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00:00 So this is electric 12 of neuroscience we have covered quite a bit of

00:09 information may be new for you because you didn't hear it in other courses

00:15 we talked about the differences between neuro junction in the central nervous synapses and

00:22 had these things written out on the . So for those that are not

00:27 up to class, it doesn't show always the best on the board.

00:31 you kind of lose out or information directly conveyed to you and I

00:39 everyone to be attending in person, before spring break, it's really just

00:44 lectures left and then a spring break you know, so you have a

00:49 um then you could work a little harder and show up to class before

00:54 also work with the material. So you are not certain, like what

01:00 did you talk about neuro muscular junction central nervous system synopsis. If you

01:06 recall any of that information, you go back open the video, points

01:12 and watch those sections because even if doesn't show up clearly what I have

01:17 or written on the board, especially I make it drunk on that side

01:20 the board. If it doesn't show clearly, I'm speaking about it,

01:25 can still take notes, you can remind yourselves and compare if you're in

01:29 the most effective way. If you're class and took notes and you have

01:34 questions, I have some doubts about your understanding about subject matter, Go

01:39 that subject matter, look at what have in your nose. Listen take

01:45 notes, compare what you have in notes and then you're gonna be

01:50 So I highly recommend for you to that. Now. We're going to

01:55 our quiz next week on friday. on monday I will have casas start

02:01 the scheduling okay And it's gonna cover transmission and one lecture of the of

02:09 C. N. S not the one. So all of the material

02:13 next Tuesday were recovered through next Tuesday be on next friday's quiz. So

02:21 that's also a good time. If are not certain about some terminology or

02:29 the difference between nicotine nick almost Then it's a good time to review

02:35 material this week, this weekend and week going into friday to take the

02:42 . So you can ace the quiz then if you ace the quiz it's

02:46 your points. You get as many as you want And that really depends

02:51 how well you study. So if want to bunk yourself up by eight

02:54 10 points, you know study really and get a perfect score. And

03:01 what happens to your exam. Score Goes up by eight or 10

03:07 That's a lot. So that's that's . Great. I can't just add

03:12 and curve the average is fairly high advanced level undergraduate course but I can

03:18 you an opportunity to curve yourselves and yourselves better for the exam. Okay

03:25 last lecture we talked uh a lot a seed alkaline in particular and you

03:33 be able to recite and know everything acetylcholine synthesis, how it gets uploaded

03:42 the vesicles, how it gets how in the cns neurons it can

03:49 nicotine acetylcholine receptors and Mascarenas, acetylcholine . So we started looking at this

03:55 of uh neuro pharmacology. Okay, concept of neuro pharmacology where neural pharmacology

04:10 this case for acetylcholine, it's what the agonists? What are the

04:16 What are endogenous or naturally by our bodies produced agonists was a natural other

04:24 in nature, or agonists or antagonists could be produced. We talked about

04:28 and spiders and and snakes and what the, you know, what are

04:33 human synthesized chemicals agonist antagonists? What the action of Alzheimer's medication? What

04:44 the action of the nerve gasses? . There's all questions that can show

04:50 on the quiz and on the exam it's really important to know and understand

04:56 system because the system for seed locally the basis for other systems that we're

05:01 about. There is release of glutamate glutamate will bind to iron. A

05:05 and metal tropic receptors in the There's release of gaba and gaba,

05:10 learn will buy into ion a tropic metabolic tropic receptors for gaba in the

05:17 . So we'll talk about other And if you look at other means

05:23 example, cata cola means class of or tyrosine is a precursor to L

05:32 . L dopa is a precursor to . Dopamine is a precursor to

05:38 Norepinephrine is a precursor to reference. lot of these molecules are actually precursors

05:44 each other. I don't want you know the enzyme times that you know

05:49 our box late things like take ceo group or hydroxy delays which add an

05:55 age group which you should already I'm not gonna ask you for specifics

05:59 what enzymes are responsible for converting a precursor into a molecule like dopamine.

06:07 the principle is the same. And cola means and in fact cata cola

06:11 will purely actor medical tropical storms. this is this is the difference

06:17 as I discussed between acetylcholine and this here of all of the neurotransmitter types

06:24 that acetylcholine has ion a tropic receptor and metadata tropic G protein coupled receptors

06:32 it can target. But all the means are acting through G protein coupled

06:41 . So if you have cattle colony release you also have a breakdown and

06:47 talked about how you have a breakdown acetylcholine in the synapse or cata cola

06:53 they can be transported back into the synaptic terminal terminal and there is mono

07:01 mono amine oxidase and this mono amine is will be responsible for the breakdown

07:10 cata cola mean like molecules and the synaptic terminals. So you can also

07:18 basically not only synthesis but degradation of neurotransmitters at the level of the synaptic

07:26 , pre synaptic aly and uh streets illicit drugs a lot of times they

07:36 targets in the brain also. So uh for cocaine, the illicit drugs

07:44 also molecules that would be medications We talking about how you have something natural

07:50 is produced in the body. You something that is natural, can be

07:53 and used as medication. We talked Botox. Can you be used for

07:57 purposes but then it can be used FDA approved medication. And the targets

08:04 , you know are the receptors in case the target is the re uptake

08:10 cata cola means. So you can target and block the re uptake and

08:16 you do. For example, if block the reuptake of norepinephrine and epinephrine

08:22 is kind of like adrenaline of the , something that engages you or the

08:30 , then blocking the re uptake again the by availability the presence of that

08:38 within the synapse, it's a common . So you can do it by

08:42 acetylcholine nestor race in the city alkaline pathway which is in the synapse or

08:49 exam or you can be blocking the uptake or you could also be blocking

08:55 oxidize here. Mono amine oxides prison which will also not degrade the molecule

09:03 synaptic list, it would increase the of that molecule being transported and uploaded

09:09 its appropriate class vehicles. So, acid neurotransmitters in general, what we

09:16 about is that they're widely distributed uh expressed by south throughout the brain.

09:24 so I drew this diagram here where can imagine that all of the blue

09:32 is inhibition, whether it's Gaba, for amino acids, neurotransmitters and the

09:39 dots are widely distributed self that are cells. And then these black nuclei

09:48 the collections of cells that will be the means. And so they are

09:54 limited and confined spatially. But they very broad projections that will go cortical

10:00 as well as sub cortical lee and the peripherally on a lot of

10:05 That will be central and peripheral outputs out from these nuclei innovating different centers

10:11 the brain stem and the brain and the spinal cord amino acids. When

10:17 talk about amino acids, Glutamate is precursor to Gaba. So the major

10:23 neurotransmitter in the brain. Glutamate is precursor to the major inhibitory neurotransmitter here

10:30 the CMS in the brain and I want you to know that the

10:36 that converts glutamate into Gaba is atomic dicker box or God. And that

10:44 important because if you were doing certain on tissue or cell subtypes. This

10:52 one of the markers that all of inhibitory cells would be expressing. Remember

10:57 talked about how the different subtypes of cells in hippocampus, They express different

11:03 specific markers. Some expressed so matter , others expressed peru albumin that all

11:10 the inhibitory cells will be expressing. . Because if you are inhibitory cell

11:16 you're synthesizing Gaba and releasing Gaba, going to have God, this enzyme

11:24 do the work for you now, uh going back to this uh to

11:33 uh to this diagram and it's it's again, the expressions are different,

11:38 precursors are different. Now serotonin here put mood, appetite, sleep

11:46 So the common theme that I'm trying convey is these neurotransmitter molecules, These

11:53 that are expressed in certain parts of brain and have the projections and interconnected

12:00 different parts of the brain are responsible different states, different behavioral states.

12:07 if you are in a fight or response, we will have a pen

12:12 , norepinephrine on on demand being being released from these nuclei to react

12:17 that situation. If you think about , you're talking about mood and you're

12:23 about here release of serotonin which will through medical tropic receptors. Re uptake

12:29 serotonin can be blocked with brand name called PROzac which is a very common

12:38 and anti anxiety medication. What it it prolongs availability of serotonin molecule and

12:46 means that serotonin is intricately involved in of mood and normal mental state such

12:54 you know, if you have abnormal state like clinical depression uh you will

13:01 treated with serotonin re uptake inhibitors. you will hear us S. S

13:07 so serotonin re uptake inhibitors, serotonin uptake of serotonin re uptake inhibitors.

13:16 doesn't get re up taken just like and blocks the re uptake prolongs the

13:22 of this molecule. A lot of um uh precursor for serotonin we actually

13:34 during thanksgiving when we typically in this but not in Canada interestingly. Uh

13:43 Turkey which contains uh trip to fan tryptophan is a precursor to Five

13:54 which is a precursor to serotonin You can see these are the structures

14:00 they're very structurally just slightly different. have the pro boxing group or the

14:05 box elated. Uh they have the group uh hydroxy will add a hydroxyl

14:16 . A lot of the medications that on the market that target like reacting

14:21 or antidepressants. They take a while start taking a significant effect on the

14:31 . This is one of the problems serotonin reuptake inhibitors is lately being called

14:37 question of how effective they are for of mood, anxiety and depression

14:45 It's being called into question, why it taking three weeks at least to

14:50 of see the fact. And there's search for alternatives. Alternative treatments and

14:57 enough psilocybin and the molecule that comes what is called magic mushrooms psilocybin has

15:09 shown to act against depression very And it's not completely known the exact

15:19 of different active ingredients in those in mushrooms. But very serious schools like

15:27 stanford, they're doing research where these like psilocybin are being used. Instead

15:36 reuptake inhibitors to treat mood disorders and treat addiction as well. So that's

15:42 interesting. Okay, so maybe that's you get sleepy, it regulates

15:48 Start coming in the park when you a lot of turkey, not just

15:51 your stuff but you also intake a of tryptophan during the thanksgiving. If

15:58 if you partake in turkey. The other molecules that we already

16:03 our endocannabinoid and the endocannabinoid, Czar cannabinoids that are produced austin optically and

16:13 there is heightened levels of activity prison inhibitory cells are excited to ourselves is

16:19 to be released. Another phenomenal uh if the cell has significant possum attic

16:28 , it's typically going to be mediated influx of calcium. And the mechanism

16:35 that when there's a lot of activity with these neurotransmitters like glutamate, this

16:41 starts producing under anonymous and anonymous. not stored in the vesicles, their

16:48 soluble. So they exit out of cells and they travel retro greatly to

16:56 pre synaptic terminals with a bind to cannabinoid receptors. This is CB one

17:03 cannabinoid receptor one which is predominantly expressed neurons and activation of CB one receptor

17:10 is G protein coupled receptor will activate G. Protium and this G protein

17:17 actually close the voltage gated calcium channel synaptic, what do we use?

17:24 gated calcium channels Before there are two that are necessary to release the

17:31 neurotransmitters and the vesicles. The deep and the actual potential. And the

17:36 thing is influx of calcium and calcium of protein protein complex fusion between the

17:43 and the plasma membrane, correct two . So if we block calcium,

17:48 what happens there is no particular So this is a retrograde negative feedback

17:58 . So imagine glutamate a lot of , a lot of excitability. The

18:03 feedback the air conditioning kicks in and cooling by sending and the cannabinoids retrograde

18:10 to prism optics sides and regulating the of neurotransmitters. So it stands for

18:17 . S. I. Stands for polarization D. S. I.

18:23 deep polarization induced suppression, pass And that is because endocannabinoid signaling was

18:45 in the brain. Uh And when was discovered it was first discovered in

18:51 inhibitory synopsis. So it was thought oh it regulates gaba release only that's

18:57 it was called deep polarization and do of an ambition. But we now

19:02 that endocannabinoid receptors will regulate both inhibition excitation. So there is D.

19:12 . I. And D. E. Which is deep polarization induced

19:18 of excitation. What that means is polarization where there is a lot of

19:25 apostle active activity, it will induce suppression of even inhibition or excitation.

19:35 by this virtue in the cannabinoids are well positioned in regulating and balancing the

19:43 and inhibitory signaling in the branch. you. The two major in the

19:49 on molecules that we know and we learned a lot about them and the

19:55 1990s when they were discovered. So is in the cannabinoid system. You'll

20:01 a couple of pages in your book that but it was discovered only about

20:06 years ago. So things take time get into the textbook but it's slowly

20:12 its way the whole endocannabinoid system which of enzymes that synthesizing the phenomenons their

20:22 to which these under Canaveral molecules bind then any degradation enzymes again. So

20:30 the Simula theme that you saw with neurotransmitters. The classical neurotransmitters right at

20:36 synthesized release the greatest and what's emerging is anandamide and two A.

20:43 Or to our katana glycerol. The major in economics of the brain emerging

20:49 one of some of the major a static regulatory functions in the brain

20:56 the body. So keeping up the and regulation of synaptic transmission now fit

21:06 with delta nine THC. Delta nine is a phyto cannabinoid. Anything that's

21:12 , it comes from the plant to nine THC is a phyto cannabinoids.

21:17 this is the most famous active ingredient the cannabis plant or marijuana plant,

21:26 it's cannabis plant. So Delta nine comes from Canada's plants and DELTA nine

21:33 although it looks different from anandamide and A. G. Has a binding

21:39 and interact with CB one receptors. nine THC is now an exogenous molecules

21:46 this plan derived non animal. So molecule that acts on the same receptor

21:53 the brain as in the cannabinoid molecules . Delta nine THC O. Is

21:59 known to cause and be responsible for high effect or euphoria effect. When

22:06 consume Canada's, it contains delta nine . You also know now because everywhere

22:13 gas stations and everywhere you see CBD here. So this is the second

22:18 famous cannabinoid after DELTA nine THC. we will address some of these differences

22:25 in the course, when we look the endocannabinoid system and interactions with these

22:29 . And my last comment to make that you also will see things like

22:34 eight and Delta 10 THC. And and Delta 10 THC is a derivative

22:44 either delta non or CVD CVD s dial Delta nine THC stands for tetrahydrocannabinol

22:53 Delta and Delta Town a synthetic derivatives these active molecules. And so as

23:02 learn things in the scores, be of things that are around, you

23:06 aware of things that you may be in consuming your friends are consuming because

23:11 a wild wild west of legal and cannabinoids. Fidel and synthetic cannabinoids and

23:20 of them can be quite dangerous. um Typically naturally derived by the cannabinoids

23:28 shown significant safety issues, dangers or apart from poisoning for kids and things

23:35 that. But with the recovery, other synthetic molecules, that's where there

23:40 a lot of unknowns and there are lot of unknown ways in which they

23:44 be prepared that concerns all of the drugs, cocaine have a huge problem

23:51 fentaNYL, which is opioid. And problem with fentaNYL is because it's a

23:58 dose is so small. And in for opiates and opiate medications when people

24:07 opiates, there's an effective dose. do people take? Opiates for

24:13 What is effective dose, Pain goes or pain is reduced. What is

24:18 ? Does you die? So, opioids, the effective dose is

24:27 The order of milligram or two And the lethal dose can be just

24:32 or three times of that effective And you see that patients overdosing when

24:38 using medications and that's why we see lot of fentaNYL deaths. Two because

24:44 it's extremely potent b it's a lot unknowns. It's illegal. There's no

24:52 process that regulated in any way. and that's why it is so

24:59 So the more you learn about these and the pharmacology in the brain and

25:04 pharmacological substances out in the world and know pharmaceutical cabinets and things like

25:11 Just be more aware about things that out are available and be smart about

25:19 . Now there's ways that we can neurotransmitters, a good way to study

25:24 as immuno chemistry in other ways in hybridization with immuno chemistry, you're using

25:31 , you create antibodies. So for you can take a mouse molecule neurotransmitter

25:36 interest and inject it into a And this rabbit is going to recognize

25:41 foreign molecule found from a mouse. it's going to start generating antibodies for

25:46 . So you can extract the You can isolate the antibodies. These

25:50 the wide looking wide structures under those could be tagged with the visible marker

25:57 as colored marker fluorescent market, that image under a microscope. And those

26:03 are going to be specific to that of interest that you isolated and injected

26:08 another animal to generate the antibodies. now what you do is you want

26:14 ask a question, which ones are cells here are God positive. So

26:20 have a slice and looking at the of the Hippocampus which sells the Gods

26:26 . How many are looking at 100 going to be five cells out of

26:31 . Where are they located? So would use them, you know history

26:35 and you would apply that antibody typically procedure is I'm in a slice brain

26:43 and you add a little bit of that detergent breaks the walls of the

26:47 a little bit allows for the antibody go into the cells. And then

26:52 wash it several washes and the municipal procedure. And you know because it's

26:57 on the immune reaction antibody. you wash the slides really well.

27:04 so the cells that don't express there's nothing for that antibody to stick

27:09 and bind. So they get washed . And the cells that contain the

27:16 that we looked at before the sauce will be inhibitory cells. They'll all

27:20 the antibody stock to them when you it under the microscope. The south

27:25 positive will light up with some visible color marker. Typically fluorescent market and

27:31 can do dual triple quadruple some some some labs and some um uh The

27:39 and clinics are very sophisticated. They do 678 antibody. And you notice

27:45 chemist to confirm staining and there's a of details about these antibodies. But

27:52 is a good way to visualize. are the cells that are expressing a

27:58 or an enzyme will use God you do equivalent for God. And you

28:02 do it for neurotransmitter. Hybridization is different technique here. You have radioactively

28:09 probe that has the proper sequence which the known sequence of complementary nucleic

28:15 The non sequences because we know what genes code for. So you can

28:21 a certain sequence to be prepared for radioactivity label and sent to you that

28:27 target a specific strand of messenger RNA Euro. And the cells that will

28:33 that messenger RNA, which means that cell of interest that's a messenger for

28:39 will show a radioactive label and themselves like the wood wood. So the

28:46 antibodies versus radioactively labeled strands target RNA antibodies bind directly to enzymes or

28:59 of of of interest mimicry. We know about this. If I stimulated

29:06 cell we learned that this is excited itself is going to excite. This

29:12 is going to be deep polarization And so if I uh isolated glutamate

29:18 the Saxon or this neuron and uh glutamate here would also excite this den

29:25 and I would see a deep polarization we also talked about in Cajun

29:30 So this is the original kind of neurotransmitter of mimicry and application of the

29:36 that we talked about how to be from the to have a lot of

29:40 and especially non specific spread of the and that using uncaged of neurotransmitters

29:47 Just reminding you with photo lice, you remember in the cage neurotransmitters occasion

29:52 chemical cages and those cages are broken very fast lasers. So we discuss

29:58 briefly before two and immunize the chemistry cdo hybridization. Either one of these

30:05 could be used not only to study small circuit but look at for

30:09 the whole expression of a molecule of in this case it's an expression of

30:15 drug B I was ST chinese type receptor and R. T.

30:20 Two and it's in the embryo. this is uh an important slide because

30:27 tells you so does that mean that molecules and expression of these molecules is

30:33 same throughout life. Is the expression different receptors and different chemicals change as

30:42 develop. Of course it does. about the location where they located?

30:48 did they start first? Uh showing with the chemistry? It's uh 12

30:54 of age or 20 days of That tells you something about the

30:58 If you catch one of the first for a specific receptor. So you

31:03 that this is 14.5 day miles What if you stand at 12

31:09 12.5 days and you saw nothing 13.5 and you didn't see any stain

31:16 The stain is everywhere. You see is this receptor, you didn't see

31:20 . And then on day 14.5 you saw this? What does that

31:25 you? That's when maybe the expression that molecule started. It doesn't all

31:31 at the same time or maybe that's you located the final in the in

31:35 tissue or brain area of interest that looking at and now you're have a

31:41 . So you can look at the expression of these molecules. You can

31:47 at the temporal expression of these molecules as a function of development, as

31:52 function of aging. They can be as well. Now when we talked

32:01 neurons, we said that neurons receive and inhibitory inputs and we also talked

32:12 how excited they inhibit the inputs. inputs are small. So we talked

32:19 in the neuro muscular junction, we inflate potential. So typically a change

32:24 about 70 million volts and numbering And in the C. N.

32:31 we have E. P. P. S which are excitatory synaptic

32:36 and I. P. S. . S. And those are approximately

32:42 mill ball change. Right? So E P. S. P,

32:47 would be a deep polarization and for . P. S. P.

32:50 going to be hyper polarization. And we talked about how if you have

32:56 threshold for action potential generation at -45 bowls and you have the cell resting

33:05 potential, Resting membrane potential of -65 balls action potential gets generated only if

33:14 member and potential reaches this threshold So the cell, as we talked

33:19 could be receiving small excitatory inputs, inhibitor inputs, stronger excited for an

33:28 inhibitory inputs. And finally if it this threshold, these are graded potentials

33:37 . P. S. P. . I. P. S.

33:39 . The graded potentials. The synaptic are for graded and then it will

33:44 an all or non action potential. what needs to happen in order for

33:52 change of 20 million balls to take , you have to engage a lot

33:57 excited synopsis. This excitatory synopsis may counteracted by the inhibitory synopsis. So

34:05 you have one excited tourists in apps and at the same time you have

34:12 inhibitory synapse activated on the same neuron at the same time what is going

34:18 be the average response? Virtually no . Okay, maybe even inhibition could

34:25 stronger and it could be biased or . In addition maybe in addition was

34:29 and excitation was 0.37 million rolls because slightly different. Uh number 2.5 the

34:37 and slightly different. Number 72 notable the neuro muscular junction. So there

34:42 a strategy. Now if you I to cause a strong polarization you can

34:50 multiple neurons and synopsis in the same similar region. And this is called

34:57 summation. And if you activate multiple at the same time you will see

35:02 instead of the small deep polarization from synapse from many synopsis you can get

35:08 larger depersonalization. So it's a spatial . What happens if you have one

35:15 but instead of producing one action potential from one neuron to get a Smalley

35:24 you send a train of action repeating action potentials, what you're seeing

35:31 that there is a summation over Which is temporal summation. You can

35:39 see that the summation over space is than information over time. Because over

35:47 as you reach the peak of the it also starts decaying. So it

35:53 on the frequency of the stimulation will the amplitude of the final complete

36:04 And as we talked about when you polarize dendrites, dendrites are not

36:10 So there's going to be leakage of from the cable. So you inject

36:17 strong current here at this location with electrodes and distance away you can record

36:23 see what is the attitude of that which we've injected. And you'll see

36:28 it dies down the voltage that you the DM. Change it dies down

36:34 distance. So if you injected here the electorate is 100% maximum change in

36:43 you cause with that electrode here you the maximum. Change 100%. And

36:49 electrode actually is located here and when reaches the 37% of central very

36:57 37% value of the maximum which is . O. Value. That's what

37:04 call the lambda or the length, voltage. How far can this voltage

37:14 before it decays to 37% of its allowing how far can this current without

37:21 out travel. And what is going be evolved and changed from the original

37:26 to the location from distance away. some cells have varies uh length

37:36 So if it's a long length constant ? If it's a really long lambda

37:44 means that there's decay can take a time. So this is A short

37:54 from 100 here. 2 37%. you can have a long lander here

38:09 it reaches 37%. But this specialty mean a difference of five micrometers along

38:19 dendrite longer length concept. That means longer length constant, the voltage change

38:24 the current changes sustained and preserved longer length, longer length, longer

38:34 Now this is what's happening excitation. excitation is active. You can cause

38:40 E. P. S. In the done drive. And that

38:44 that only a fraction of that polarization gonna be. And that's only if

38:50 no inhibition. But now you have . When we discussed this in many

38:55 there's a lesser number of inhibit ourselves the CMS in hippocampus. 10 to

39:01 of all the cell population. Very with lesser number. But we also

39:06 that inhibit ourselves will target these proximal . They're just strategically located to target

39:12 proximal areas around the selma. Why is important because you can really influence

39:17 integration properties of the cell. Whether cell you can affect whether the cell

39:22 going to be inhibited or in this you have a lot of times distal

39:29 . You have excitation of this P. S. D. In

39:33 absence of inhibition is small in the in the selma but in the presence

39:39 inhibition it's also referred to a lot fans as shunting inhibition and channels are

39:45 and more current cell. Even when inhibitor synapses are activated, what happens

39:50 the level of the soma. You see any response. So this one

39:58 here excited to input distantly was completely by a proximal inhibitory input. And

40:06 does it mean for the boss that action potential or no it means nothing

40:13 change. And that's why you have engage multiple synopses et spes in order

40:20 reach the threshold for action potential generation the in the C. N.

40:26 . When we talk about medical tropic transmission, you'll also see a lot

40:31 times neuromodulation and this is another way talking about modulation while in the brain

40:39 neuromodulation neuromodulation. What is the difference neural transmission? The neuromodulation neuro transmission

40:50 you have a release of neurotransmitter that binds post synaptic receptors and it generates

40:57 pure I PSP through ion a tropic but you also have medical tropic signaling

41:05 in the case of medical tropic You are affecting downstream targets through this

41:12 protein complex are affecting nearby receptor channels can cause they're possible relation adding a

41:18 . 04 group which can change the of the channel for a longer period

41:25 time. You can also activate secondary and even the transcription factors in the

41:33 of the cell which will exert long effects on the system. So it's

41:38 the quick neuro transmission and generation of P. An I. P.

41:42 . P. D. Polarization and polarization or actual potential. But it's

41:46 the cellular mechanisms that are typically longer and typically needed nuclear mechanisms to be

41:54 if you want to have really significant long lasting changes in the brain

42:04 Alright, so these are all of good ways that we can study.

42:07 is another way of thinking about amina . Acetylcholine serotonin like molecules cata cola

42:18 like molecules uh And this is what been discussing. Um The last couple

42:27 lectures so review all of the information acetylcholine synthesis, neural pharmacology of acetylcholine

42:38 metabolic tropic signaling. Most suffer will G protein complex and this g protein

42:49 will target potassium channel which will open passing show. Hmm. So neuro

43:01 junction. We have only nicotine in . Yeah. Thank you. Thank

43:14 . So we only have nicotine building happens in the C. N.

43:23 . We have an academic calling receptors are channels right. We already talked

43:34 how they will allow for the influx sodium and also the flux of potassium

43:42 initially the influx of sodium is gonna small deep polarization to these cns narrows

43:51 not talk about neuromuscular junction cns well us now. So the same molecule

44:01 gets released as little Colin nearby may a G protein coupled mascara Mick acetyl

44:11 suffer and that muscular acetylcholine receptor through jew protium is going to open potassium

44:22 and it's going to cause costume and what happens when positive charges leaving it

44:34 hyper polarization. So this is where the same molecule on the same

44:40 the same neuron Mako express nicotine, and metra tropic masculinity receptors. Same

44:46 will bind, causing small deep polarization nicotine And through medical tropic with some

44:52 it will cause a small hyper So in the end the effect on

44:59 cell is very different and the effect the cell depends on what it doesn't

45:04 on the chemical, it depends on post synaptic receptor. It's a receptor

45:09 nicotine. It does one thing if most chronic it does another thing,

45:24 , it's called shortcut catholic because there no chemical intermediaries there sometimes chemical intermediaries

45:30 this case there's no chemical intermediary, one of the accomplish that catalyzed and

45:35 targeting this potassium channel and opening the channel causing the hyper polarization. Uh

45:49 that's great, still Killeen cata colon serotonin cattle colonies, movement,

45:58 attention, visceral function, mood appetite , learning g proteins. Let's look

46:04 these g proteins before we come back talk about the glutamate synapse. Uh

46:10 talk about glutamate synapse. I'll come to that image. So we have

46:18 messengers and this is another example of and effort molecules. Now here I

46:26 you an example where the same chemical activate basically opposing action receptors. One

46:36 the receptor channel, Another one is protein complex. Can you have opposing

46:41 through medical tropic interactions? This is opposing action of iron A tropic versus

46:46 tropic. This shows the north another and it binds to the beta,

46:53 and beta beta receptor that catalyze is it's linked to the G stimulatory GS

47:03 which stimulates the production of cyclo PNP the expression and production of protein kindness

47:11 . And kindnesses or molecules kindnesses of that add field for group Okay,

47:21 are kind nations as opposed to foster sis which removed Phosphate Group P

47:40 Uh so this pathway through beta nor is stimulating P. K.

47:47 And it's pushing the system to produce of this podium. Finance a PK

47:53 same there on may also to express to binding on north into the alpha

48:04 stimulates G. I. To inhibit inhibits the production of cycling campy and

48:14 china's essentially pulling the system away from more P P. A. So

48:20 is opposing actions the same chemical but alpha versus beta receptor exerts opposing actions

48:32 early on the same target which converge the same target, regulate the same

48:37 . One of them is pushing to more P. K. I don't

48:41 us pulling the system away from producing PK. Mhm. All right.

48:48 is a in the image that I drawing because uh I don't have color

48:55 so I can draw in colors but can also draw. And I always

49:01 that the best way to learn is only to see but also to

49:06 I want to replicate something. So the exam I would like for you

49:12 know that norepinephrine is produced in the nucleus called locus Aurelius, locus or

49:24 lo sai locus cerulean stands for Does it cut the brain tissue this

49:32 and it oxidizes in terms of So it's local civilians. And that's

49:38 you have expression of norepinephrine. And can see that you have diffused projections

49:43 these neurons throughout the C. S. And into the spinal

49:49 The other thing I would like for to know is raph nuclei that are

49:53 for the expression of serotonin and you the purple rafting nuclei. And the

49:59 from these purple wrapping nuclei neurons that serotonin will target the C.

50:05 S. The cortex of cortical areas cerebral cortex cerebellum. The green wrapping

50:12 located in slightly different locations and the will send their projections into the spinal

50:19 into the peripheral. In the meantime and gaba cells will be widely distributed

50:29 expressed. Wouldn't be located in just nucleus. Like in these cases if

50:36 look here you have magnets cellular basal is green and this another green color

50:48 todung killer pontin and lateral dorsal take nuclei. The green ones. Green

50:56 are responsible for civil Colin. So we talk about alzheimer's disease, we

51:05 that there is a loss of acetylcholine , you would be losing neurons in

51:14 regions particularly here basil or brand and and having an apology associated with cool

51:27 the cannabinoids are different. So this just deciphering because I didn't know where

51:31 was going to stop where it was to pick up where I was going

51:33 review. But THC tetrahydrocannabinol phyto endocannabinoid anandamide to a g. A

51:42 interesting thing. Also remember we said dennison and I said that a denison

51:50 and you activated dennison receptors every morning you consume caffeine and denizen receptors would

52:02 increase caffeine would increase release. So other molecules prison optically apart from other

52:11 that can regulate and we'll see if can regulate neurotransmitter release. This is

52:17 out polarization induced suppression of ambition, induced suppression of excitation. Okay amino

52:25 neurotransmitters. A very important thing about being converted into gaba and glutamate control

52:34 general. So first of all, you release either glutamate or Gaba,

52:40 gets transported back into pre synaptic terminals it gets reloaded back into the vessels

52:47 what's really important that emerged in the 20 or so years is this concept

52:55 tripartite synapse um I know these slides jumping a little bit, but maybe

53:04 just follow the video to match the . But here, what it shows

53:11 the right is a glial cell and have glued in it. When it

53:18 released will target ion a tropic and tropic glutamate receptors will get transported back

53:26 glutamate neuronal transporters into pre synaptic terminals in the vesicles and released again.

53:34 Julia have their own glutamate transporters and will react to glutamate will convert it

53:43 glutamine with glutamine synthesis and this glutamine going to be given back to neurons

53:50 into neurons and with the help of AIDS converted into glutamate and uploaded into

53:58 vesicles. So this concept of tripartite especially with glutamate control, where the

54:08 player number one is pre synaptic neuron two is posson optic neurons. And

54:16 third try part. The third part this is leo sauce that are intricately

54:24 glutamate, which means they also can the availability of glutamate. And if

54:29 have a dysfunction and glutamate transporters in , then you can affect glutamate levels

54:37 the system. If they're not uh properly, there's going to be too

54:42 glutamate here, there's going to be much excitability between neurons because of glia

54:49 leah cannot transport the from the same or vice versa. Maybe it's up

54:56 expression of glutamate transporters. And now much of glutamate is being sucked out

55:02 the synapse too fast by glia. affecting how much of this glutamate is

55:08 for neuronal transmission. Alright, so have their own individual transporters and for

55:20 next hour or so we won't finish . We'll finish next lecture. We

55:28 focus on gloomy motor GIC, neural And Gaba urging. So what is

55:35 ergic Lutin eight ergic gaba ergic Cerrito , under energetic and then force it

55:48 and it's actually Colin ergic. So little bit of a vocabulary neurotransmitter,

55:55 , endogenous agonists, everybody with me arguments. Good. Okay, chemical

56:03 that our individual glutamate subdivide these based the pharmacology into ampara and India and

56:11 and receptors. So that means that will bind to all three in a

56:16 glutamate receptor channels but they will have specific agonists which they can be distinguished

56:24 ecological one of them will be reactive called Tampa and therefore called receptor,

56:31 one molecule found in the NBA that in the a receptor the third one

56:36 kind and it was called kinase These are exogenous or chemical agonists that

56:44 us to pharmacologically distinguish these three subtypes glutamate island A tropic channels pharmacology kinetics

56:56 is channel opening kinetics. Remember we about kinetics of voltage gated sodium channel

57:03 we said that that channel is much but it also closes in activates in

57:07 very fast fashion. But we said kinetics of potassium channel is slower but

57:12 also prolonged opening of that channel. what are the kinetics and when glutamate

57:19 released? That means that glutamate combined all three subtypes ample in India and

57:26 eight which one gets activated first if all go expressed and they can be

57:32 expressed on the same patch of the membrane if all three of them get

57:39 up by glutamate which one gets activated the same all at the same time

57:45 they conduct the same amount of do they allow the passage of sodium

57:50 potassium or something else? All of questions that we can ask and find

57:56 in the slide that when glucose gets these green molecules and here for simplicity

58:04 a lot of problems and receptors and are grouped together because they have very

58:10 features and a lot of times at are going to be referred to as

58:16 an M. B. A. they are not an M.

58:20 A receptor. So for now let's about APPA in blue and an

58:26 D. A receptor here in pink what it shows that once glutamate gets

58:34 in these green molecules here it binds ample receptor and as soon as glutamate

58:41 to a receptor this ample receptor or N. M. D. A

58:46 starts conducting sodium inside and later potassium glutamate remember glutamate signaling through these Alpine

58:57 . And kinda receptors are going to responsible for producing the E.

59:03 S. P. The excitatory possible of the country including Mexico.

59:11 So how what what which receptor channel to which fortune of E.

59:16 S. P. Just like an potential which I am contributed to rising

59:20 and following phase. So obviously when see the initial D polarization it's sodium

59:28 in right that's deep polarization followed by flux of potassium which is going back

59:37 hyper polarization to the pre stimulation pre levels. And when glutamate binds to

59:46 NMDA receptors they immediately open and start sodium and potassium. But when glutamate

59:53 to an M. D. A they don't open immediately because they have

60:02 that is blocking NMDA receptors. And is a physical blockade of the

60:11 By dive a link a tie on . And the only way that this

60:17 is going to be permeable to ions if you kick that magnesium out so

60:23 remove the magnesium block, what needs happen is there has to be an

60:29 deep polarization from the resting membrane potential about minus 65. Two more positive

60:37 minus 50 minus 50 minus 48 minus minus 40 to minus 30 and so

60:45 . And only with the initial. . Polarization will you relieve this magnesium

60:51 And if you do you can see an M. D. A channels

60:54 conduct not only sodium inside all an . D. A channels will conduct

60:59 and calcium inside the south influx of and calcium and also e flux of

61:09 . So when we talk about the first channels that open are ample

61:15 and they cause the initial D. . The later channels that open with

61:21 because of magnesium block or an D. A. Receptor channels.

61:25 ? We talk about selectivity and for typically with some exceptions impermeable to sodium

61:33 potassium selectivity for ion passage. Some receptor channels will be permissible to

61:41 You will see that the latest lines an N. D. A.

61:45 always a significant source of not only but also counselors and then the receptors

61:51 always cause the influx of calcium significant not for visualization but for the intracellular

62:00 synaptic signaling cellular signal conductance. So you open non NMDA ampara receptor cane

62:12 channels they will conduct 20 PICO PICO simmons remember that we can have

62:20 channel conductance is and this is PICO . So 20 PICO simmons, if

62:25 open an M. D. A it will conduct 50 PICO simmons.

62:32 here what it means the conductance is strength of the amplitude of that

62:38 How much of it it can obviously responsible for conducting a lot more ions

62:45 an NBA receptors is significantly contributing to E. P. S.

62:51 They have their own blockers are So AMP kinase receptors will be blocked

62:57 C N. Q. X. M. D. A. Receptors

62:59 be blocked by another blocker. PV. And M. D.

63:04 receptor is also referred to as coincidence coincidence detector because binding of glutamate is

63:14 enough to open an M. A receptor. So detecting pre synaptic

63:21 or release of the pre synaptic consider not enough to open an empty

63:26 It also has to detect the deep so it has to detect pre synaptic

63:34 release and fast synaptic polarization in order be functional. But say there's glutamate

63:39 and apple receptors are upset and there's deep polarization and a it's not going

63:46 detect the synaptic equalization, it's not to alleviate magnesium block. Therefore it's

63:53 going to to cause an opening of receptor. So it's coincidentally detecting pre

63:59 and post synaptic activity in a way is binding the pre synaptic neurotransmitter release

64:08 the post synaptic deep polarization. The thing to notice is this is lie

64:19 just for working all of you license is licensed doing here? Didn't you

64:28 us advising is released by inhibiting neurons the spinal cord that's a major neurotransmitter

64:35 the spinal cord there's some gavel a bit of Gavin spinal cord too.

64:41 this is not an addition. this excitation and in this case by scene

64:47 a necessary co factor that is present the CMS. So glutamate receptor NMDA

64:58 is a co factor or the glutamate properly agonize or openness receptor channel and

65:06 receptor has to detect synoptic decolonization. if you have coincident detection and you

65:12 also a co factor here is licensed you can see that glutamate has it's

65:18 a little key that has its own on this receptor. It has to

65:22 into this law. What is this ? This lock is the three dimensional

65:27 of communal essence and the structures of chemicals and molecules that will bind and

65:34 fact that opening or closing. Now can see that license has a separate

65:40 size on this receptor channel. Remember very complex three dimensional structures each individual

65:47 that we're talking about here. So have zinc binding side, there's two

65:53 binding sides in an M. Receptor there's also a binding side for

66:01 which is another very dangerous solicit uh drug that's called a popular Angel dust

66:11 crystal methane and it induces hallucinations. PCP by acting very strongly in an

66:19 receptor can cause acute psychosis. And chronic schizophrenia following a single use our

66:32 of uh the synthetic drug PCP. that's why these receptors are important for

66:40 and memory and then the receptors are for binding pre synaptic post synaptic activity

66:48 there are substances that can upset the and the function of these receptors.

66:53 sometimes these substances and chemicals especially synthetic can be so powerful. I'm not

66:58 about pharmaceutical. I'm talking about illicit can be so powerful and dangerous that

67:03 can cause a permanent effect following a use. Okay um knowing that these

67:17 not for M. P. Or ones like for the denuclearization.

67:30 the initial D. Polarization happens to because glutamate is enough to open up

67:36 receptors and conduct sodium. And then later part of the PSP we're gonna

67:42 it a little bit in the next . But if you took E.

67:46 . S. P. Which is E PSP and you broke down this

67:52 part of the PSP is mostly due ample receptor and this late part of

67:58 PSP is due to an M. . A receptor activation. And we'll

68:04 look at some studies or out of today but we're gonna look at some

68:10 I. V. Curves and pharmacological that address exactly this in the next

68:16 . So what we'll do on Thursdays finish neuro transmission which will be neuro

68:23 for and we'll start C. S. Yes for which molecules uh

68:38 there something endogenous li that mimics said there an endogenous molecule like it depends

68:56 how strongly advised this is uh this yeah this is what we call uh

69:05 versus partial. So a lot of are reversible partial agonists, uh or

69:15 they're full agonists, they're reversible sword . Like. Yeah. And then

69:22 are others that are chemicals that will stick to that it's too long to

69:29 it, like two hours, which is significant, the fact that the

69:33 Republic, so Longan

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