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00:00 Good morning. Welcome back. It's lecture 13 of neuroscience. And you

00:08 more than halfway through the semester and than halfway through covering all of the

00:15 that we intend to cover in this . Uh If everything goes smoothly with

00:21 force in the world in general, a reminder, we have been talking

00:27 neural internal submission. We are gonna talking about neural transmission today and begin

00:35 about some of the major parts of C MS. We'll continue talking about

00:41 also on Wednesday and I'm waiting to back from Casa for their confirmation.

00:46 was actually trying to check my email too about your quiz on Friday and

00:52 can give my email to update for second. So let's see, not

00:58 , but maybe later today, it be available and you'll see it if

01:04 not. And there's some issue with will communicate over email before next

01:10 but most likely it will be there today. Ok. So neural

01:18 we covered a lot of ground, lot of information, a lot of

01:22 molecules and we ended here, we by talking about excitatory optic potentials and

01:34 these excitatory synoptic potentials are generated when binds to A and, and MD

01:42 receptors. And we started talking about differences between these two subtypes of ionotropic

01:53 have made receptor channels. And just remind you where we all are

02:00 Now, when we talked about uh , we talked about this tripartite

02:10 And we said that for glutamate, it gets released, it will target

02:16 and metabotropic receptors. In the C S, it will get transported back

02:21 neuronal transporters, but it will also transported by glial transporters into glia.

02:27 , glia is a part of what call this tripartite synapse where essentially takes

02:31 glutamate, turns it into glutamine and it back to neurons, the pre

02:37 neurons. So they can synthesize glutamate of it again. So here,

02:42 , the third part of the synapse intricately controlling this excitatory signaling. You

02:50 transport for glutamate, you have transport glia for glutamate. We talked about

02:57 . So, endogenous agonist for and A and age receptor is glutamate.

03:04 a molecule that gets produced in the . And then we have exogenous agonists

03:11 are chemicals by which these different subtypes tropic. And the can be

03:20 They also have their distinctive antagonists. talked about that when glutamate binds the

03:30 receptors, ample receptors open immediately and are responsible for the initial phase of

03:38 E P S P and, and A receptors have a magnesium block.

03:44 the only way that this magnesium block alleviated if the membrane depolarizes from resting

03:51 potential into more positive potentials, which for magnesium to leave and for an

03:59 B A receptor channel to open a of the conductance of sodium calcium inside

04:05 potassium to the outside. So if look at that E P S P

04:09 general, this early phase of E S P is primarily due to alpha

04:16 . And this late phase of E S B is due to an MD

04:21 receptor. Thanks, They're both ionotropic the sense that they both conduct on

04:31 . Now, Alpa will have uh 20 PICO of conductance and MD a

04:41 will have 50 PICO of conducts. that tells you that this is a

04:47 uh once you open an MD A , it can conduct a lot more

04:52 that channel. But you have to it an MD A receptor and Aina

05:00 channels that have their own blockers or . So Aina will get blocked by

05:07 N Q X and then MD A will get selectively blocked by A PV

05:13 A P five. An MD A is referred to as coincident detector.

05:20 in order for it to open and conducting, it needs to detect the

05:26 synoptic neurotransmitter release, which is And it also needs to detect the

05:34 optically. So that it can alleviate block. So it is very well

05:41 in M B A receptor in having ability to bind a presynaptic activity with

05:47 , with a significant postsynaptic activity so it engages and opens the channel.

05:55 , glutamate in the C N S also have glycine as a co

06:02 So in the spinal cord, you that glycine is one of the major

06:07 neuro transmitters in the spinal cord. in the C N S, glycine

06:14 a co factor, which means that glycine also in the synopsis and it

06:19 to bind together with glutamate in order this channel to be really effective open

06:25 both and regulated properly by glutamate and synaptic depolarization. So the other difference

06:35 that all the M B A sufferer allow for sodium and calcium to come

06:42 calcium doesn't contribute that much to change the numbering potential as it is contributing

06:48 the intercellular processes that it can set sally. But it does flock through

06:56 MD A receptor channels of potassium e . Now, only certain or not

07:03 MD A receptor channels, only some those aut channels will be permeable to

07:09 , but they're all permeable to sodium potassium. So there's a selectivity here

07:14 some channels aut channels are selected just sodium influx without calcium. And we'll

07:21 that why in a second. obviously, since alpha receptor channel is

07:28 first, it has fast kinetics is for the early phase of the E

07:34 S P. And then MD A responsible for the late or the late

07:39 of the late phase of the E S P. Both channels are on

07:45 , not to be confused with the signaling. And we'll look at some

07:48 the examples of metabotropic glutamate receptor that be linked to G coin complexes.

07:56 also these receptor channels is the rule . Later, you'll see today,

08:02 as well. They have multiple binding for different substances. So,

08:08 endogenous substances, but also exogenous agonous antagonist also binding sides for ions

08:17 magnesium, for example. Uh it also is a target for certain

08:26 narcotics or certain illicit drugs like PC , also referred to as angel dust

08:32 a lot of times a single use repeated use of that drug has very

08:39 interaction with an MD A receptor that have very long lasting changes. Because

08:44 MD A receptor is a coincident An MD A receptor is perfectly positioned

08:50 mediating the plasticity or the communication between synoptic and posy tic cells. A

08:56 of these molecules that are endogenous are binding properties where they may bind to

09:03 receptor and they may dissociate from that a certain period of time later.

09:09 a lot of synthetic and illicit drugs have much stronger binding properties to these

09:14 . They may not dissociate and fully this receptors or alter the function of

09:19 receptors for days, sometimes weeks. that can lead in the case of

09:25 P S to psychosis uh to bouts acu schizophrenia and even permanent or chronic

09:33 dysfunctions mental conditions like schizophrenia and So, it's a very important

09:40 But when that receptor is affected by wrong substances, it can also induce

09:47 long lasting changes versus the positive long changes that are just normal brain functioning

09:53 plasticity. So recall that in the section of this course, we talked

09:58 this concept of voltage clown and we that voltage clown, what it allows

10:03 to do, it allows us to the numbering potential at a desired

10:08 your desired value. It's very valuable voltage clamp allows us to study to

10:15 inward and outward currents And allows us look at the in the case of

10:22 ions such as sodium and potassium allowed to look at the ionic or reversal

10:30 for an individual ion such as right? And we saw that

10:37 for example, reversal potential was -80 reversal potential was positive 55.

10:45 we can perform equivalent type of experiments the voltage clamp. But now we're

10:51 at these receptor channels that are permeable both sodium potassium, sodium, calcium

11:00 potassium in the case of an MD receptor. So we do a voltage

11:05 and in this experiment. It's two in the first conditions. It's physiological

11:13 of magnesium and the extracellular solution. 1.2 milli molar on the left on

11:20 right, it's an experimental condition in magnesium has been removed from extracellular

11:27 There's zero magnesium and extracellular solution. that magnesium has a binding site,

11:34 MD A receptor and it can block MD A receptor by binding to the

11:41 and it can only lead that receptor there is depolarization. So first in

11:47 physiological level, also of magnesium at 60. When we apply glutamate,

11:53 we have isolated an MD A receptor at minus 60. We see very

11:59 MD A receptor burns and that's because is no depolarization. So, glutamate

12:03 not enough to start the current fluxing these. So you're seeing almost a

12:08 line here. This is electro physiological voltage flat at minus 60. The

12:14 the start you're starting to see foxes happens at zero millivolts. This is

12:22 instead of ionic, what we have is a reversal potential. So in

12:31 case, it's a reversal potential e at which potential. Basically there's no

12:39 of cars in either conditions on the of the right at zero millivolts.

12:45 when I, when we, when looked at the uh the I V

12:51 for potassium and we said that this if you, if you look down

12:57 , OK. This is uh this all um outward current and this is

13:13 excellent, let's start with this, looked at the I V plot.

13:19 this is the current and this is voltage. And we, when we

13:24 at the potassium, we said that minus 80 millivolts, we have a

13:30 potential for potassium. In this it's equilibrium potential for potassium.

13:36 Because below minus 80 millivolts, potassium going inward. I just uh I

13:44 have miswritten these two. And here this side where the current is positive

13:53 , the current is outward. So remember when you depolarize the cell potassium

13:59 be fluxing outward. So the equilibrium for potassium was -80. Now,

14:07 looking at ions fluxing through an MD receptor channel, multiple islands and they

14:16 a reversal potential. So we cannot it's equilibrium potential because equilibrium potential is

14:21 single island only the reversal potential of , currents fluxing inwardly. So here

14:30 fluxing inwardly and here the reverse. here you can see the currents of

14:36 and outward. And so this is reversal potential value. When MD A

14:42 channel is zero millivolts, we'll look it in, in in more detail

14:46 a second. So essentially E P P and a potential in the neuromuscular

14:57 , which is mediated by nicotinic acetylcholine and E P SPS, which are

15:05 by alpha and an MD A receptor . They all have a reversal potential

15:15 zero millivolts And you'll see that. now what's the difference between left and

15:22 and the right, we removed we now have glutamate in the presence

15:27 glutamate and -16, we've just proven if you remove magnesium and MD a

15:33 channels will be open at negative So this is the point of this

15:38 but to prove this experiment, you to use voltage clamp, you have

15:42 have a condition in which you are . In this case, the amount

15:46 magnesium. And you prove that it's magnesium that's blocking an MD A

15:53 , uh these normal physiological concentrations and you remove it, you can actually

15:57 an MD A receptor activation here. let's go back to. So some

16:03 the drawings that I did before and let's go and look at this uh

16:08 here. In this case, we a voltage clamp -80 -40 positive

16:17 We have this dash here. This small dash here which is an artifact

16:24 . It's let's say glutamate release. . Following that we are recording

16:31 So these are inward currents and these outward currents. Now, when you

16:44 and you produce this response, you're at least two dash lines. The

16:50 dash line is measuring the response about milliseconds following stimulation. So you're

16:56 really measuring this peak early current And the second dash line is taking

17:02 measurement about 2030 milliseconds following the stimulus the same traces, these electrophysiological

17:13 And so when we climbed at -80 plus 20 and measure an early

17:21 that early component is the nom an component. And we can see that

17:26 early non MD A component has this ID plot which is the triangles.

17:33 we can see that this alpha which the non and MD A component has

17:39 reversal potential at zero millis when we the measurements at the late component

17:50 30 milliseconds later these in different holding And this is current. So you

17:58 , I so these are the closed and these are the measurements of

18:04 There's barely any current, you're measuring change from here to here to change

18:12 here to here. OK. At X Y. How far away is

18:17 trace from this? How far away the trace from this is how you

18:22 the altitude of, of the current anything or? Uh or or?

18:28 it turns out that an M B is the closed circles. It has

18:31 nonlinear M V P with the reversal of zero M vats. And these

18:37 the closed circles and the MD A is responsible for this laid and MD

18:43 receptor component card, which is pictured as the blue area under the

18:50 And the final experiment here is that add a PV where you have these

18:56 circles, late current is remaining after added a PV. And you do

19:04 measurements again. So you added an MD, a blocker specific blocker

19:10 an MD A and you can repeat measurements for ample receptor and guess

19:16 It's not going to affect ample receptor so close circle uh closed uh triangles

19:23 open triangles. It, it, doesn't matter in the presence of an

19:27 A receptor or blocker or an absence that blocker. It still is a

19:33 component. It doesn't affect it because tells you it's a specific blocker,

19:40 ? A PV specific to an MD or sock. Now, when you

19:47 the current in the presence of A , you get this curve here that

19:53 the open circles and it's essentially blocked zero current. There is some

20:00 but it's essentially blocked to zero. a current. So that tells you

20:06 you can block this la component with PV, that an MD A receptor

20:12 responsible for that lead component. And an MD A receptor channel I V

20:17 is nonlinear just compared to a, have a reversal potential of zero M

20:24 . And so does that potential in neuromuscular junction that's uh mediated by nico

20:32 cole receptors. So some ample receptors indicated are permeable to calcium but not

20:40 . So why are some permeable and are not? So when we look

20:46 the structure And this is remember we transmembrane segments. This is transmembrane

20:53 M one and two and three and . Yeah. Part of the subunit

21:00 is comprised of amino acids as building with a protein channel. Everybody with

21:14 . No, remember this, you sub units and then you have M

21:23 M two M three M four. we studied voltage gated sodium channels,

21:27 had transforming segments as one as two is four. So it's a little

21:32 for Ligo G and ion channels. that was an example of nicotine uh

21:37 codeine receptor. So M one M M three M four and you take

21:41 sequence that contains Q or glutamine. remember this is a very complex three

21:50 protein with a very long amino acid . But if that sequence contains

21:57 you apply glutamate, you get sodium and you get calcium cars, but

22:04 versions of apertures will have arginine where uh where that glutamine iss Q,

22:13 is substituted with arginine. And there basically variations so that they will have

22:19 and in the presence of that arginine amino acid. Now you apply glutamate

22:24 you still have sodium currents, but don't have any calcium currents. So

22:31 a single amino acid in this really structure in a single trans numbering segment

22:37 significant, whether that channel allows for flux of calcium or not.

22:42 calcium doesn't contribute that much to the and potential change, the fast number

22:47 potential change. Like we're talking about E P SPS or action potentials and

22:53 , but it contributes to intracellular signaling activating calcium binding molecules and calcium homo

23:01 and so on or or development. early synopsis in neurons, it's early

23:11 stage of synopsis will contain only an A receptors. So they will not

23:16 ample receptors. So that's not very if you release glutamate and there is

23:22 ample receptors. That means there is synaptic depolarization. That means that if

23:28 is released, it's going to be . And they're referred to as silence

23:34 for the ones that express only in A receptor. And then later in

23:40 , a receptors get expressed in this . And so there are rearrangements that

23:45 developmental that are development dependent, but are also rearrangements as part of the

23:55 , we call activity dependent proper processes can rearrange a number of the sufferer

24:00 and the plasma membrane. And such other thing is the subunit compositions are

24:06 subunits that comprise these protein channels. can be different subtypes. Here,

24:13 go back again to the nicotinic acetylcholine . And here you have alpha two

24:23 , beta gamma delta of unus that this receptor protein channel. OK.

24:31 if we go back to an MD , they're just called something a little

24:37 . They're called N R two A R2B subunits. But as a part

24:44 the development and sometimes a part of activity which is plasticity processes, there

24:51 be a rearrangement in the composition of subunits within an MD A receptor where

24:59 some point there's a greater ratio of R two A to an R two

25:03 and then it could switch greater ratio an R two B to an R

25:08 A or equal ratio of the two types of subunits that are a part

25:14 this with up channel cellular location. activity dependence is changes with age and

25:24 . A receptors moves fast. So lot of receptor channels, as you

25:32 are expressed in the synoptic densities. a very specialized area confined the synapse

25:40 synoptic densities. But there are extra spaces in the membrane that goes beyond

25:48 synapse space. And you can actually apa receptors through plasma membrane from extra

25:56 spaces into the synapse. You can that as a part of the

26:01 you can do that as a part the demand. So let's say there

26:06 a lot of activity, there's a of glutamate release and you need to

26:11 the synapse. And one way in you can change the efficacy or the

26:16 of the synapse, which we refer as plasticity. One way in which

26:21 can do it is by insertion of receptors such as glutamate output receptor

26:28 So that s Sino becomes even more at depolarizing, even more effective at

26:33 an MD A receptors. And if have significant amount of activity, it

26:41 cause long term plasticity to abbreviate as T P. So long term plasticity

26:49 likens to long term memory. things that you do rehearse repeat many

26:55 , get ingrained in your head and hard to forget him, Things that

27:01 do once or twice, remember a number and then you forget it 10

27:04 later, short term memory, things that. Things that you study for

27:08 test and you forget over spring short term memory. You know,

27:13 you're gonna have to repeat it Hopefully, it's gonna be a long-term

27:16 . So you can still repeat it after the course is finished.

27:20 and MD A receptors and the cycling import of additional glutamate receptor channels and

27:27 are all very important cellular substrates or processes that underlie learning and memory metabotropic

27:37 receptors. This is an example of glutamate receptor that is linked to gate

27:44 that interacts with a molecule called P two. And with the fossil I

27:51 , it converts that P IP two IP three or no trios and an

27:58 trios can bind to calcium channel. these are basically IP three regulated calcium

28:07 and smooth endoplasm reticulum and S er loaded with calcium and stimulation and opening

28:16 this calcium channel can now provide a of calcium from internal vesicular stores

28:24 And the smooth endoplasm reticulum into the freely floating or what we call cytoplasmic

28:32 calcium is very tightly regulated when there's of calcium. If it starts interacting

28:39 molecules, secondary messengers, kis and like that, it's tightly regulated.

28:45 so if you stimulate even more of calcium, you have another way for

28:51 cells to access calcium in the cytoplasm releasing it through from the, the

28:57 endoplasm reticulum. You can see that of this molecule causes a divergence in

29:03 molecular pathway. IP three stimulates the on smooth endoplasm reticulum and diacylglycerol or

29:13 A G remains membrane associated in It interacts with protein kinase C which

29:20 a kinase. And this also says calsci can interact with calci module cave

29:26 or CA KIS. So what KS is kis for spate channels. So

29:36 can phosphor channels, they can add P 04 group and that's and phospho

29:43 de phosphorylation or will chew up the 04 group. A lot of times

29:51 can cause longer lasting effects, can the channels and dephosphorylation can impede with

30:00 with activation of these channels. So , there is a regulation of these

30:07 and phosphate AIS intercellular as well and will influence a lot of what has

30:13 in gods stream from metabotropic. In case, glug metabotropic signaling, there's

30:20 different metabotropic glutamate receptors, but they're activated by glutamate and linked to G

30:27 complexes. All right. So now moving into inhibition, we understand a

30:35 about excitation A and MD A agonous , early lady P S P magnesium

30:45 and also substances that bind uh to MD A receptor. Now, when

30:51 talk about IP SPS as a E P S P poop is exci

31:00 pontic potential or depolarization, right? an IP S P, I'm trying

31:07 find another diagram but maybe it's not . I'm just gonna have to drive

31:14 P S P is a depolarization and S P is a hyper polarization inhibitory

31:25 potential. So you get inhibitory postsynaptic when inhibitory neurons release gabba, this

31:34 gabba, a receptor channel. Gaba gamma a receptor channel which is permeable

31:45 chloride and chloride influxes inside the So negative charge chloride negatively charged ion

31:55 inside the cell will cause a hyper . This is E P S P

32:03 is depolarization and IP S B will hyper polarization. So chloride coming in

32:10 the E P SPS, you had coming in at first, right?

32:13 that was depolarization and the IP SPS chloride coming in. So it's hyper

32:20 . Now notice that this receptor channel has a lot of different binding

32:28 Yeah, obviously opens the channel. is it agonist or antagonist? I

32:37 , I guess. And so are molecules? So ethanol, alcohol binds

32:46 Gaba a receptor channel, benzodiazepines, which are classic antiepileptic anti seizure

33:01 benzodiazepines that find their way into popular as Bezos barbiturates and there are

33:13 So all of these molecules are like and they have to find the correct

33:20 . And so S N O will its key hole in the Gaba A

33:25 not in the glutamate, not in M B A to. So a

33:32 of these molecules have their distinct So you can imagine that this receptor

33:38 is like a door. You can that door, the channel is

33:43 you can close that door, but not simple. The door has multiple

33:48 on it and some locks can open and close it, some locks just

33:54 it a little bit more or keep open longer, but they don't have

33:59 ability on themselves to open. So are different variations of agonous and

34:05 And that's why I was saying that of the molecules that are uh uh

34:12 induce chronic or unwanted chronic effects are ones that are synthesized. And we

34:18 know precise interactions with the receptors or have very strong interactions with different

34:25 So, Benzodiazepines will increase inhibition, will increase inhibition. Barbi nesters will

34:33 inhibition. The people that are taking is medication for epilepsy seizures. They

34:41 often report that they feel drunk because activates gale a receptor channel. The

34:48 that ethanol will be activated. So it's Monday. So we're gonna,

34:54 talk about what happens during happy So that's when I leave it for

35:00 or maybe a review later this OK. So now that's Gabba A

35:08 we also have Gaba B and this what's a little bit different about IP

35:14 versus I E E E P SPS that this early depolarization, this early

35:23 is Gabba A, it's chloride, . Chloride coming in and this la

35:34 is Gabba B and it's potassium going . Gabba B is a metabotropic Gaba

35:48 channel. The poop is linked to channels. So when it gets

35:55 this receptor protein complex opens up potassium and the flux of potassium inside the

36:04 outside the cell from inside to the of the cell hyperpolarize the membrane potential

36:10 further. So this early component of S P's Gamba A really. And

36:18 late component is the right and that through tropic activation of G podium complex

36:31 opening off a synoptic potassium channel. Gabba B with separate complexes can block

36:41 of calcium. So we'll look at examples in the second. But now

36:50 happens typically, we'll talk about the diagram in a second. What happens

36:56 is that you will have excitation. is an E P S P.

37:01 if you stimulate the fibers and a of times when you do these

37:08 you may have different projections from the . You're recording here with an

37:14 A lot of these are gonna be or glutamate projections and some of them

37:21 gonna be inhibitory. And typically after stimulate a collection of fibers, you're

37:28 stimulate excitatory and inhibitory. That means going to release a lot of

37:33 But you're also gonna release some gaba this posy tic neuron. And all

37:38 these synapses are targeting this postsynaptic So what is common to see is

37:45 E P S P that is followed IP S P. So this is

37:51 P S P, the excitation that followed by IP S P. So

37:57 engage excitation. And what happens is inhibition keeps this excitation in check

38:06 and if you apply by Culin. there's a lot of information on

38:11 This is actually uh experiments that I over uh 10 years ago in journal

38:19 Neurophysiology by Curricula is a gabba a antagonist. So all of these substances

38:26 agonists, they will allow for more of chloride, more hyper fluor.

38:33 where they sedative there is increase then we block gamma A. So

38:41 is trace number one E P S followed by IP S P and we

38:46 inhibition and this is trace number Now we have this unchecked excitation,

38:51 large depolarization and action potentials even produced . So it's that that experiment

38:58 is in the visual system is very uh set of experiments that really illustrate

39:05 tightly inhibition controls excitation. And if block inhibition of bicuculline, this excitation

39:13 massive. Uh I recall it a of times runaway excitation, it becomes

39:19 strong and large in amplitude and spreads the tissue as well. OK.

39:27 every section, I say that this a great diagram where you should print

39:31 for yourself in a separate page or know, have a digital copy of

39:36 slide to take it apart in digital , whatever you wanna do and all

39:40 skills you have to use and put of the information here about excitation inhibition

39:50 this summarizes a lot about what we about excitation and inhibition. Um recall

39:58 neurons will have both excited and inhibitory targeting them. So the response of

40:06 neuron will depend on the subset of receptors it has, whether it has

40:10 A only or Gala A gappa whether it has a lot of APA

40:15 an MD A or little APA and on. Now, what is happening

40:21 in this diagram is a lot, you have a key here and that

40:28 shows you the major players. Now talk about what exactly is happening.

40:33 first of all, we have gaba presynaptic terminal and glutamate, releasing presynaptic

40:42 . That means that this is an cell that's starting this synoptic neuron.

40:47 this is an excitatory cell that's targeting synoptic neuron. So when Gaba gets

40:55 from this inhibitory synapse here it binds gabba A receptors, chloride influxes and

41:02 get IP S P hyper polarization nearby have gabba B receptors, binding of

41:11 to gabber B receptors will open potassium and cause more hyper polarization.

41:18 Gaa A gala B also the inhibitory have Gaba B that are expressed presyn

41:32 . And when there is Gaba that released by the inhibitor synapse, these

41:39 are Gabba B auto receptors because they're the same synapses released as gabba,

41:46 activation of these Gabba B O receptors regulate and close calcium channels, voltage-gated

41:59 channel. So calcium is necessary or binding and release of neurotransmitter. So

42:08 is if there's Gaba, it can inhibition synoptic gabba A Gabba B IP

42:16 , but it can also self inhibit own release by regulating calcium influx presyn

42:25 nearby. We have this excitatory Obviously, when glutamate gets released,

42:31 gonna activate APA first and then an A receptor is but an MD A

42:36 shown here in yellow are typically a source of calcium influx. And when

42:42 comes in oop, it can interact calcium molecules such as calcium, co

42:51 kis camus. And these Aes on own can affect potassium channels posy or

43:02 affect gal B receptors optically which will potassium channels openly. Potassium channels will

43:13 hyper polarization and hyper polarization is not . Hyper polarization is going to be

43:22 an MD A receptor function. So , Gaba B actually has nothing to

43:30 with inhibitory synapse. This is in excitatory synapse but is located synaptic and

43:39 regulating potassium, it can cause hyper synoptic through the cellular mechanisms. There's

43:48 Gaba released here. Now, the way in which Gabba can control presynaptic

43:55 release is that glutamate synapses have Galba heteros. And if there is a

44:04 of Gaba being released here, this is going to spill over into adjacent

44:11 spaces. And if it binds to B receptors on this pre synoptic excitatory

44:22 , it will block calcium influx and will regulate the release of glutamine.

44:29 , Gabba B receptors are expressed on inhibitor and excitatory on the inhibitory

44:36 They're called auto receptors on the excitatory . They're called hetero receptors. But

44:43 both cases, Gabba can presynaptic regulate glutamate or Gaba release its own

44:53 So this is reminiscent actually of the signaling. If you remember, maybe

45:00 have this in this presentation here And then the cannabinoid signaling, we

45:05 retrograde signaling activation of CD receptors which down calcium channels, blocked calcium channel

45:16 and controlled both the excitation and So now you have Gabba B receptor

45:27 does the same. So there's redundancy ? There's multiple ways in which you

45:34 control pre synoptic inhibitory or exci neurotransmitter , you can do it through Gabba

45:41 , you can do it through cannabinoid presynaptic. But it's a very different

45:47 , very different molecules. But they all converge on the same presynaptic calcium

45:54 . You can do it in, other ways through a demo receptor signaling

46:00 . So there's multiple ways in which will start affecting the same calcium

46:06 In the end, when you affect tic calcium channels, you're regulating neurotransmitter

46:12 , excited to inhibit their neurotransmitter, G pros are different than structure.

46:20 and they're different in such a way they're coupled to uh G part coupled

46:25 . So which are seven trans member segments, acetylcholine glutamate gaba,

46:33 dopamine orne and coin cannabinoids A T . They all will act through metabotropic

46:41 receptors. In addition, acetylcholine glutamate Gaba will act through ionotropic receptors.

46:49 , acetycholine nicotinic glutamate A MD A a their ionotropic, but then they

46:58 have their distinct metabotropic muscarinic, different of subtypes of receptors that are metabotropic

47:09 one through probably 14 or 15. now, it grows every year.

47:15 subtypes of these channels get discovered and functions get precisely described and distinguished from

47:21 channels. So this shows you again more time. This is a lion

47:26 receptor channel, nicotinic. Remember we uh two acetylcholine molecules to bind to

47:33 receptor in order to open the OK. That's nicotinic, you will

47:39 M one and two and three and , you will have some of the

47:44 replication, uh very similar sequences of acids and gabba, a alpha

47:52 gabba a, a beta one but they will express them one and

47:58 and three and four Coline Gaba glycine uh glutamate um receptor channels. In

48:06 case. And the composition of these again, for nicotinic, it's alpha

48:12 . And then the A receptor, talk about N R two A and

48:15 two B. They're called little different all of these channels. OK.

48:21 there's a lot of information on the . But what do you need to

48:25 for the quiz or the task acetyl ? You have to know nicotinic and

48:30 , of course, nicotine and That's easy as agonous nicotinic muscarinic.

48:37 you cannot say that nicotine is an or muscarinic. That would be grammatically

48:43 . I'm just kidding. But uh would be incorrect antagonist, Cura and

48:52 Norine. You should know that alpha beta receptors have this opposing action,

48:58 atropic action of push pull mechanism. activating through G S another activating through

49:05 I converging on cyclic A P. is pushing the production beta AIC,

49:11 alpha Denner is pulling away the production cyclic A P made A NBA A

49:18 MD AC N A P five for , Gaba Gabo A Gabo B and

49:24 is an antagonist for Gale A because saw that really nice. Uh

49:29 Just a short time ago. A P acts through a type receptors and

49:39 two X receptors. A type receptors also the target of the denison.

49:45 , agonist is a dennison or a receptors. A T P will bind

49:52 those receptors that which is a, endogenous substance. It goes up at

49:57 and it blocks the release of calcium glutamate synopsis. So it slows our

50:01 activity down and then caffeine is an for denine receptors. And caffeine allows

50:12 calcium channels to, to function. it blocks the denine receptor function allows

50:17 calcium channels to open and stimulates glutamate . So it encourages kind of your

50:23 to wake up every morning. There's of coffee there, by the way

50:29 of caffeine uh gamma A receptor you can play games. So like

50:36 beta gamma delta row, but it's just games structure equals function, which

50:43 that if you change the the subunit , delta gamba versus uh gamma gamma

50:52 subunit, the current flux may have properties. There may be more current

51:00 through that. Uh g acceptor, chloride coming in, maybe it's open

51:06 . So it's not fluxing more but it's staying open longer and it's

51:12 more chloride to come in. But conductance is the same and you have

51:17 iterations of these subunits which basically dictate different subtypes of metabotropic receptor channels that

51:25 saw here. M one M two three and four and so on,

51:30 have a significant level of amplification and chemical synopsis. So when you have

51:38 or cellular signaling, you have binding that molecule to the receptor, it's

51:44 a channel, but it can be to several G part complexes.

51:49 depending on the binding properties of that , the receptor, the time,

51:54 duration of time that it stays bound to that molecule or where it is

52:01 it affects the function and interactions with Gin complex. Maybe you can activate

52:06 G complexes, maybe you can activate G per complexes. One can cause

52:12 effect on multiple effector systems or a cyclo conversion of A T P multiple

52:19 T P S into cyclic A MP cyclic A MP can now affect multiple

52:26 kis and those K one K can multiple channels. So from one

52:32 one G protein uh coupled receptor you have amplification um of the

52:42 Now you have amplification, you also divergence in the sense of neurotransmitter,

52:47 same neurotransmitter combined to subtype one, type two, subtype three. So

52:52 example, Norine alpha data, sub one, sub type two, sub

52:58 two will diverge and actually interact with effective systems like y whatever the kind

53:06 is possible cases of molecules you also convergence. So three different transmitters.

53:15 three different receptors would be converged on same effector system Examples, three different

53:23 and cannabinoids. A. Dano gabba or gabba neurotransmitter, different receptors.

53:33 all converge on a factor system, channels. Now, you also have

53:42 and parallel streams. So you have . These neurotransmitters can have parallel streams

53:51 a one receptor and a two receptor parallel will converge on the same factor

53:58 in parallel. They may also diverge , you can access, for

54:05 this effect to three Here by either a, a one receptor factor three

54:12 BB receptor factor three. So even you lost a neurotransmitter, you can

54:21 get to the same factor through these divergence um mechanisms. And there's a

54:30 level of redundancy so that your signaling cellular level is protected. If you

54:37 a chemical, if you lose a type of the receptor potent with this

54:49 material, we're gonna remind ourselves that studying the brain and that all of

54:55 chemicals, all of these molecules we're , they're part of these networks,

55:01 part of these structures, these networks these structures that have their distinct

55:09 This is the brain. So the to scale. So a really small

55:15 like rab rabbit, cat brains just few centimeters in size, the human

55:24 , the dolphin brain, the largest I think are in um elephants.

55:32 if we listened very diligently to phrenologists remember the science of phonology, one

55:40 their arguments that um other things being size is a determinant of the power

55:48 the organ. Like the size of muscle is determinant how much of the

55:52 it can lift. So dolphins should with their bigger brains and bigger skulls

56:03 be on top of the food And I always make this argument if

56:08 in the water, they are, you're not in the boat and you're

56:13 the water, do you hope that, that the dolphin are,

56:17 gonna help you in some way, be much smarter and better survival in

56:22 marine environment using different sensory cues and physical um and mental abilities uh by

56:31 same virtue. Um Maybe elephants rule world, then we should go back

56:39 this ancient painting of elephants holding the on their backs uh because they would

56:47 the biggest bridge. Now, when look at those brains not to

56:52 you also see similarities in structures. see differences in in structures and one

56:58 difference is a lot of the lower , organisms, animals like rat and

57:06 , their brain surfaces are relatively There's even a saying in, in

57:11 , the lizard brain or a smooth , which means it doesn't have much

57:16 . You know, you can see you have a lot of salsa and

57:22 , these ridges and imaginations and the common species of what these gyra provide

57:31 is the surface area. And the in the three dimensional wiring and connectivity

57:39 these neurons wiring is connectivity because it's wiring cables. So if you have

57:45 a, a flat box, you put the cables through a flat

57:48 That's, that's all you have. , if you shape that box in

57:53 ridges and edges and curves and stuff that, now you introduce a lot

57:58 complexity into the system. So uh , you see stimulus structures, but

58:07 you see that some animals like rats, dolphins even will have very

58:13 factor balls which are actually very small humans and certain structures are bigger than

58:20 depending on the function that they need perform or what they need to do

58:25 order to survive and procreate in their environments. Whenever we talk about

58:32 we have to remind ourselves of some medical terminology. Interior rostral,

58:40 coal dorsal, the back, the , the front, medial in the

58:49 , lateral away from me. So more lateral you are the more further

58:55 you are from midline. When we the brain, we typically cut it

59:02 slices because we want to reveal the anatomy and connectivity of the brain.

59:07 typically this is done as miso horizontal sections or coronal sections. Uh

59:17 this is for example, a, miso view off the inside of the

59:22 , the two left and right hemispheres right through the mid line here and

59:29 major parts, you know the the left and reb hemisphere there is

59:34 uh uh of course different functions that performed by left and right. We

59:40 the language areas, for example, the left atmosphere, cerebrum are bellum

59:46 stem spinal cord and will go over lot of these different areas of the

59:52 and their functions in the next couple lectures. So you have cerebral and

60:00 hemispheres where the sensory and the motor is processed in the contralateral fashion.

60:08 that when I move my right it's my left motor cortex and constructed

60:15 move my right arm. Cerebellum or little brain in the back of the

60:23 the cerebral cerebellum is also involved in control. But cerebellum controls the movement

60:33 the same or if the lateral So left cerebellum will control left or

60:39 cerebellum will control right uh motor uh and movements is the area where we

60:49 a lot of cerebral cereal and So, in anatomy, besides the

61:04 lateral interior, posterior superior inferior, , we should probably add on to

61:10 diagram too. You also have these names. The typically the first is

61:19 origin where it is coming from. if it's cerebra cerebella, that means

61:26 are inputs coming from cerebral into And if it's from cerebellum to

61:36 that's cerebella, cerebral. So we'll study tracts, for example,

61:41 the spinal cord spinothalamic, that means from the spine to the thalamus,

61:48 means it's from the cortex into Ok. Brain stem is the area

61:56 has uh nuclei that regulate a lot vital body functions, breathing consciousness,

62:06 of body temperature. For example, , heart beat, it's very important

62:14 these vital bodily functions. Not as for the cognitive functions. Of

62:21 in the periphery, we have peripheral system and we have the somatic which

62:28 voluntary. So we talked about joints, movement of the muscles,

62:34 sensory and motor. We looked at reflex arch which illustrated both, although

62:43 didn't talk about the sensory inputs and nerve endings that will carry the

62:47 We look at that when we study soma sensory system, but all of

62:53 sensations from basically your head down below brains, stone somatic sensory sensations and

63:07 the motor output, my motor command move my right hand will come from

63:13 left motor cortex and basal ganglia and move my right hand. Ok.

63:22 this is, this is, this voluntary. Uh and visceral is autonomic

63:32 something that you don't really control. uh internal organs, blood vessels and

63:41 . And there is even a mesenteric system that surrounds our gut, surrounds

63:51 digestive system. And it is emerging as complex as the C N

63:58 And there is a lot of interactions the last decade and studies that are

64:03 what is called the gut brain axis how the microbiome in your gut because

64:11 carry a lot of microorganisms and bacteria probiotics and things like that in our

64:16 , how their presence, the genetic metabolizes that they produce in our digestive

64:25 and helping us digest. And sometimes setting our digestive system, how all

64:29 these things are intricately interacting and can intertwined with the, with the,

64:35 the brain function. Oh, so everything from neck down when we're talking

64:44 per nervous system, everything from neck in the spinal cord is motor nerves

64:51 sensory inputs coming in. Everything from up is a part of the central

64:57 system. It's the brain stem. . And that processes the information from

65:05 head and the face and we'll talk that. In the next lecture,

65:09 learn about the cranial nerves too. brain is also protected apart from being

65:15 by a really thick skull. It has these meninges that protect the brain

65:25 times the dual matter or the hard . So dually, you have Arachnoid

65:32 or arachnoid membranes. And on the surface of the brain tissue, you

65:37 the PM MO the jungle model that the nutrients and support and uh protection

65:46 the brain. You can see there's lot of microvascular, your blood vessels

65:51 innervate into the brain. And throughout brain, the smallest distances between the

65:58 is only 50 micrometers inside the So there's a a lot of

66:03 innovating in, in the brain dura is uh hard. A mother.

66:10 is literally hard. It is something cannot poke with a finger. You

66:17 to cut through it and you have typically use a, an experimental

66:22 a scalpel or a very sharp knife cut through dura matter. So it

66:28 is like a very thick durable skin that is sitting right underneath the

66:35 protecting the brain. Well, we about great trepidations. Remember we

66:41 well, uh at first, it believed that the trepidations maybe were a

66:47 of torture. And then it was that maybe they were actually medical procedures

66:54 they were necessary for the conditions that you to actually open the skull and

67:02 potentially a window into the brain. now imagine a situation where you have

67:09 injury or you have an aneurysm which abnormal blood vessel, uh thinning of

67:18 blood vessel wall, the blood vessel , you have a stroke. What

67:24 to the blood, the blood will in this area depending on the size

67:28 the breakage and the leakage, the . What does next? It starts

67:36 . The clog is hard, it causing pressure, it starts causing pain

67:41 the wound. The only way this can be cleaned up is if you

67:46 the skull, open the window into brain like in brain and clean it

67:53 . And if it is happening in locations. You would have to do

67:57 brain rens. If there is a build up abnormal fluid, build up

68:02 Cebr spinal fluid, you may have repeat that procedure multiple times and that's

68:08 we saw evidence also of multiple uh in the same location, not in

68:14 locations but repeated multiple times. Kind . Let's see where we are,

68:20 out of time. So we'll leave here today. When we come

68:23 we're gonna continue talking about the central system and stand by for more information

68:30 your

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