the stress hormones. you have hypothalamic HP a hypothalamic pituitary

13:16 axis. So when you're stressed you an increased level of stress hormones and

13:21 can be increased accurately. Or it be a part of the chronic stress

13:26 changes the system in a different But so this is also externally in

13:31 stimulus. Then in addition to what discussed here, we talked about the

13:37 that if you look in the in anatomy of the brain that I'm drawing

13:43 in a cartoon like fashion. Glutamate expressing themselves are going to be found

13:54 the C. N. S. . Gaba express themselves are going to

14:01 found throughout C. N. And hundreds of millions of neurons and

14:09 will be found in in the in spinal cord. So this is

14:16 Uh this is glued in a his . Also glycerine for the spinal cord

14:25 . But I mean systems are different immune system and I mean expression is

14:35 to specific nuclear in the brain. there's going to be nuclei and the

14:41 that express acetylcholine, they're going to south that express norepinephrine. And these

14:53 are the only locations where there's going be cells that are making those molecules

14:59 toning those amine molecules. Okay so nuclear are all I mean production is

15:08 on in these nuclei everywhere and they're in different places in the brain stem

15:15 and partly in the in the sub regions. So now the projections from

15:24 nuclei very wide and they go everywhere the brain and also into the

15:35 So it's a very different way of of the amino assets that you have

15:42 of millions of cells throughout C. . S. In different regions,

15:46 and cortex in the occipital lobe and lobe. You have glutamate and Gaba

15:53 . But when it comes down to means they're confined to these nuclei and

15:59 spatially confined their expression that means to much that produce these semi neurotransmitters are

16:06 in these nuclei. By definition nuclear of cells that are responsible for the

16:12 or similar type of function like producing synthesizing acetylcholine and then releasing that little

16:20 in through this very wide what we it a sprinkler like system, almost

16:26 non specific effect that you would have the C. N. S through

16:30 immune system's cells can co express amino and neuro peptides so cells can co

16:40 multiple neurotransmitters. They can remember that signaling is happening here at the level

16:51 the synapse. So the vesicles are in these pre synaptic terminals. The

16:57 are loaded here. You learn the are recycled and reloaded here at the

17:02 . They're primed and docked and ready be released. As soon as there's

17:05 action potential, there's going to be release of neurotransmitter. It's just not

17:10 to be causing this huge template potential going to be causing a much smaller

17:16 synaptic responsible get to that in a a few minutes. But neuro peptides

17:20 different because you need to activate the for prolonged a sustained period of

17:26 We have to jolt this neuron for while in order for it to start

17:31 peptides storing them in Secretary Granules and releasing them somewhat non specifically along the

17:38 of the axon, not just external , so they don't have as much

17:42 the spatial specificity. So they're different but they you can see here that

17:47 same cell will co express neurotransmitters neuro molecules that we're talking about here.

17:55 in addition to these molecules we discussed his neurotransmitters and that nitrous oxide and

18:05 monoxide. We discussed endo cannabinoids to . G and anandamide and we'll come

18:24 and talk about this more in the election. Also later in this course

18:30 also talked about this molecule called our acid and our economic asset can be

18:41 precursor to cannabinoids and it also can a breakdown molecule of endocannabinoid. So

18:47 of these molecules that you're seeing here precursors for the other molecules and the

18:54 of norepinephrine and so on. So difference is that the gasses the

19:03 our economic acid, They're not stored vesicles, they are not stored in

19:12 , they're not stored in the Secretary . They're produced a lot of times

19:16 demand and they are lipid soluble or soluble and membrane soluble. That means

19:23 once they're produced inside the cell they float through the plasma membrane will be

19:29 and target their respective receptors and the will target cannabinoid receptors. Nitrous oxide

19:36 target nitrous oxide synthesis nitrous oxide The other interesting thing is that these

19:43 apart from being lipid soluble, so lipid soluble, no, that's a

19:59 can be synthesized on demand and they in a retrograde fashion. That means

20:19 they are actually released automatically and their are located preseason operability. Most of

20:28 other elements that we're talking about on the I mean assess their already released

20:33 optically released prison optically. These are specifically released specially those are released reason

20:41 released reason optically and these are all posten optically. So if you release

20:49 typically have an effect on post synaptic is called interrogate. If you release

20:52 cinematically have uh effect on pre synaptic is called retrograde activation. And then

21:00 also talked about 80 p. In to this and dennison and we talked

21:11 the fact that a denizen triphosphate is only just the energy molecule, it's

21:17 a neurotransmitter and it combined to a and receptors and the core molecule of

21:23 . T. P. A dennison also a neurotransmitter. Dennison has a

21:28 effect. It actually regulates glutamate So dennison activation of a dentist in

21:37 reduces the amount of glutamate reduces the of excitation in the brain and the

21:44 levels for example will fluctuate during the and they will go up in the

21:48 and at night to help you sleep calm the brain by reducing glutamate release

21:59 is an a dentist and receptor antagonist what it does, it actually stimulates

22:05 release so caffeine which we typically use the morning. Also we have a

22:12 with exogenous substances. Some substances exogenous use throughout the day and people have

22:18 systems that can accommodate things throughout the . For example like caffeine in the

22:24 of tea and some cultures people drink before they go to bed but it

22:29 has caffeine or in the evening And in certain cultures caffeine is typically

22:36 morning and lunch thing and after you because it keeps you awake and that's

22:42 if you're consuming coffee rather than But so we also form our own

22:48 with with different exogenous substances that interact our receptors such as caffeine will stimulate

22:56 release in the morning and during the at denison levels go down now glutamate

23:01 more likely to be released and then typically don't consume caffeine in the evenings

23:05 we need to pull an all So yes, some people basically stay

23:10 from, they say that some people be president not working. It's a

23:17 I think that what what I've experienced least I don't know the research on

23:23 . But culturally if you grew up as Children, we drank tea and

23:28 drank tea in the evening. So systems accordingly adjusted to to that substance

23:33 our receptors became plastic to that you know, so you are correct

23:39 we all individually adjust, We adjust part of color, part of the

23:44 and growing up most of the caffeine and most culture starts a teenage

23:50 that's when you still have a lot plasticity in the brain too. So

23:54 could be whatever cycle you're setting up of the cycles we're setting up in

24:00 , you know, teenage and early and late twenties are going to be

24:05 know, cycles potentially for the next 2030 years. So uh and that's

24:10 we're adjusting the systems and the the numbers of the receptors, How

24:14 they be activated? Somebody's a dentist is blocked for four days in the

24:20 and somebody else's for 12, I , for four hours in the morning

24:24 others for 12 hours throughout the whole . So it's it's yeah, it's

24:28 very interesting way to think about Um So all of the key elements

24:35 on here, I'd say. And hope that again, I'm gonna stop

24:40 chair to see what this looks I think you can see everything.

24:45 you're welcome on zoom too. Take screenshot. Uh We're going to lower

24:53 scheme. Mhm. Okay. So talked about how important this calcium in

25:07 and when the action potential life arrives , you have pre synaptic polarization,

25:16 have polarization and you require calcium So when this terminal gets d polarized

25:26 the action potential, you open voltage calcium channels and influx of calcium through

25:33 channels as necessary as we discussed vesicles have this protein complex. In

25:39 this is what the outside of the looks like. This very complicated hairy

25:47 of different proteins and things like that off of it, calcium is necessary

25:53 activate the protein protein binding protein complex the vesicles to neuron membrane and to

26:01 the fusion of the two membranes to protein protein interactions. So calcium will

26:07 some certain sides and up to tag as one of the calcium sensex sides

26:11 the vesicles. That tells vesicles that calcium. But we can proceed with

26:16 psychosis and following exercise psychosis, there's to be endo psychosis. The

26:21 the membrane organelles are going to be back and refilled with the neurotransmitters.

26:28 is the electron microscope pictures uh pre calcium channel. So we're looking from

26:38 on the cell into the plasma And these little dots you see like

26:42 line of dots. These would be presumed both educated calcium channels in the

26:47 synaptic active zones. And this is same pre synaptic active zones that have

26:55 started releasing the vesicles. So the came from inside of the south.

27:00 fused and it opened up. if you're looking in our little creators

27:06 these openings here, the craters that be the vesicles themselves. You're looking

27:13 the inside of the bicycle from outside the south. So this shows very

27:18 how this anatomy of the vault educated channels and he's beating like wines corresponds

27:25 very well with neurotransmitter vesicles fusion and . This is another image of electron

27:35 showing that where there is narrowing and at the two neurons, one and

27:42 together, close about three nanometers you will have formation of gap

27:47 So these are little dotted. Each is like a gap junction. This

27:52 what it appears like an electron microscope on both sides. So you would

27:59 it on on both sides of the the south and you see it also

28:03 the outside of itself. Uh as discovered different components of the membrane in

28:10 1950s and 60s. It was really to kind of understand that the membrane

28:17 comprised of the phosphor lipid bi So there are two layers, there

28:20 an the face and there is a . And the science by chemists were

28:26 interested in finding out which phase how proteins and the trans membrane and the

28:33 with extra cellular face and the associated intracellular cytoplasmic side of the membrane

28:41 And so there was this freeze fracture is being used at the time.

28:46 neuronal membranes would be very quickly flash frozen in liquid nitrogen. And

28:51 a small needle would be placed next the membrane. A little vibration

28:56 tap tap on the table, sometimes the floor and hoping that that little

29:00 actually taps the plasma membrane perfectly, just splits it open in half.

29:08 the analogy is like you have a and you froze that sandwich has the

29:14 from the bottom side. And now put a flathead screwdriver to that

29:21 And you're hoping that if you tap light lit that sandwich to face,

29:25 going to break apart and it's going show you where the lettuces with a

29:30 and mayo and so on. So the analogy of that one on the

29:35 scale, that was really neat. and then in the 1990s and 2000's

29:44 had the ability to visualize fluxus and . So when we initially talked about

29:52 the south, we talked about Golgi , missile stain and the features and

29:58 of these stains on the south. these guys are sensitive to ions.

30:06 they're not necessarily staining a particular type cell. They are indicating to us

30:13 levels of concentrations of different ions are in this experiment. It's concentrations of

30:20 . And this experiment looked at, do these calcium micro domains look

30:28 If we image them, we'd like know here, The higher the concentration

30:32 calcium, the more red color, and red color you would be

30:39 And so when rodolfo llinas, uh other neuroscientists started using calcium sensitive dyes

30:47 questions as well. We see this , we see these calcium channels in

30:53 microscopy, they seem to have some specificity here. Can we image,

30:59 calcium have spatial specificity as calcium everywhere the synapse equally distributed. And indeed

31:06 the synapses are not very active. see these pyramid or very clear mountain

31:12 like structures representing calcium micro domains, calcium micro domains will be assoc with

31:21 pre synaptic vesicles that are docked and in the active zones. And then

31:28 second question was what happens to this specificity if you stimulate the cell,

31:37 that cell receives action potentials gets d , what happens to the spatial specificity

31:43 this calcium arrangement? And what is concentration? So the concentration was 200

31:50 mall that's getting cut off here on slide we saw that the p concentration

31:55 way up during vesicular release and during deep polarization. So it's really like

32:01 what is calcium doing during this particular . And it's showing that it goes

32:06 this especially very specific locations magnus synapses being present everywhere. Pretty much pre

32:14 optically everywhere at least in these active synaptic zones and that the p concentration

32:21 . So you can see that there's more of the spatial specificity here.

32:26 there's a lot of calcium available in pre synaptic side of the neurons.

32:32 I had this image from neuron to . It's uh one of the older

32:38 that's still really good book to read you're into neuroscience. So in the

32:45 . N. S. Synapses versus junctions. The steam will continue.

32:50 actually going to continue on this drawing . But you have basically production of

32:56 bicycles. After early in this film have the filling of the neurotransmitter docking

33:04 these vesicles climbing of these vesicles with energy and other factors once there is

33:11 influx of calcium. So you must pre synaptic action potential and influx of

33:16 for the vesicular fusion to take But interestingly enough in the C.

33:21 . S. It's not not only response is not as big as in

33:26 muscular junction and non played potential. Sometimes the fusion pore opens only partially

33:36 for some reason maybe there wasn't enough . So the sensors and the protein

33:41 complex didn't activate completely to produce this fusion and the neurotransmitter vesicles and returns

33:49 this prime position and back into dark back into prime position. So this

33:56 called kiss and run. So you released a little bit of neurotransmitter.

34:01 you ran away. You didn't commit to the vesicular release here. But

34:07 there is enough calcium and if you this proper protein protein complex binding here

34:14 will have full fusion Uh dilation and fusion pore dilation and full release of

34:23 . Notice that when you fuse the you can if you're fusing 10 or

34:31 vesicles to the pre synaptic plasma remembering increasing the surface area of these cells

34:37 quite a bit. And as you're the surface area of these cells the

34:42 also gain more capacitance. So remember . The storage of charges depend on

34:48 large is the surface area to store charge. And this is what's

34:53 So during the the secular fusions if using a lot of vesicles, the

34:57 properties of the cell will also show . They will increase after the sexual

35:04 . There's endo psychosis process and this membranes get coated with the recognition particle

35:12 in and those vesicles are transported back pre synaptic side. The inside get

35:20 with age. Plus it becomes very . And with the help Of this

35:25 driven gradient and transport is new transmitters refilled back into the vesicles placed into

35:32 dark prime position, ready to be again. In some instances maybe the

35:38 needs a little bit more like a mile service versus just the oil

35:45 And in that case the vesicles can shuffled back into the early end,

35:51 , sat out here and and refill neurotransmitter. Go into the cycle.

35:56 can actually exhaust cns synapses from vesicular . If you have a sustained stimulation

36:04 sustained vesicular release for a few seconds will deplete neurotransmitter vesicles that have neurotransmitters

36:13 you will have to wait for about seconds for this recovery to take place

36:18 the neurotransmitter vesicles are reshuffled refilled and for subsequent release. Okay we'll come

36:27 to this in a second. But talk about the C. N.

36:32 . Synopsis and this is our neuro junction. But cns. Synopses are

36:39 and we'll get to talk about cns but cns synopsis can have either positive

36:47 negative synopsis. So positive is glutamate inhibitory input negative. It's got

36:56 All right. So this is different the you know muscular jungle that we

37:01 about. Because you're muscular junction only acetylcholine, it only has nicotine,

37:10 receptor, it's only excited her. no inhibition here. The only inhibition

37:17 have is at the level of the cord right with the spinal cord into

37:22 . The circuit that we talked about with the reflex arch. So when

37:28 have glue to late You have that's the same -65 no balls.

37:36 you excite one synapse one synapse will a positive deep polarization of about half

37:45 million fold. If you have this for action potential minus 45 you have

37:55 excite many many synopsis at the same . And if you excite them at

38:00 same time this response is deep polarization summit. So one synapse half a

38:06 volt to one million volts. For , two million volts eight synopses,

38:10 million volts, 16 synopsis eight million and so on. And only if

38:17 activate a very large number of these will you reach the threshold to produce

38:25 action potential. Okay this is the for the action potential here. So

38:33 the neuro muscular junction you just need synapse activation. You get em plate

38:41 of 70 million balls and you always the action potential in the C.

38:48 . S. Release of glutamate activation one synapse will cause the deep polarization

38:54 only half a mil a bold. so you need to activate tens of

39:00 excitatory synapses at the same time. proximity in time in order to reach

39:06 threshold in order for that neuron to action potential. And in addition while

39:13 is getting excited to a synopsis, same happens with inhibitor synopsis. If

39:19 synopsis get activated, you get If more and more inhibitors synopsis get

39:27 you get this member and potential more more hyper polarized. So you're drawing

39:35 with gaba. You are hyper polarizing numbers. These are excitatory post synaptic

39:48 . So when acetylcholine bonds the nicotine receptors, it produces this anti potential

39:55 your muscular junction it does something different the C. N. S.

39:59 there is a single calling signaling in C. N. S. And

40:02 the cns. The central cooling is going to produce this massive response and

40:07 is a neuro muscular junction. Mostly . S. P. S.

40:13 the strongest deep polarization that you will through glutamate. Okay excitatory post synaptic

40:22 and that is one glutamate neurotransmitter molecules buy to glutamate receptor channel that will

40:28 for influx of sodium. This will for influx of sodium. This is

40:38 this is out Mrs sodium. It also allow for the flux of

40:48 Yes. So again these are ligand channels. This is for E.

40:54 . S. B. And for . P. S. P.

40:57 . To produce this hyper polarization. , this is our neurotransmitter. Gaba

41:07 bind to Gaba receptor channels and Gaba channels. This is glutamate, This

41:16 Gaba. And Gaba receptor channels will for influx of chloride. So negative

41:24 coming inside the south, making the hyper polarized more and more hyper

41:29 more and more hyper polarized. Okay the comparison is that you have and

41:43 neurons cns neurons. If your recall can have an excitatory neuron, connect

41:51 neuron connect another excited turn neuron connected inhibitor neuron. I'm gonna call these

42:03 and those are gonna be connected to . Around here Gavin you're on this

42:12 neuron is going to be connected to Gavin neuron. Okay and this excited

42:19 is going to be connected to another neuron. So you can have inhibition

42:27 excitation excitation of excitation in the addition inhibition and excitation of inhibition as

42:37 So all of these different scenarios are in neuronal networks and they're absent at

42:44 neuro muscular junction and that's why we neuro muscular junction is a very simple

42:49 of understanding wondrous separate citation employee potential potential in the muscle but at the

42:57 of C. N. S. more complex. We have to activate

43:02 excitatory synapses to reach the threshold. G. P. S.

43:06 Is very small. So once the activation is just a fraction of a

43:10 of all you have excitation through glutamate channels and you have inhibition through gaba

43:18 channels. And we will build upon knowledge in the next lecture and will

43:23 the glutamate and gaba signaling Gaba A gaba B. Yo gabba,

43:32 And remember that show. The other is when we're talking about C.

43:39 . S. We have eye on tropic signaling and the and the tropic

43:45 . The tropic receptor channels are the to edge. You have a ligand

43:50 such as acetylcholine here you have a binds such as glutamate have a ligand

43:57 here such as Gaba and open the . So these are ion a tropic

44:03 channels. So they have their receptors they receive a molecule also channels because

44:08 conduct ions but also as you can they're non specific to an ionic

44:14 So when we studied action potential, talked about both educated sodium channels selected

44:19 sodium. Both educated potassium channels, potassium here we're talking about acetylcholine receptor

44:26 to allow flocks of sodium and potassium channels, receptor channels allow blocks of

44:32 and potassium here you have chloride activation Gavin. Uh And in addition to

44:40 ion a tropic channels these are a tropic channels. And then I

44:45 medical tropic channels the medical tropic channels when you have a receptor that receptor

44:52 not a channel. So I just . It's a medical tropic G protein

44:57 receptor, this receptor is not a . Instead it's coupled to G protein

45:04 activation of these G protein complexes can activate or inhibit downstream the other island

45:12 . But on their own G 30 couple of receptors on a channels they

45:17 allow the blocks of islands through In addition of affecting this is what's

45:22 the shortcut um pathway in addition to immediately adjacent ion channels on the plasma

45:32 . In addition to that, the activated G protein complexes can also interact

45:39 different enzymes and molecules and sinuses and messengers and the secondary messengers can have

45:48 the facts. Or they can have effects in regulating the transcription factors at

45:53 level of the nuclear scene. Same , little different effects in the same

46:01 s. Is missing. There there's aim sell different the fact in the

46:06 cell, same neurotransmitters. So in . N. S in C.

46:11 . S. You will learn that has nicotine IQ channels that we're talking

46:18 the same similar academic channels but they produce something potential in the CMS to

46:22 something different. And they also have tropic Mascarenas couple of her suffers and

46:29 two nicotine versus masculinity will have a effect on the same cell. It's

46:34 same neurotransmitter, acetylcholine. But if activates the receptors whichever one is more

46:40 or activated first will win. They have opposing actions to each other.

46:46 neurotransmitter, different effects on different So Siegel Colin is the same neurotransmitter

46:51 the heart that slows down the heart . Medical tropic acetylcholine receptors and the

46:56 muscle, it increases the contraction that's IQ. Acetylcholine receptors that are iona

47:03 different different effect on different cells but same chemical molecule. So the fact

47:10 depends on the type and the properties the post synaptic receptive to which these

47:17 bind. Okay, alright, we're talk a lot about acetylcholine system but

47:26 acetylcholine system will serve sort of as canonical system of what is happening in

47:31 amine systems in particular. And we'll be looking more into the amino acids

47:36 glutamate and gather. So with acetylcholine will find acetylcholine in the brain,

47:43 find acetylcholine and motor neurons and muscular . All PNS began Raonic and parasympathetic

47:52 . Um acetylcholine gets synthesized when the Kalay and choline come and chat

48:01 chat is an abbreviation for choline acetyl . And so yes you will be

48:07 for all of the details of this system produce acetylcholine acetylcholine, the common

48:15 is the neurotransmitter vesicles they'll have So if it's glutamate it will have

48:20 transporter for glutamate. If it's a colon will have a transporter for civil

48:24 will stop the testicle with the civil once the civil code in is released

48:31 can target in the cns both academic mastering acetylcholine receptors. But once the

48:38 colon is released and binds to these it gets broken down by Seattle

48:44 S turns so a single colony takes civil Colin, breaks it down into

48:50 acid and Colin. And choline from synapses. Acetylcholine Colin nestor is breaks

49:00 acetylcholine, it doesn't stay here for in synapse Colin gets transported back here

49:07 the pre synaptic terminal through the sodium transport. So there's another transporter here

49:14 will take the chemical from the synapse back into the pre synaptic terminal.

49:20 there with the help of chat with seal koei will form acetylcholine again.

49:27 loaded up and can repeat the When we talked about Alzheimer's disease.

49:35 the first section of the course, focused mostly on the cellular pathology.

49:41 hallmarks cellular pathology of Alzheimer's disease. in particular we talked about uh

49:49 inter cellular tangles. And we talked extra cellular plaques, uh senile plaques

49:57 amyloid plaques. We call them And we also looked at the gross

50:02 changes in the severe advanced stages of disease. And we saw loss of

50:10 tissue degeneration shrinkage, especially the gray where you have the axon where you

50:18 the selma's and you have the dendrites neurons and what I do for you

50:26 on the board, I also said amine systems in case of acetylcholine expression

50:38 these immune systems are going to be to specific parts of the brain to

50:43 specific nuclear. And I also said each neurotransmitter is you can think start

50:52 about each neurotransmitter as different behavioral different mood and a different pathology or

51:03 or neurological disease association for Alzheimer's It turns out the Colin ergic neurons

51:11 neurons that produce acetylcholine. We call Colin ergic norepinephrine, we call the

51:17 ergic serotonin, we call them serotonin . But those Colin ergic neurons,

51:23 neurons that synthesize acetylcholine, they seem be really vulnerable and are affected earlier

51:32 into the progression of this Alzheimer's And most of the medication. So

51:38 you can add on to your announced Alzheimer's disease that the pathology of the

51:43 pathology before you have this massive shrinkage loss of brain tissue could start selectively

51:50 out certain populations of neurons in this , that population as acetylcholine producing

51:58 Now you don't have enough acetylcholine, majority of alzheimer's medications, our little

52:10 Aries blockers. So now we're talking therapy and medications. Remember we started

52:17 about mechanisms symptomology a little that is developmental diseases, that aging uh more

52:25 to be prevalent in aging population. we're talking about more cellular mechanisms but

52:31 talking about systems, the neurotransmitter systems are more vulnerable. It's Alzheimer's

52:37 acetylcholine system that is really vulnerable and see the loss of these kahlan ergic

52:44 and. So the medications that block single colonist Aries. If you block

52:51 then you're prolonging the amount of you're increasing potential in the amount and

52:59 prolonging how long it'll Colin can stay the synapse and combined to these past

53:06 receptors. Alright, so that's overwhelming and therapy of Alzheimer's disease. There's

53:13 cure for Alzheimer's disease. The therapy down the progression of the disease at

53:19 best. But think about this, this really effective when you're thinking about

53:28 ergic neurons that are dying that are lost? What happens that you had

53:37 pollen ergic neurons? Now you have colon ergic neurons. What do you

53:41 is going to happen to medication? it still going to be effective or

53:48 you more likely now to have to the concentrations of these medications because you're

53:55 losing more and more of the choline ergic neurons and you have to increase

53:59 medication to make this remaining acetylcholine just available as possible? Right, so

54:10 what happens if there is no more nurtures producing neurons? Is that medication

54:20 ? No, probably not. Um happens when you raise levels of pharmaceutical

54:28 or or or things over the counter that you're in taking, you start

54:35 other parts of the body. That's when you're reading directions for ibuprofen or

54:42 , It says, you know, on your age or size, take

54:46 tablets? 400-800 mg maximum every six . So you cannot take 100 tablets

54:55 six hours because why? Well you not die but it may cause all

54:59 of complications of your on your other . A lot of the pharmaceutical over

55:03 counter drugs and even botanical corporations are through the liver. You can overload

55:10 liver and cause liver toxicity and it's an older person. So you're gonna

55:15 tent and more drugs and compromise the of other organs or systematic failure

55:22 Now you have to weigh that. , what else can you do?

55:29 to come up with a better strategy treating Alzheimer's disease. I use that

55:35 that came up I think a year two ago in my class, somebody

55:39 why don't you just eat acetylcholine? don't you just feed a single coding

55:43 Alzheimer's patients? And of course, know, if you eat something,

55:47 digest it. I don't know how of it would get into the

55:53 but precursors? Right, that's that what that student was thinking about.

55:58 can't you give some sort of Why can't you make more subtle

56:04 So what do you need? Maybe need somehow to stimulate the enzymes.

56:09 you need to stimulate chat. Maybe strategy is not as good. Maybe

56:14 need to stimulate transporters and trying to it as back as much as possible

56:19 fast rather than trying to keep it . So what about receptors? Maybe

56:25 make receptors a lot more sensitive so a little bit of a single cone

56:29 doesn't take two molecules, it just one and it's active. So all

56:34 these are strategies that when you're thinking neurotransmitter systems, neurotransmitter dysfunctions and in

56:42 when you think about neurological disorders, of the neuro drugs they will target

56:47 that will be blockers for receptors. will be uh agonists for receptors uh

56:54 will be antagonists for receptor channels or for voltage gated channels like sodium channels

57:00 potassium channels when you're talking about this transmission and the cycling within the

57:07 Now you can think of all of different strategies that could potentially be employed

57:11 the future to try to preserve these systems, like a mean system in

57:17 case Cullen ergic acetylcholine system if it so vulnerable. Okay so you can

57:25 think about that transporters synthesis was post response degradation of the neurotransmitter in the

57:34 cleft. Uh there's other medications for disease that not a single building base

57:41 the overwhelming majority are Qala necessaries inhibitors sometimes some commercials for other drugs you

57:47 hear for especially older population are you since So it's not like online doing

57:55 . But are you taking Colin estrus ? C. I. M.

58:00 that's that's what it stands when you the little text. Sometimes in these

58:04 on tv actually or online. So is Alzheimer's system. It's a it's

58:12 sorry Siegel polling system. You should all of the details that we're talking

58:17 here and you should add some notes you save space for Alzheimer's disease or

58:23 keep the information here. Come back this slide here. I wanna talk

58:29 poisoning neurotransmitter release. It's a special from your book bacteria, spiders,

58:37 and you. So there's a lot different elements out in nature. We

58:44 talked about different microorganisms producing toxins and fish uh in shellfish harboring in certain

58:55 . These microorganisms and producing these You also have spiders have snakes.

59:02 have venoms. Uh And uh you have also heard of clostridium botulinum or

59:12 . The botulism is uh not a common disease but it can occur when

59:19 is canned food that wasn't prepared canned properly or stored properly or has

59:27 expired, started warm temperatures, Clostridium will produce these botulinum toxins a

59:38 Okay, so clostridium botulinum uh microorganism if you consume this bad canned food

59:46 can kill you. So we'll talk little bit about how it can kill

59:50 . But so this is a bad news if you have botulism but you're

60:00 invited to a Botox party and clostridium and the toxin that it produces botulinum

60:09 but first was taken advantage by the and aesthetics industry. So Botox injections

60:18 what do both ox injections do? in general, what does this toxin

60:22 ? It turns out that this toxin forms of the B. D.

60:26 . E. C. Interferes with protein protein complex, the protein complex

60:32 the classical physical polling and the So it targets specifically this protein protein

60:38 on acetylcholine signaling and vesicular fusion. why would the beauty industry want to

60:45 it if you can get poisoned and from consuming these toxins? How can

60:51 toxins be used for aesthetic purposes? what happens when you are aging and

60:59 speaking and you're flexing your fingers and and stuff like that. You get

61:06 , things get worn out. Skin stretched, it gets stretched and

61:10 A lot of times you form wrinkles your face and chin and lips and

61:17 people don't like that so they want look youthful. So this is where

61:21 take advantage of the toxin molecule and modern science and modern medicine, you

61:27 localized injections. And when you do injections that actually relaxes the muscles that

61:35 causing these wrinkles because it blocks the release. And sometimes these procedures Botox

61:44 also used together with filler injections so something a little bit different. That's

61:50 you want your eyebrows or eyes or to look fuller and bigger. So

61:58 would be some fluid injections that are like warm that could be basically for

62:06 purposes, making it look different. And sometimes after Botox injections when people

62:13 around their mouth. They may have like completely moving their lips properly.

62:19 that is because the colon reception releases and they're not properly activating the

62:26 It's similar to like when you have and you have anesthesia and a little

62:32 of swelling after dental work. It's kind of a little bit of that

62:36 . But so this is what people with Botox now. So this is

62:41 beauty industry and aesthetic industry cut onto Botox now is also an FDA approved

62:49 Botox injections for the treatment of migraine case you didn't know migraine is a

62:55 disorder. It's not a headache. is a neurological disorder. And Botox

63:01 seem to alleviate some of the And it's improved uh d a food

63:08 Drug administration approved medication for treating So this is an example of how

63:15 can take something that poisons and kills . You can look at it in

63:20 lab, isolate the toxin and see this toxin does understand the mechanisms of

63:26 of that toxin, which is the binding of acetylcholine. Use it for

63:31 purposes locally to get rid of wrinkles such. Use it for clinical purposes

63:37 treat migrants. Uh There are many parts of the system here. This

63:43 the pre synaptic system. But remember we talked about the pre synaptic and

63:48 synaptic components of this system and there different molecules that can affect different parts

63:54 this pre synaptic synaptic system. Black spiders to produce this toxic venom,

64:03 will release acetylcholine, I'm sorry they interfere with acetylcholine release. But a

64:09 from Taiwanese cobra toxin will have an on post synaptic acetylcholine receptors. So

64:18 toxins will target pre synaptic pasta, pick sides. Okay some of them

64:24 be deadly. Black widow bites can deadly and we have black widow spiders

64:30 in this area actually even though the case of a person that that past

64:36 days following a bite on the Uh so they're very powerful. We

64:42 about toxins being used by roderick Mackinnon they had binding properties and roderick Mackinnon

64:49 studying the structure of the potassium Was looking to see how it affects

64:53 flux of potassium and gating of potassium using these toxins. Uh then we

65:00 human synthesized toxins. Organophosphates that will target this acetylcholine system. Organophosphates are

65:12 for agricultural purposes and they used for purposes. Organophosphates that are also produced

65:20 illegal warfare purposes. So chemical warfare and nerve gasses such as salman and

65:29 . And there are famous instances of nerve gas is being used by terrorist

65:36 and attack and Tokyo Metro and Japan the early nineties uh nerve gasses released

65:45 a couple a few years ago, can't remember exactly in syria. Uh

65:50 bad guys around the world will take we know from the mechanisms of action

65:57 will also make weapons out of this and weaponize these different molecules. And

66:04 way that organophosphates work is nerve When there is a lot of nerve

66:10 injection, inhalation or intake. Uh happens is they act as a Theological

66:19 inhibitors so they act as Alzheimer's So it's so great. So they

66:25 be great for Alzheimer's nerve gasses. if you have normal levels of of

66:31 , remember that these substances are not affecting your brain. Acetylcholine is also

66:36 muscular junctions. Acetylcholine will also be to the diaphragm contraction as you're

66:44 So if you activate the muscle too , too much of a single coding

66:49 organophosphates will block acetylcholine esters. There be a lot of acetylcholine and the

66:54 . What happens when you activate muscle . If you activate the muscles

67:00 they enter into what is called a state, the muscle tetanus where they

67:05 polarized and they're no longer producing action . That means they're locked up and

67:12 you can imagine is when you have muscle cramp, If you have it

67:17 than 10, 15, 20:30 it's painful and if it's all all over

67:25 leg you can't move the leg now that type of muscle cramp on your

67:32 muscles. That means you can no breathe. So most of the

67:37 S. Medics and other advanced army would carry some of the antidotes and

67:44 to re stimulate the block and we and put some adrenaline into the hearts

67:49 the hearts of stopping to to recruit soldiers. A few years ago,

67:54 had a special forces medic taking the from the U. S. Army

68:01 he did a tour of duty in and he encountered nerve gas attack in

68:08 . And so he told his story what happened and because he was the

68:15 , what transpired and how he had get off the guys off the rooftop

68:20 rush them down below. Uh for number of reasons to get them

68:25 So it's not something that doesn't It does exist. And you can

68:31 stories, the most recent stories you know, these nerve agents,

68:37 gasses, look at the story of trying to kill the main opposition

68:44 Now, volley by it's an incredible actually. It's a movie by placing

68:49 of these nerve gas agents into his . And uh failing, failing basically

68:57 this, at this uh you killing mission of the of the opposition

69:01 at the time. So, these exist and you will hear about them

69:06 the news almost in the yearly whether they use on a single person

69:12 instance by bad guys or they're just by crazy people on a larger

69:17 Alright, we'll end on this interesting here. I'll see everyone on Tuesday

69:24 we will try to finish, neuro transmission. No transmission. Three

69:28 . Take care. Everyone. Thanks being on zoom,

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