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00:02 this is neuroscience. Midterm to review also a portion and the ending of

00:09 central visual system processing. And we the connections between retina thalamus and

00:20 We looked at the anatomy of the circuits. We looked at the output

00:25 comes out of the retina. We at the anatomy of the lateral manipulate

00:29 of the thalamus, the sixth layer comprised of magnum carver layers. All

00:35 that information was unoccupied for information we looked at in layer four there are

00:42 dominance columns that are formed but that four cells are still processing Manaka color

00:50 in the primary visual cortex. And at layers 23 the men ocular information

00:56 becomes binocular. So we discussed the of information the llama cortical inputs.

01:03 and I intermediary mp. Going into layer four I bypassing layer for going

01:10 to three. I'm primarily concerned with processing. There's 23 allow for the

01:16 range and intra Colin er and intra connections to take place and spread.

01:23 intra cortical loop between 4-3, five four. Again this is an intra

01:30 loop and then there's the cortical hypothalamic that goes from the cortex into the

01:36 . So recall that there's salama cortical into cortical loop in a certain fashion

01:42 then cortical thalamic outputs. This is going to influence in this case visual

01:47 processing. In many other cases it be dealing with other sorts of sensory

01:53 in different parts of the brain. the color is concerned mostly with Larry's

01:58 . 3. The properties of the . The receptive field properties in area

02:04 . One is that they process A simple cells process bars in certain

02:10 they will produce and be responsive to bar of light and a certain orientation

02:16 a maximum number of action potentials. also have direction selectivity. So those

02:22 in the cortex will prefer a bar light to cross through the field of

02:27 through the receptive field in a certain that will be preferred left to right

02:33 to bottom diagonally and so on. we saw how simple cells and the

02:40 from the retina which are concentric on off cells can converge onto L.

02:44 . M. Cells and how a of L. G. M

02:48 The processes center surround concentric like receptive properties can converge onto the simple cells

02:56 the simple cells can further converge onto cells. So you can get different

03:05 of receptive field properties in different shapes the level of the primary visual

03:10 That, because of the convergence of . G. N. Cells and

03:15 simple cells creating bars, creating various like this. Of the receptive field

03:20 of the primary visual cortical cells and simple cells further converging onto the complex

03:25 . And that is all happening within . One. And with complex cells

03:29 have even the greater variation of this nice um forms and shapes that you

03:36 play with. So if you recall ocular dominance columns, I'm gonna review

03:43 quickly are these projections that if you to look where the projections come from

03:52 , I am to trace them from eye into the L. G.

03:56 layers. And as we discussed you to look and to appeal where those

04:02 in this case of radioactive probing which trans synaptic to it will cross the

04:07 from the retinal ganglion cells until jeon LG installs into primary visual cortex.

04:13 in the primary visual cortex will get stripes or striatum. These are ocular

04:18 columns. So one of these blue in layer 23 belongs to one eye

04:24 the white column belongs to that I this is where you still have the

04:29 ocular vision and then leads to three molecular vision becomes binocular vision. Now

04:36 this course, I'm going to go to one slide here that we didn't

04:41 in this course, we've emphasized the of plasticity and we said that during

04:48 there is critical period of development during very early age where there is the

04:53 chemistry, the right factors in the environment for the synopsis to form and

04:59 for the synopsis to be trimmed and connections to be specified. And so

05:05 is an experiment that tells you something this critical period of development and if

05:11 is sensory deprivation during that critical period development. This could be likened.

05:16 example if a newborn child somehow was of census during some early stage of

05:23 , how would that affect the anatomy the brain. And obviously anatomy or

05:29 means function too. And if you this is an experiment that can be

05:34 in rodents And in rodents you can one eyelid and you would perform this

05:43 at the very end of the first of life. So the first month

05:47 life is really this period that we critical period of development where there is

05:52 lot of plasticity, a lot of and in this case the animal is

05:59 off the visual input. That's why wearing a pirate like patch here on

06:03 eyes. You have sutured island And island is only suited for three

06:10 And then three days later the sutures . The animal is allowed to recover

06:17 a whole month and a month later experiment was performed where both eyes of

06:24 stimulated the left and the right And it turns out that there is

06:29 slight bias and this is number of that are responding from the iptc lateral

06:36 . And the itsy lateral. I the one that remained open and there

06:41 a bias of response In Layer In these ocular dominance columns toward the

06:49 that remained over. It's not much you can see that the blue problems

06:54 the number of cells have shifted. over the red ones. Now if

07:01 repeat the same experiment but instead of the eyelid for three days The island

07:07 future for six days. And it sutured all the way until the basically

07:14 of this first month where the critical of development also ends. Animal is

07:22 to recover for a month. And two eyes, the sutured I hear

07:28 lateral and the open eye of being and it is now very obvious that

07:36 cells and therefore in the primary visual are only responsive to the eye that

07:43 open. They are no longer responsive the eye that was closed. That

07:51 that if you have short term deprivation three days there might be a small

07:58 in the functional structure. But if have a prolonged deprivation in this case

08:04 six days without vision. In one you can have a permanent reconstruction of

08:10 connections from the cortex and therefore the loss of function. And if you're

08:17 that critical period of development where there a lot of plasticity, you may

08:22 be able to rebuild that function a or two months later forever. So

08:29 the short term deprivation there's obviously a loss of function to the eye that

08:35 closed and the bias toward the eye was open. And if you look

08:39 the fibers. These are the These are the thermometer cortical projections into

08:45 four coming in. This is following term binocular deprivation. This is an

08:51 eye and below here is deprived dot what that tells you that that I

08:59 that was not receiving the inputs, Kalama particle processing of that information which

09:05 conscious perception. Right? First the sketch and later the whole visual

09:12 You already have lost a significant number inputs and synapses. You have rearranged

09:19 you have structurally changed the connections in anatomy in the primary visual cortex.

09:25 obviously that reflects very much on either or prolonged period of visual deprivation and

09:33 full loss of function. Okay, that's that's really important to to keep

09:40 mind again this plastic period how such is so important. How deprivation during

09:47 development during this critical period of development long term deprivation can result in long

09:55 um functional loss for prominent functional So we walked through the anatomy and

10:04 ended up on this slide last lecture I said I'm gonna put this all

10:10 of it together for you and here have these columns and you can see

10:17 these bars here are shown in different and this color here has nothing to

10:22 with actually color processing but this color represents a different orientation of the bar

10:28 light. And so we said that this primary visual cortex itself responsive.

10:35 prefer certain orientation or orientation selectivity. these are referred as the orientation of

10:43 columns where the cells that are in within the yellow part of the

10:50 It will be responsive to a bar light that is at a certain

10:55 The cells that are located within the column, it will be responsive to

10:59 bar of life in a different And if you sort of a circle

11:04 this column and sample and this micro , the cells Here, you will

11:09 able to find the south that will responsive all the way 360° maximum and

11:15 to those bars of light and the that process similar orientation. So

11:22 dark, orange or red would be orientation. This versus this. They're

11:27 located closer to each other within the of this micro column. Now,

11:33 you were to look in the middle this call, in the middle of

11:36 column looks sort of like a pinwheel from which you have orientation specific cells

11:42 out of that central pinwheel. And central pinwheel will contain south that will

11:47 responsive to pretty much all orientations because really the collection of the cells that

11:52 coming from the uh from the bigger of the outer boundaries of this micro

12:00 centering into, into this pinwheel like . So these micro columns will find

12:06 individual cortex of monkeys of other animals well. It's called orientation columns Hubble

12:14 weasel where the scientists have studied it micro electorate recordings. Imagine how many

12:21 electrode recordings you have to make to out how this brain circuit actually processes

12:27 orientation columns. So now we have complex cells, we have concentric fields

12:35 we also can use techniques like both sensitive diets. So instead of using

12:40 electrodes we can actually image single cells numbers of cells within these micro

12:47 That's a huge huge advantage because we image potentially 10,000 cells versus making a

12:54 electorate recording from one or two And when you use voltage sensitive dye

13:00 it's a functional type of imaging. voltage sensitive dives communicates membrane potential

13:08 So you can see if the cell d polarized if its hyper polarized.

13:12 if you stimulate the vision right, stimulate the retina. You're looking in

13:17 cortex. Now you can look at whole window in the cortex and see

13:20 cells are active to this orientation, cells are active to this orientation and

13:25 on. And by doing that now can describe all of these. You

13:30 see this is a much larger chunk the visual cortex but within that you

13:34 see a number of these orientation micro that are about 3200 and 50 micro

13:41 wide and neocortex is about two millimeters or so you can see that these

13:49 be individual cells. For example each of these dots is an individual cell

13:54 on top of these dots and then apply this color coded pattern which the

13:59 coded pattern really represents orientation selectivity. this is how we know. Not

14:06 poking endlessly. You have to record how many of two million cells

14:15 Well you can image two million cells one experiment and if you have good

14:21 resolution you can resolve it in a cell level. If you don't you

14:24 see sort of a circuit level Now these orientation columns is just a

14:33 of the largest structure, bigger what call hyper columns. If you think

14:38 hyper columns and even orientation columns that some way are very elementary computational

14:46 And these hyper columns are also somewhat because these hyper columns would still be

14:52 closing only limited information processing within uh structure of the brain like the

14:59 So but they're still interconnected. And the elementary computational modules interconnect, they

15:08 more complex. When they interconnect multiple with multiple modules in another brain structure

15:17 also becomes more complex hierarchically functionally and processing of the information in the higher

15:27 centers. What you have here is you remember ocular dominance columns, Ocular

15:33 columns here are shown by these So C stands for contra lateral I

15:39 stands with bilateral area. This is a lateral area. So within these

15:46 ocular dominance columns. That's what we early on basically. There is a

15:50 more specificity and there are other hyper and orientation columns that are located

15:58 So what this shows that within the of the ocular dominance columns you will

16:04 multiple of these beautiful pinwheel like color . Which means that within each ocular

16:11 columns you have multiple selectivity, selectivity micro columns. You can see

16:21 these are the blobs. So this the side of chrome occident, see

16:26 and you can see that it's somewhat the center of the ocular dominance

16:32 It's concerned with colour information processing. you have the blob like structure especially

16:38 layers 2, 3. And then is another type of really interesting

16:44 So we talk about both extensive I'm gonna in the next section show

16:50 a little bit more about that. what's really interesting is you can actually

16:55 activity of the brain without applying any . And it's called intrinsic optical signal

17:01 . When we talked about F. . R. I. Or pet

17:04 we said what what is the functional really represents? It represents metabolic

17:10 It represents changes in the oxygen glucose levels represents how much those neurons

17:18 demanding the oxygen of workouts and when get active and they demand oxygen and

17:24 and they fire a lot of action and they d polarized what happens to

17:28 . They also swell to act in circuits. The south that are very

17:34 on fire, they become slightly larger they swell. And what happens when

17:38 swell? The plasma membrane stretches a bit. And as a consequence of

17:45 you have changes of the reflective properties the tissue. And this is called

17:51 optical signal or intrinsic optical signal meaning its intrinsic because there is no

17:58 that is being track there. And you are looking only at the

18:04 activity to these kinds of experiments with optical signal may actually show you if

18:10 have the surface if you can get layers four, that's one thing.

18:14 on the surface you can see the and darker shades And that's because when

18:19 stimulated one I one of the cells cells to responsive to that I would

18:25 swelling. And there was like with would be slightly different. So you

18:30 to employ multiple methodologies, experimental neuroscience . Multiple sensitive dye imaging, imaging

18:38 voltage or imaging calcium fluctuations is another way of tracking activity. Or intrinsic

18:45 signal imaging which is reflective properties of the south based on the self

18:51 That one particular number in potential ion calcium tracing. Of course the fact

18:59 the matter is you have sophisticated vasculature innovates the cortex and innovates the primary

19:06 cortex and the micro capillary is the distance that you would find in the

19:12 between the micro capillaries is only 50 apart. That means that only five

19:19 Mazz 10 micrometers in diameter. Maximum so moses away is the further station

19:27 2.5 so much is because five and so 2.5. So much away.

19:31 is micro vasculature of blood, oxygen nutrient supply going into the brain.

19:38 with intrinsic optical signal. If you the correct set up, you can

19:44 visualize the ocular dominance signals and you visualize the preferred orientations using another imaging

19:53 and then you can put it all together. These are my small orientation

19:58 . Those small orientation columns go into ocular dominance columns. These larger ocular

20:06 columns make larger hyper columns which will information from both eyes, contra lateral

20:15 . So this is really the true . So this is kind of a

20:20 all of the central processing together Within circuits. And this indicates that hyper

20:29 is about 1 mm in in So we talked about 5240 50 micrometers

20:37 orientation selectivity calls. So you can the math that it will include about

20:44 or so orientation. Uh selectivity Poor ocular dominance columns or so.

20:52 this is the structure. This is anatomy that underlies the function the function

20:58 the representation of the primal sketch that discussed. And so there's of course

21:03 anatomical structural properties. Then there's orientation as cellular or um receptive field properties

21:12 which the information that we generate visual is built on. So this concludes

21:19 information on the visual system. This now the review for midterm too.

21:30 I'm just continuing as a part of lecture and end of in this

21:37 In the initial lectures we talked about discovery of chemical neuro transmission. We

21:44 about how water polo, we used vagus nerve stimulation which you now know

21:51 cranial nerve 10. And you know that vagus nerve released the single Colin

21:57 that acetylcholine was inhibitory on the cardiac and that there are two types of

22:04 that we know chemical and electrical and synopsis allow for very fast flow of

22:13 and small molecules like secondary messengers and Synopsis is very important for synchronization of

22:21 networks themselves. And I refer to gap junctions. In the last reference

22:28 gap junctions we made was in the circuit When we talked about horizontal cells

22:34 are inhibitory cells that contain gap junctions them. And that should indicate that

22:41 how the broad areas of luminescence in retina or sharper areas are created through

22:50 the gap junction signaling in the You have the pre synaptic components with

22:58 zones and the pasta nappy components with past synaptic densities have a variety of

23:05 . The excitatory synopsis are asymmetrically synoptic post synoptic with round vesicles, inhibitor

23:14 . If you were to look at microscope imagery would have these flattened vesicles

23:20 symmetric synopsis. Then we spent quite bit of time talking about neuro muscular

23:26 . So we talked about how the that come out from motor neurons in

23:31 spinal cord and we use this neuro junction because it is simple, there's

23:36 one neurotransmitter acetylcholine and when the civil is released it will guarantee acetylcholine receptors

23:44 the civil choline receptors will generate this potential that we call and play potential

23:49 will always result inactivation of both educated and calcium channels deeper within these junction

23:58 falls which will be responsible for the of the action potential skeletal muscle action

24:06 . And in this case the seal is excitatory because its skeletal muscle and

24:12 also excitatory because the past fanatical you have I on a tropic nicotine acetylcholine

24:20 . It's only only one neurotransmitter acetylcholine it's only excited for boston ethically for

24:27 gated receptor channel. You only have acetylcholine receptor. There are certain criteria

24:34 neurotransmitters that have to be synthesized there to be transported into vesicles really

24:41 Re synthesized. Re transported, buying applicant caused post synaptic effect, activate

24:49 trophic cascades and we'll come back to slide because we talked about different neurotransmitter

24:57 and different neural transmitter system types. and we highlighted the amino acid neurotransmitters

25:05 glutamate and glycerine gaba and glutamate uh major excitatory is glutamate the major inhibitor

25:14 gaba in the brain. And the inhibitory neurotransmitter in the spinal cord is

25:20 . But we also talked about licensing co factor in excitatory N.

25:27 D. A. Dramaturgical transmission in C. N. S. It's

25:35 function of the molecule depends on what it binds and what what part of

25:40 receptor it binds. Yes. Or you repeat the question? But for

25:59 holding like excited for a home in guarantee the reversal potentials for different

26:07 We discussed as uh for acetylcholine it's also zero melon balls. It's

26:13 employee potential. Yeah it's the same for ep sp also. Well for

26:20 . P. S. Speed is and I PSP if you're looking at

26:24 Gabba A it's chloride reversal potential dependent B. Is potassium. But if

26:32 don't mind, let me get through of those sections because those themes are

26:36 up ahead and then I'll pause in 10 minutes or so and see if

26:41 have any questions about that. We discussed the meaning neurotransmitters and different

26:47 Acetylcholine dopamine norepinephrine histamine norepinephrine serotonin. talked about peptides but only how they

26:55 different in the sense of their synthesis and storage in comparison to the neurotransmitters

27:02 neurotransmitter vesicles that are located mostly optical and inside this box we inserted

27:09 neurotransmitters. So I urge you to this unusual neurotransmitters such as gasses nitrous

27:17 carbon monoxide such as endocrine adenoids such our economic asset and A.

27:25 P. So mentions of these may up on the exam but in general

27:32 pre synaptic neurotransmitter vesicles to fuse. have to have pre synaptic deep polarization

27:38 is the action potential influx of An influx of calcium is necessary to

27:44 the protein protein complex fusion so that can be a neurotransmitter molecules release.

27:52 it can be in the C. . S. This really is going

27:55 be partial or full which doesn't happen the muscle. So you can have

28:00 partial command if partial contraction that means if something is wrong. And so

28:07 the C. N. S. potentials the E. P.

28:10 P. S. Are much smaller on the order of only half a

28:14 volts as opposed to in the neuro junction, 17 million volts. So

28:18 need many many different synopsis and neurotransmitter fusions in order to activate the cns

28:28 . So the PSP is generated when is released and binds to glutamate receptors

28:35 there is this deep polarization. The is generated when Gabe's released. It

28:41 to gather a suffers and causes the polarization in the form of IPs there's

28:47 a tropic signaling versus metabolic tropic signaling tropic signaling. You can see the

28:53 of the ligand never opens a But instead it actually activates the g

29:00 complex which can activate enzymes and downstream messenger. Then we use the single

29:06 in system sort of exemplary system for that the means signaling. All

29:12 And we really talked about amino assets great degree glutamate and gaba and dopamine

29:19 . But we refer to immune And we talked in great detail about

29:25 synthesize the sudoku and choline with chat , acetyl transfers loaded up into vesicles

29:34 in the cns. We distinguish as C. N. S. Acetylcholine

29:39 you have on a tropic which is academic acetylcholine receptors and you have metabolic

29:44 acetylcholine receptors as well, not as as neuromuscular junction. Once a single

29:50 is released, you remember neuro muscular and here you needed to acetylcholine molecules

29:55 bind to the receptor in order to it. Once a single covid has

30:00 , it binds to the receptor temporarily then it gets degraded by a cyclical

30:09 . Once it gets degraded by into and acetic acid Colin gets re transported

30:18 through the sodium co transporters and Colin re synthesize acetylcholine with the help of

30:25 and re uploaded into the vessels. we discussed that going back to your

30:32 medications slide acetylcholinesterase inhibitors, some of most common alzheimer's medications because the acetylcholine

30:45 is impaired since an early pathology of disease. So by blocking a pseudo

30:52 degradation. You know, I'm making simple coding more bio available within the

30:58 where it still exists. So still will be an agonist to both nicotine

31:04 Mascarenas. Acetylcholine receptors. Nicotine will an agonist nicotine, it must korean

31:12 tonic and they will have their own , cure ari from little poison frog

31:17 atropine. So for example, if put your are in the neuro muscular

31:23 , you would block acetylcholine receptors and you block the silicone and receptors you

31:28 block the end plate potential. And you block downplayed potential you would block

31:33 action potential and the skeletal muscle. if you block the action potential you

31:37 not see a contraction of the Okay. To an antagonist blocking the

31:43 receptor here, it would basically resolved no deep polarization in the muscle.

31:49 also talked about other means such as , l dopa dopamine norepinephrine,

31:57 I said that you do not have know they're into intermediary uh enzymes here

32:03 synthesis but you do need to know details of acetylcholine but it does follow

32:08 similar Cascade here that we discussed. three update and we discussed how the

32:17 that degrades catacomb means is located on membranes off the mitochondria, I mean

32:28 and so the therapies that would be cata column immune systems can also be

32:35 A O inhibitors. So you would inhibiting the enzyme that is degrading the

32:41 column and this is another strategy therapeutic . You can have something that goes

32:45 the synapse and blocks of degrading a Colin asteroids in the studio collection system

32:51 you can have something that's inside the and maybe inhibiting this enzyme around the

32:56 mitochondria that's responsible for degrading catacomb. thereby prolonging uh by a little ability

33:05 more violent available. Also blocking the . I mean with amphetamines or cocaine

33:14 cause if you think about norepinephrine, is like nor adrenalin or adrenaline of

33:19 brain that would cause a speed That's why they're called, What are

33:26 called? Not the speed drugs but uh uppers uppers. It's it enhances

33:33 signaling within these pathways but it can be highly addictive a negative effects as

33:42 . Uh Those are illegal substances that talking about. We're not talking about

33:47 substances. Glutamate, glycerin, glutamate synthesized with God turns into Gaba

33:58 into neurons. Serotonin an interesting Each one of these systems deals with

34:06 different. Norepinephrine, Abramoff rana's fight flight response. Serotonin mood,

34:15 sleep learning a different response. Serotonin . PROzac which is pharmaceutical medication will

34:23 controlling the re uptake of serotonin from synapse. So start o'nan is in

34:27 way a happier mood molecule. And will see certain logic treatments and cases

34:33 depression and the cannabinoids are different because they can adenoids are synthesized on demand

34:39 synaptic quickly. They're not stored in vesicles there. The number is

34:44 They will use this retrograde mechanism to back into the pre synaptic side where

34:51 receptors are located. So if you receptor activation prison africa we will activate

34:56 G protein complex which will shut down channels by shutting down please sign up

35:03 calcium influx and the cannabinoids will regulate release of both excitatory and inhibitory

35:09 So there is deep polarization induced suppression inhibition when there's a lot of deep

35:16 . There's going to be under cannabinoids of that release of inhibition or that

35:22 of excitation essentially balancing the release of to inhibitory neurotransmitters. Delta nine THC

35:30 is a molecule that is found in plant. It's a psychotropic psychoactive molecule

35:37 causes the high effect THC DELTA nine will be acting through CB one receptors

35:44 it's a natural substance that is synthesized cannabis plant. And if you are

35:49 my other course the graduate course, just finished talking about how DELTA eight

35:54 which you find advertisements for around different shops and gas stations and baby shops

36:01 . Delta H. THC is a synthetic cannabinoid that doesn't come from the

36:06 . The process that turns DELTA eight from another can avenue it's called CBD

36:12 is not the cleanest process. There's medicinal benefits that are known to DELTA

36:18 THC. There is very many accepted and medicinal benefits for DELTA nine

36:27 We don't know exactly the methods each uses to produce after a THC And

36:35 . People have really strange reactions to eight and once they've used Delta nine

36:41 also report they have very strange reactions Delta eight. So it's not because

36:45 tried something that is new psychotropic away that's something to be aware of.

36:50 these molecules interact with the cannabinoid system also interact with other systems in the

36:57 . You know is the chemistry and hybridization of the two common techniques but

37:02 you can label neurotransmitters. One uses , another uses the radioactive the label

37:09 of nucleic assets engaging neurotransmitters or neurotransmitter . We discussed that if you are

37:17 neurotransmitter in the fluid you would have significant dialysis. And so if you

37:22 to study very precise activation of single you would use something like engaging of

37:28 and laser photo license in order to very precise areas or single synapses along

37:35 down right? So you can study the currents flow along the done dr

37:41 have different types of synaptic integration. we talked about how you produce a

37:46 ep sp and we'll look into the of that E. P.

37:49 P. And if you have spatial where three accents are activated at the

37:54 time you will have the maximum response will some overtime at the same

37:59 And if it's summed over over Sorry but if it's summed over

38:04 Like in temporal summation you can see the PSP is going to be much

38:09 than just by producing a single action to producing three action potentials. You

38:15 grow on this deep polarization. It not be as maximal as spatial estimated

38:21 , but it will be longer in actually. And that is important.

38:28 as we look at the concept of voltage lambda, which is the length

38:35 . And dendrites that are non myelin structures that are non myelin ated were

38:41 will leak out over distance. It's doesn't have the cable installation like the

38:49 do. And if you insert the and produce the maximum current here,

38:57 at this Area, right here, distance away from that area, that

39:04 is going to die down and at point it goes to 37% of maximum

39:10 at the injection side. This distance space is referred to as the length

39:17 . So the cells that have a length constant this will persist over longer

39:23 . The cells that have short line are leaking. This curve would be

39:30 in much steeper fashion. In order the cell to generate the action

39:37 you have to have many synapses that active. Each synapse is half a

39:42 evolved And the threshold for action potential -45. So you have to have

39:49 of excitatory synapses activated and then you inhibitory synopsis and those inhibitor synopsis are

39:55 to cancel out part of this excitatory a lot of times inhibitory synopsis are

40:00 to be located closer to the That's just by design. And cns

40:05 they have this control of the paris region so there's strong control but remember

40:11 outnumbered only 10 to 20% in the will be inhibitor in generals. They're

40:18 very diverse and the population many different of inhibitory cells and they have a

40:25 of targeting mostly these para somatic regions controlling mostly the integrative properties, how

40:31 cell is going to integrate all of inputs coming in. And so if

40:36 is an activation of excitation and inhibition the same time at the level of

40:41 soma you may not see any response maybe it's essentially will cancel each other

40:46 . Part of the current will leak . Part of the current will get

40:49 through this inhibitory currents to And so have to have very significant activation on

40:56 down director of the selma significant input order to have the cell generate the

41:02 potential. Uh metabolic tropic signaling is referred to as modular. A torrey

41:10 because it modulates downstream cascades. It also modulate downstream channels and it can

41:17 so by force for relating them with kindnesses. Or it can do so

41:22 defrost, correlating them using phosphate So this is the point we say

41:30 . This is what we're referring to that's switched. These are our major

41:45 again repeated here. This is the I really want you to know all

41:50 the details on. So I showed live five times maybe six times in

41:57 contexts. So you can expect at five or six questions along these systems

42:02 we're talking about. A single And so Mascarenas. Acetylcholine signaling would

42:08 linked to the g protein cascade. you can see that in some cases

42:13 call this g protein signaling shortcut That means that the g protein complex

42:18 is going to bind to a nearby which in this case is potassium channel

42:23 going to open potassium channel, opens channel positive charge is going to be

42:31 the cell. Therefore activation of this . Acetylcholine receptor is going to cause

42:38 hyper polarization of the plasma mom. . So we talked about the fact

42:43 nicotine nick acetylcholine receptor will cause an of sodium and potassium sodium D polarizing

42:51 cell and masculine IQ will cause the of potassium channel downstream, causing the

42:57 polarization. So they that the central system synopsis, they act in opposing

43:04 . As far as the numbering deep hyper personalization assets are different from uh

43:13 mean neurotransmitters assets are produced everywhere in brain. So you will find assets

43:18 different neurons and brain stem throughout brain and the C. N. S

43:22 the cortex. Primary visual cortex and is very intricately involved in control of

43:31 glutamate can be imported into glia with . Santa's turned into glutamine and then

43:37 imported back into neurons with contaminates. synthesize into glutamate and reload it back

43:44 . And post synaptic aly glutamate receptors also iron, A tropic and metabolic

43:50 . I don't know why I jumped catacomb and start Tony Already reviewed

43:55 This is another system and metabolic tropic . In this case you have norepinephrine

44:03 which is stimulatory and produces cyclic GMP turns on the production of protein

44:09 And you have alpha two receptor which inhibitory will reduce the general cyclist production

44:15 control protein kindness by reducing its So unlike the amino assets that we

44:22 be coming back to in a But we're finishing with the means

44:25 Those means are expressed in very specific . So rafi nuclei will express serotonin

44:32 the projections from the stone Amos of neurons that produce produce serotonin will project

44:40 lee throughout the cortex of cortical areas into the preference of the spinal

44:45 No more referendums producers and not a locus Aurelius. Acetylcholine is produced in

44:55 couple of nuclei here. Uh This this is uh you can't really read

45:04 the slide. Uh Let me see I can larger though but so be

45:11 to answer the questions. For example which nucleus is producing norepinephrine which nucleus

45:17 producing serotonin which nuclei are producing a Colin. So please please review

45:24 It can be a labeling question can just a simple multiple choice questions related

45:29 this. The big difference here is you have these nuclei. So if

45:33 were to take out local civilians like remove local civilians there would not be

45:40 made in the brain anymore. So if you were to take out one

45:45 hemisphere of the cortex you would still a lot of glutamate Gaba and all

45:51 the amine acid neurotransmitters that are being produced everywhere. And the cannabinoids are

46:00 and also nitrous oxide, carbon monoxide also not stored in the vesicles.

46:05 acid is also number insoluble. These the major endocannabinoid anandamide and two

46:10 G. And the two mechanisms or the polarization to suppression of the

46:17 the polarization of the suppression of This retrograde negative feedback mechanism by which

46:23 cannabinoids act in the brain. Just uh glutamate. Gaba also has transporters

46:32 gets uploaded into vesicles and gets released . We focused on iona tropic and

46:40 tropic signaling a little bit mostly on tropic, ample kind nick and India

46:45 they have each own agonists and We talked about the fact that once

46:52 is released it will bind to ample NMDA receptors and ample receptors will open

46:59 and ample receptors are responsible for the the rising phase of this excitatory post

47:04 potential and then M. D. receptor is have a magnesium block and

47:09 order to alleviate that magnesium block and . D. A receptor has to

47:13 glutamate. Mountain also has to detect polarization. Is the initial deep polarization

47:18 happen to ample receptors which will kick the magnesium from an M.

47:23 A receptors and then an M. . A receptor will be responsible for

47:26 late portion of this E. S. P. And will also

47:32 large amounts of sodium and calcium inside south. So AMp A cane has

47:39 conductance of about 20 Picasso demons and D. A. Has a conductance

47:43 50 P. Cosima. So it's to open that channel. It needs

47:47 have both pre synaptic and post synaptic . That's why it's referred to as

47:52 detector coincidentally it detects pre synaptic glutamate post synaptic deep polarization in order to

47:59 . Once it does we will conduct times more current causing that prolonged deep

48:05 in the PSB al pacino and have own antagonists or blockers. Just CNN

48:11 . X. And N. D. A. Has its own

48:13 HPV. And that comes up when talk about the ivy properties of amber

48:18 an M. D. A receptors be a tropical intimate receptor is not

48:25 any way in an M. A receptor NMDA receptor is on a

48:30 just blocked with magnetism don't confuse it metabolic tropical element receptors. Measurable tropical

48:36 and receptors well again actively the G cascade, just mostly acting through possible

48:43 . They see signal. This is experiment which shows that in normal physiological

48:50 $1.2 million magnesium, there is very of an M. B.

48:56 Current and hyper polarized potentials that the potential for an NBA receptor occurrences zero

49:03 volts reversal potential for ampara receptor currency also zero million balls, which makes

49:11 reversal potential for MPS B also zero vaults because CPS P is a combination

49:19 Tampa and N. M. A. Signaling and these potential the

49:23 potential. So you can see that receptors are quite active. Now if

49:28 remove magnesium. So if you eliminate from the solution, extra cellular

49:35 then at these negative holding potentials minus hyper polarized potentials. You will be

49:42 an M. D. A So that proves that magnesium is blocking

49:45 M. D. A receptor. is not enough to open this receptor

49:50 hyper polarized potentials. But if you magnesium glutamate is enough to open an

49:57 . D. A receptor and this abnormal conditions. So if you have

50:01 in the levels of magnesium, you have the excitability of the cells go

50:07 because there will NMDA receptors will be lot more responsive to even ambient levels

50:13 of glutamate and the zero magnesium can used as a model to induce abnormal

50:20 and even seizure like activity and also be used as a model for

50:27 There are some similarities physiologically between the that happens in the cellular circuits during

50:35 and the one that happens during a attack. These are the I.

50:40 . Plots for an app and an . B. A channel. So

50:43 you measure this early component, which already know is an ample component and

50:48 follow this first race line just a milliseconds after the stimulation And you hold

50:53 number in potential at different voltage levels -40 plus 20. You can have

51:00 ivy block for this early component. can see how much current is flowing

51:04 different numbering potentials. And this will the early component plot which turns out

51:09 be linear. So ampara ivy plot linear and an M. D.

51:15 . I. V. Plot which measured at the second line, which

51:18 the late component here and represents really blue area under the curve here.

51:24 is an M. D. A and you can see that there is

51:27 blue area under the curve under hyper potential. So it's nearly zero.

51:32 when you do polarize the salad you see a little bit of an NMDA

51:36 here in late component and you can recording this. These are the closed

51:40 as the cell D polarizes the number potential D polarizes the minus 40 and

51:46 start seeing significant NMDA receptor current and current reverses its zero mil evolves just

51:54 the ample current and it prefers to in the opposite direction, in the

51:59 direction. Physiologically of course the cell potential is going to be fluctuating only

52:07 resting membrane potential around resting membrane firing action potentials and coming back hyper

52:14 a little bit. So it shouldn't sitting there constantly locked at positive,

52:19 of positive 40. But this is voltage clamp experiments that we can do

52:24 order to define the curves the V . So NMDA is nonlinear current And

52:32 is one. The other portion of experiment applied a PD which is an

52:37 . D. A receptor blocker. you can ask a question. So

52:41 a PV affect the early current. just told the Ap D specific to

52:45 M. D. A. And it doesn't. But you can prove

52:49 and you can closed or open It's in the presence of a PV

52:54 without a PV. It's not going affect the ivy plot for the sample

53:00 something. If you put a PV you were tracing this late current,

53:05 second line then this blue area under curve would disappear. This is without

53:12 PVS. The top line. This with a PV. This is without

53:17 P V. Bottom line and this with a PV and what it

53:22 These are the open circles. Now got this almost flatline which indicates that

53:27 no flux through N. M. . A channels. There's no late

53:32 current here. So this proves that PV only blocks the late component which

53:39 an MD. A compartment interestingly if have a single amino acid substitution in

53:48 M. Two trans membrane segment of emperor receptor you can have that cell

53:55 one condition with are with Q. is Letterman it will conduct calcium.

54:01 if you substitute glutamine with arginine are cell and that sorry that channel receptor

54:10 is not going to be conducting calcium . Apple receptors. So we distinguish

54:15 fact that all of them the receptors calcium but some emperor receptors will conduct

54:22 and the ones that will have the and MD. A receptors are only

54:27 at early developmental stages and that's why talked about silent synapses, meaning that

54:34 you have glutamate release and you only an NBA receptors, the synopsis will

54:38 silent. So there will be different that will be activating excitation during the

54:44 developmental stages. And NBA receptors have sub units and these subunits during the

54:50 and they also reshuffle and different subunits dominate during different parts of this critical

54:57 of development. Post critical period of into adulthood, ample receptors are very

55:05 So they can move from extra synaptic that are located outside the synopsis into

55:10 synopsis and they can move across plasma . Micrometers within milliseconds. Member tropic

55:19 for glutamate is this P. P. To breakdown through possible

55:24 P. C. Into a membrane diacetyl glycerol D. A.

55:31 Which can then activate protein chinese sea into the new hospital triphosphate which binds

55:38 I. P. Three receptor channels are calcium permeable. And so it

55:45 call up on the intracellular calcium stores cause the release of calcium from cytoplasmic

55:54 , smooth ectoplasmic meticulously kindnesses and phosphate . And there's a balance of these

56:03 someone specific that will control the phosphor and the phosphor relation of these

56:09 Gaba signaling amino acid channel. Gaba . This is where Gaba binds and

56:15 a chloride channel but other substances alcohol, then there are the as

56:23 uh which are anti epileptic medications, , sedatives and there are steroids that

56:33 have their own targets in these So when you think about agonists and

56:38 but some of them will be competitive . And when you hear a stable

56:42 agonist that means the two molecules are for the same binding side on this

56:48 channel. Non competitive means that one its own binding site. Neither has

56:52 own binding site. So these molecules lot of them will have their own

57:00 sites and sometimes they can be competing for the binding sites activation of Gaba

57:06 receptor tra will result in the influx fluoride and hyper polarization activation of Gaba

57:13 receptor boston optical, it will open channels and will also cause hyper polarization

57:21 present optically it will close calcium channels can control neurotransmitter vesicles release this similar

57:31 mm hmm. Um push synaptic Similar mechanism to the endocannabinoid. It's

57:41 similar mechanism. This mechanism of closing synaptic calcium here that we're seeing is

57:48 found with a denizen stimulation. And reason why I'm mentioning this to you

57:53 there's a redundancy in control of neurotransmitter and the cannabinoids can control neurotransmitter

57:59 But so there's Gabby can control neurotransmitter and so can a dentist in

58:04 There are transmitters abilities and they can it through these pre synaptic mechanisms we

58:09 do through the post synaptic mechanisms. I really like the slide and I

58:15 that if you have the slide in of you can understand everything in the

58:18 and add your own details to That this is a really good way

58:23 review things about neural transmission. So we talked about in the slide is

58:30 there's inhibitory synapse and there's excited to synopsis. This inhibitor synapse will the

58:40 Gaba. So it should stay in God. So you can add that

58:46 . You know it's staying for Alright now Gaba gets released and pastrnak

58:53 you can put this as Gaba a is formidable to chloride is going to

58:59 polarize and boston optical. you also Gaba B. And activation of Gaba

59:07 . Through G protein complex right through jew protein cascade will open potassium channel

59:15 cause more hyper polarization. So you put chloride means that this channel will

59:21 to reach acqua Librium potential for chloride is about -17. This channel potassium

59:28 will hyper polarize the cell will try reach the equilibrium potential for potassium Which

59:34 -80 -90 and themselves will be causing polarization. Now that same Gaba synapse

59:45 also contain pre synaptic Gaba B And prison optically you can see that

59:51 same Gaba B receptor is linked to too. So posten optically this do

59:58 complex targets potassium channels but prison optically calcium channels and what it does it

60:06 blocks calcium channels. These voltage gated channels that are necessary for the

60:12 bicycle fusion and neurotransmitter release. So does God would do? Well if

60:17 is Gaba that is spilling over retrograde back onto its audio receptors. Order

60:25 released gable and I am binding to own order receptors here. I'm going

60:29 control my own Gaba release Mhm. now nearby you have an excitatory

60:39 Senators and house will target ample and receptors posting typically this is an

60:44 D. A receptor that have shown is a significant source of calcium not

60:49 deep polarization of calcium and guess what discussed that calcium also as a secondary

60:56 . So there's calcium cal module and and that kind of is can affect

61:06 B. That are located fast synaptic in the excitatory synapse since and also

61:14 affect these channels through potentially phosphor relation channels in both cases doing what in

61:25 cases opening a potassium channel and causing of positive ion and hyper polarizing these

61:37 . So there's glutamate coming in deep through AMP and NMDA the cell and

61:42 calcium rushing in through NMDA on the stage of the PSP activists secondary messenger

61:51 . And through the interactions with Gaba . And potassium channel hyper polarizes the

61:59 . That has nothing to do with release, has everything to do with

62:03 metabolic tropic intracellular signaling. And the of Gaba B receptor is post in

62:08 and excited to the synopsis. So glutamate is here and then in addition

62:15 that if this Gabba allergic synopses very , then there's a spillover of

62:22 Remember it will diffuse through this interstitial in between the cells you have a

62:28 of Gaba Gaba b receptors are also preseason optical and excitatory synapses and their

62:37 receptions. Because these synopsis don't produce So Gaba binding to these gaba receptors

62:45 shut down calcium channels and will shut glutamate release. So now through this

62:53 mechanism Gaba and activation Gaba B receptor topically can control glutamate release and that

63:05 uh fairly significant to the same mechanism calcium channels present topically under cannabinoids control

63:15 channels through their own g protein coupled Denison also controls calcium percent catholic channels

63:24 its own g protein cascades. So targets through multiple medical tropic cascade

63:31 This is an example in many synopses will see in the initial deep

63:36 this E. P. S. . That is followed by Gaba ai

63:42 . And then the late component of will be gone by BP SP I

63:47 which is going to be even more polarizing because it is driven by potassium

63:52 is very briefly. We discussed it protein signaling and the variety of all

63:58 the jew protein receptors that we have notice that all of the means except

64:06 a single a single coding has an receptor. But most of the other

64:14 that you're seeing here and receptors are metabolic tropical. There's a huge variety

64:18 these metabolic tropic receptors, the seven member in segments. They are different

64:24 the transmitter gated channels. We reviewed Sistine locally in channel structure briefly and

64:31 said that there's different subtypes of these . Alpha, beta delta gamma and

64:35 you can have like a mixing of sub units in order to produce proteins

64:42 have slightly different functions. So what you have to know from this

64:46 Acetylcholine everything. Okay, Norepinephrine. functions of alpha and beta receptor,

64:54 they're different glutamate everything. Yabba you to know Gaba, A chloride,

65:04 b potassium and we only talked about eucalyptus gaba antagonist but I may ask

65:10 a question as ethanol and agonists. . Okay 80 P. Again

65:17 T. P. Is an agonist also dennison is an agonist. So

65:22 should know that and caffeine is an and you should know it because you

65:27 consume it every day. So if will block those present at the calcium

65:34 and block glutamate release caffeine is an to dentists and channels and it will

65:42 keep the calcium channel open and will glutamate release. This is the cascade

65:49 amplification that you have through the chemical transmission of activating multiple downstream cascades.

65:56 it's different from electrical because only a of electrical signal transfers. But immediately

66:02 synaptic transmission and chemical transmission you have delay whether you can activate these downstream

66:08 that can multiply the effect and then review that you have all sorts of

66:14 divergence convergence redundancy of parallel streams between receptors transmitters and and their downstream of

66:24 . This concludes our review session and out of time for this lecture as

66:32 . But I will be happy to any questions. I'm just going to

66:36 the recording so it starts

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