| 00:01 | This is lecture 12 of Neuroscience. one of the reasons why I say |
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| 00:06 | the beginning, what lecture number it because if it gets mislabeled by |
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| 00:12 | the title of the lecture, it's much true what I say verbally in |
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| 00:18 | recording. So we've been studying a of different neurotransmitters, right? We've |
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| 00:26 | looking at many different neurotransmitters. We've looking at amino acids, glutamate Gaba |
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| 00:35 | we've covered glutamate in quite a great , both ionotropic AM and MB A |
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| 00:42 | and metabotropic signal. We talked about and we'll finish talking about Gava |
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| 00:50 | Uh Today, we'll also spend quite bit of time talking about the immune |
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| 00:54 | which are very specific and different uh the glutamate and g allergic systems that |
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| 01:01 | talking about. And also remember that discussed peptides, we discussed peptides and |
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| 01:08 | peptides are uh something that can be expressed in the synopsis, but they |
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| 01:14 | their own synthesis, their own transportation their, their own release properties of |
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| 01:21 | that are different from neurotransmitters. So when we talked about rheumatic |
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| 01:29 | we talked about three types of ionotropic . It's ionotropic because one a molecule |
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| 01:38 | luminate binds to these receptors. There channels, they will start conducting ions |
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| 01:47 | that receptor channel. So that the and the big difference was the fact |
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| 01:54 | an MD A receptor contains a magnesium with an MD A receptor, resting |
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| 02:01 | of potential is blocked by magnesium. the initial depolarization happens to the amper |
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| 02:09 | and delayed part of epsd or depolarization due to an MD A receptors. |
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| 02:15 | early Epsp component is ample because ample open in the presence of glutamate and |
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| 02:21 | A is blocked by magnesium and the of glutamate. And there has to |
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| 02:27 | a depolarization that unblocks, it alleviates magnesium block from an MD A |
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| 02:32 | So a lot of times students will an MD A receptor with metabotropic |
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| 02:37 | It is not, it's an ionotropic channel except that it is blocked with |
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| 02:45 | metabotropic is G protein coupled signaling. . It's not channels anymore. The |
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| 02:53 | protein coupled receptors, an MD A will then have a lot of binding |
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| 03:02 | to uh different molecules. And glycine be a cofactor in the proper activation |
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| 03:09 | an MD A receptor. Remember that once it gets released, it can |
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| 03:19 | , we find ionotropic and metabotropic couple . We also saw that these metabotropic |
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| 03:29 | what we call MLU Rs divided into different groups and some of the groups |
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| 03:37 | group one is postsynaptic and group two group three M gars are presynaptic. |
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| 03:45 | talked about how postsynaptic and gars will influencing more of the calcium and modulating |
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| 03:53 | excitability through the cellular signaling cascades. we talked about how these metabotropic receptors |
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| 04:01 | are located presynaptic will be influencing and lot of problems blocking the release of |
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| 04:10 | or blocking the exocytosis depending on where are, their functions are going to |
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| 04:16 | different. But an important thing that learned is that once glutamate gets |
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| 04:24 | it will bar tropic and metabotropic And that same glutamate is gonna get |
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| 04:31 | or reintroduced, ret transported back into presynaptic terminal, re uploaded into the |
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| 04:40 | , so it can be released. we spoke about the fact that you |
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| 04:45 | glutamate transporter that is neuronal gl neuronal that will bring glutamate and upload glutamate |
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| 04:54 | vesicles. You have a vesicular glutamate on the vesicle so that glutamate gets |
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| 05:00 | into the vesicle apart from neurons during cycle of glutamate glia. In this |
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| 05:10 | , astrocytes also will absorb glutamate. they have G leo g glutamate transformer |
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| 05:19 | say glial it will we take the , they will break it down with |
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| 05:26 | , sensitive taste into glutamine. And gln glutamine will be transported into neurons |
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| 05:38 | excited to neurons will turn glutamine with help of glutamate into glutamate and that |
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| 05:48 | will get uploaded into vil. So this virtue, ostracizes control and are |
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| 05:59 | in the biosynthesis of glutamate and control available amount of glutamate to neurons. |
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| 06:07 | you damage your block glial glutamate you'll have an increase in glutamate |
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| 06:13 | But maybe later on, you'll not enough glutamine to synthesize glutamate by |
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| 06:19 | So it could be in the fact reduces increases at first but later reduces |
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| 06:25 | amount of glutamine that's not unique to . It also happens in Gaba in |
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| 06:33 | ou A diagram that discusses this particular . So we talked about Gaba |
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| 06:41 | When we looked at Gaba, a channel, it's an ionotropic receptor |
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| 06:48 | And when Gaba A gets activated by , it's a molecule that will bind |
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| 06:57 | them, there's going to be influx chloride and chloride negative charge going inside |
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| 07:05 | South. It's gonna cause IP sp initial phase of this IP SB is |
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| 07:13 | A mediated. But we also know Gab is aside for all of these |
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| 07:19 | molecules that can bind to it. all agonous tons of Aine barbiturate neuros |
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| 07:25 | ethanol that can increase the amount of by opening up that receptor channel. |
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| 07:34 | addition, nearby on these membranes, can also contain Oop Gaba B |
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| 07:43 | This is Gaba B and Gaba B are G protein coupled receptors and this |
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| 07:50 | protein OYN is linked to the potassium . And when Gaba binds to this |
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| 07:59 | protein, this is gabba binding to receptor G protein coupled receptor. The |
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| 08:07 | of the unit of this G protein open potassium channels and cause positive charge |
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| 08:15 | so positive charge leaving will make the of the cell more positive and the |
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| 08:21 | of the cell more negative contributing to second slower Gabba Dean Ed A and |
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| 08:29 | SD. OK. So these are polarization, let's say from minus 65 |
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| 08:35 | . OK. This is GBA this is God, this is the |
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| 08:42 | SP or inhibitory a postsynaptic potential. the early phase of the inhibitory apo |
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| 08:49 | potential is due to chloride influx and polarization. The B phase, the |
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| 08:55 | phase of IP SB is through activation potassium channel, the G codeine coupled |
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| 09:03 | further deep hyper polarization. Here by be, it also shows that Gaza |
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| 09:12 | which is shown here can have an on voltage gated calcium channels which are |
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| 09:18 | out. So, postsynaptic will cause SPS by opening a potassium channel presyn |
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| 09:27 | by targeting well educated calcium channels that interfere with exocytosis. It also shows |
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| 09:35 | y the bee can interact with an A receptor through the G protein intracellular |
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| 09:43 | . Put in pa A finally activating MD A receptor. So, ionotropic |
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| 09:53 | metabotropic ionotropic is causing the early IP fee and metabotropic is causing the late |
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| 10:02 | S fee. They will have their agonist and antagonist yaba A agonist, |
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| 10:09 | , small antagonist bicu. So remember bicu was an antagonist to ya A |
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| 10:15 | means it's going to block ya A you bla gabba A, you're targeting |
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| 10:22 | portion of the IP S speed. typically when you stimulate the fibers and |
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| 10:30 | of these experiments are done in the slides, love the brain slide. |
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| 10:39 | love the brain slide. So typically have all of these axons. I |
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| 10:44 | somebody up. I saw it. typically you stimulate the fibers. These |
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| 10:51 | the axons coming in into some cell interest or neuronal network of interest. |
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| 10:58 | you have these whole cell patch clamp , right? Or electrophysiological recordings from |
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| 11:05 | cells. And when you stimulate these , guess what some of these fibers |
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| 11:11 | be re released in glutamate. But of these fibers may be releasing |
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| 11:21 | You guys remember that these cells will both excited or inhibitor synopsis. So |
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| 11:26 | cell will have hundreds thousands of excited in inhibitor synopsis coming on to one |
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| 11:32 | . And quite often when we stimulate fibers, this is part of my |
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| 11:37 | work. When I was doing my at uh in New Orleans, we |
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| 11:42 | studying the developments of this retina geniculate right now. It doesn't mean much |
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| 11:48 | you. But when we study the system, you'll understand the path of |
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| 11:53 | into lateral geniculate nucleus or retina geniculate . And then you'll also understand projections |
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| 11:59 | lateral genicular nucleus, primary visual That's all coming with the visual |
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| 12:05 | But this is what I was So when we would shock these |
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| 12:09 | you'd get both, you would first an EPSP says EPS speed and that |
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| 12:17 | would be followed by Gaba A and be IP. SP. OK. |
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| 12:28 | this is IP SP. So what's on? So you are trying to |
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| 12:34 | the cell and it produces an Epsp immediately this EPSP gets cut off. |
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| 12:40 | doesn't allow for the number and potential depolarize the threshold value. Instead it |
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| 12:47 | hyper polarized by Gaba A and the of Gaba here and eventually by Gaba |
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| 12:54 | . So you would see a we call it a composite EPSP IP |
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| 12:59 | response. The most important diagram on is a, it's showing you this |
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| 13:09 | Gaba A and Gaba B and In C, we applied by two |
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| 13:19 | is a Gaba A antagonist, We're blocking Gaba A with bit |
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| 13:30 | we're blocking the initial inhibition of this SP here and guess what happens? |
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| 13:39 | . She's in the presence of Look at this massive excited to |
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| 13:45 | That's why we, when we talk synaptic transmission and integration of excited inhibitor |
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| 13:51 | , we also use a language that that IP SDS will sculpt the |
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| 14:00 | It's like a sculpture, right? it's going to mold it in some |
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| 14:05 | . If it, if it is inhibition, if it is strong |
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| 14:12 | you're gonna get a small EPSV that flanked or that is essentially prevented from |
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| 14:19 | the threshold by this IPs fees But if you block. If you |
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| 14:27 | this Gaba A, you're blocking this . Gabba V is actually not strong |
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| 14:33 | . Now, you're making this massive EPSP. And that's why we |
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| 14:38 | that the inhibition sculpts how the the shape of this EP SS P |
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| 14:44 | like a sculpture. OK. So for the inhibitions. All right, |
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| 14:53 | kind of uh talk about this diagram then we'll come back and talk about |
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| 15:00 | cycling of gag and glutamate. And is something that puts it all together |
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| 15:07 | you. We studied inhibitory synopsis, studied excitatory synopsis, glutamate transmission and |
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| 15:14 | transmission. We looked at when Gaba released, Gaba can bind to Gaba |
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| 15:22 | receptor. So it will cause influx fluoride causing with IP SP and it |
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| 15:27 | bind to Gaba BG protein coupled receptors can open potassium channel and cause more |
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| 15:34 | polarization. Poop. Gabba VIP sp recall that Gaba synopsis quite often will |
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| 15:45 | Gaba B auto receptors. Momo auto is located on the same release |
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| 15:54 | So Gaba releasing Gaba Gaba synopsis, it has Gaba B on the Gaba |
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| 15:59 | , it's an auto receptor activation of B. Pre syn optically will block |
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| 16:08 | gated calcium channel, which is necessary exocytosis. So it is a negative |
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| 16:16 | , a self regulation mechanism here to its own exocytosis nearby. You have |
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| 16:22 | excitatory synapse. So this synapse is glutamate and obviously poop, you'll have |
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| 16:30 | receptors. The most important one for functions that we're talking about. Here |
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| 16:36 | an MD A receptor oyn apply. once the MD A receptor gets activated |
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| 16:42 | glutamate, you will have depolarization. remember that an MD A receptor is |
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| 16:47 | a significant source of calcium influx. calcium inside the cells is not just |
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| 16:53 | ion, it's also a secondary So calcium going inside the cells can |
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| 16:59 | interact with different molecules including Kassis. is calcium como and kinase two. |
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| 17:09 | through the interactions with Gaba V po on the excitatory Synopsis, it can |
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| 17:18 | inhibit through opening the potassium channel The GB can cause hyper polarization by |
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| 17:27 | this hyper polarization. It can also activation of an MD A receptor. |
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| 17:35 | here you have Gama B that gets intracellular without a lien do K ASIS |
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| 17:44 | can have an effect an excitation. addition, if there is going to |
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| 17:49 | this is Gabba b again hyper polarizing . OK. If there's going to |
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| 17:54 | a spillover of Gaba from this excited this inhibitory synopsis first, if there's |
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| 17:59 | little bit of Gaba release, that all be cycled here, the ambient |
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| 18:04 | of Gaba. If this synapse is active, there's going to be a |
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| 18:09 | over of Gaba molecules and they will to presynaptic Gaba B receptors on glutamate |
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| 18:19 | now they're going to inhibit the exocytosis glutamine. So, Gabba through yo |
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| 18:27 | other receptors can control release of Gva through control of heteros yaba b receptors |
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| 18:35 | inside of 30 cells can control the of ligament. All puts it |
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| 18:43 | Uh In my lectures, I have diagrams that kind of a summarize this |
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| 18:50 | of a summarizes almost an hour of we talked about. These slides are |
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| 18:55 | slides to take notes on. Um you want to add additional information as |
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| 19:02 | presynaptic hyper polarization depolarization IP S PC SPS, you can, you can |
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| 19:08 | do it with using this diagra, ? That's not all I have to |
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| 19:19 | you another diagram to make things a bit more common. All right, |
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| 19:23 | this diagram. What you have to really is I'm not gonna ask you |
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| 19:31 | details of the transporters, the the gops. But the fact that |
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| 19:38 | thinks glutamate makes glutamine gives it back glutamate songs. Glia thinks Gaba spit |
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| 19:45 | glutamine and GVA cells will make more , they'll cycle it through the glutamate |
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| 19:51 | it becomes GVA. And uh by way, I'm more than happy to |
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| 19:56 | this figure. Legend, I just want you to spend that much |
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| 19:59 | I want you to know enough of I just said that those cells take |
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| 20:04 | ast sites regularly, glutamate and GMA they have transporters for glutamate and gabba |
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| 20:08 | they release glutamine and they reconvert it these molecules. OK? That's not |
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| 20:19 | . No. Is that it? this is a really good summary. |
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| 20:30 | , right. Study this uh and a little bit about the cycling diffuse |
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| 20:37 | systems. We will be talking about in the next couple of hours. |
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| 20:42 | we'll probably just start talking about them . Um Remember this is an example |
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| 20:49 | acetylcholine again, it just re re reinstate what we already learned. I |
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| 20:56 | you to know this acetylcholine cycle really . So the synthesis was chat the |
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| 21:02 | with acetyl cholinesterase which happens in the blast reimport of the cline re synthesis |
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| 21:10 | acetylcholine re loading of the ach transported vesicles release. And the fact that |
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| 21:17 | CN acid combined to nicotinic receptor channels muscarinic metabotropic acetylcholine receptor. So, |
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| 21:30 | will serve as an agonist to both and muscarinic. So these are ionotropic |
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| 21:38 | metabotropic and then they will have their distinct agonist. Nicotine is an agonist |
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| 21:44 | nicotinic muscular for muscarinic and they'll have own antagonist, Curare. So we |
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| 21:51 | use of curare and how we reduce size of the pl potential in neuromuscular |
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| 21:58 | . It's an antagonist and atropine is antagonist for muscular. Why do we |
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| 22:04 | them modulatory systems? And we're kind introducing acetylcholine because we've been talking a |
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| 22:09 | about acetylcholine, the modulatory because with exception of a Cylco that has an |
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| 22:17 | receptor and it has metabotropic receptor, other system. So we'll talk about |
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| 22:24 | , norepinephrine serotonin, they all act g protein coupled receptors. So when |
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| 22:30 | molecule L and binds the G protein receptor. It causes catalytic reaction, |
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| 22:36 | catalyzes these subunits and this subunit from receptor. This is not the dropping |
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| 22:45 | to potassium channel, open the potassium . This is an example in neuroscience |
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| 23:05 | this is ionotropic, this is So, ionotropic gabba a cause hyper |
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| 23:18 | . Initial IP sp and metabotropic GB the that uh little traffic because the |
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| 23:31 | polarization. Now what we saw in CNS with acetylcholine receptors is is there |
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| 23:41 | nicotinic or Cylco receptor choline binds to receptors. You need two that binds |
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| 23:50 | these receptors. What's going to happen going to be an influx of sodium |
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| 23:57 | coming in and then later potassium is to be even. But the initial |
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| 24:02 | to activation of nicotinic acetylcholine receptor is of sodium nearby on the same patch |
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| 24:12 | the membrane. You are going to muscarinic acetyl co receptor and acetylcholine binding |
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| 24:25 | this receptor will activate the G prom that is going to open potassium channels |
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| 24:36 | it's going to cause on the inside the self hyper polarization. Remember that |
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| 24:47 | coan receptors, nicotinic and muscarinic in CNS poop particularly they don't have as |
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| 24:54 | of a depolarizing or hyper polarizing effect they do nicotinic ones in the neuromuscular |
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| 25:01 | . It's always that huge plate So the cash nicotinic acetylcholine receptors will |
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| 25:07 | small depolarization. But metabotropic muscarinic acetyl receptors will cause the opposite hyper |
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| 25:19 | So what does that mean? That that can you have co expression of |
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| 25:23 | and muscarinic on the same neuron and same patch of membrane. The answer |
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| 25:26 | yes. So they're essentially on a cell numbering level of opposing actions. |
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| 25:35 | is depolarizing. Another one is hyper here in Gaba, it's additive. |
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| 25:41 | is hyper polarizing. The second one also hyper polarizing. So it just |
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| 25:46 | , depends really on the interactions with ionotropic receptors and also metabotropic activation of |
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| 25:54 | receptors. All right. So let's about some very interesting things. And |
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| 26:09 | ended up spending two hours in this . Last time I lectured it and |
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| 26:15 | see how, how this goes because some very interesting concepts that we're discussing |
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| 26:20 | are very relevant to everyday life. uh a reminder this is the introduction |
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| 26:28 | these diffused module thoris systems with the coin where I want you to know |
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| 26:32 | of the synthesis break down. I you to know the vot toin the |
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| 26:37 | story, the nerve gas story, cholinesterase inhibitors story with Alzheimer's disease all |
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| 26:44 | acetylcholine and psych that we talked Recall that these molecules are expressed in |
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| 26:51 | nuclei. There's a small number of cells, hundreds of thousands, small |
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| 26:56 | compared to billions, maybe 85 or billions of neurons in general that you |
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| 27:02 | in the brain. And most of will be expressing gamma glutamate. But |
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| 27:08 | or am means or modulatory, uh are confined to these nuclei. They're |
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| 27:16 | used because the projections are very diffuse very broad uh uh projecting throughout the |
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| 27:24 | . So abe and even in the cord and they're modulatory because they act |
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| 27:30 | g protein coupled receptors. With the of acetyl co which we just discussed |
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| 27:35 | C MS which has an ionotropic receptor . So, acetylcholine think about each |
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| 27:44 | of these molecules as responsible for different . It depends what type, what |
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| 27:51 | of the brain they invent because we that different parts of the brain are |
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| 27:58 | for different functions. And you'll learn that in the next two or three |
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| 28:02 | or. So we know that thalamus responsible for sensory perception. So all |
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| 28:09 | the visual information, auditory information it's going to enter into this area |
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| 28:15 | the thalamus before it goes into the . So thalamus is really sort of |
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| 28:20 | sensory information process and you have these , the Ponton neslo complex, the |
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| 28:29 | nucleus of Neymar and the medial cepal . These are very small structures that |
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| 28:35 | was going to supply se code to rest of the brain. It innervates |
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| 28:41 | coral encephalon, medial and vent basal . So this is interesting the basal |
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| 28:48 | areas here. OK. The function a second. Most of the unknown |
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| 28:54 | in learning and memory. Acetylcholine system impaired in what disease Alzheimer's disease? |
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| 29:05 | and learning. Yes. Is a loss of memory disorientation, inability to |
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| 29:11 | executive function is part of that. symptomology. Indeed, it is why |
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| 29:17 | it mostly unknown because we still don't a lot about these, what we |
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| 29:23 | sprinkler systems of these are means we really know exactly what particular functions. |
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| 29:28 | immediate, there's also considerable overlap between chemicals and the functions that they mediate |
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| 29:33 | the brain. But once again, also have certain specific, not only |
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| 29:39 | as if they relate to behavior, the neurological disorders that they are tied |
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| 29:44 | it. So, acetylcholine, we talk about Alzheimer's disease, dopamine. |
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| 29:49 | will talk about Parkinson's disease and we'll about motor dysfunction, uh Ponto meal |
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| 29:58 | complex here that is innervating the uh stem, the paws innervating the |
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| 30:04 | Here, it regulates excitability of thalamic nuclei. So it will influence part |
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| 30:12 | your sensory perception can influence how you things, how you see things by |
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| 30:19 | these uh areas, the uh thalamus through the pota uh uh uh MST |
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| 30:34 | . This is acetylcholine. This is the replay because I wasn't sure what |
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| 30:38 | gonna end these lectures. Uh this is an exception. This is |
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| 30:43 | only one in the C MS that have I am a tropic signal, |
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| 30:47 | the others that we talk about and ach will have none of a tropic |
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| 30:54 | . That's why they're modulatory, they're to be opposing in their actions. |
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| 31:01 | is going to be depolarizing the The other one is gonna be hyper |
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| 31:05 | . The natural endogenous substance that we is acetyl coded exogenous substances that are |
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| 31:14 | natural such as nicotine, which comes tobacco plant. It's also an agonist |
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| 31:20 | will have a binding size to So agonist versus antagonist and very quick |
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| 31:26 | of a PSE Coline and we know lot about it. This is the |
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| 31:30 | pathway to the potassium channel that we saw with acetylcholine. Ok, catecholamines |
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| 31:39 | . So we're pretty much done with . And I will ask you to |
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| 31:43 | the greatest amount of detail about acetylcholine what we call cholinergic system. So |
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| 31:52 | is catecholaminergic system, catecholamines. They are listed here. Dopamine or epinephrine |
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| 32:00 | epinephrine, dopamine and norepinephrine, sometimes called adrenaline like adrenaline of the |
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| 32:09 | . They have a common precursor tyro becomes all dopa l dopa becomes |
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| 32:16 | dopamine becomes norepinephrine, norepinephrine becomes So the cells that will have PNMT |
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| 32:27 | be able to produce epinephrine. The that don't have PNMT can produce epinephrine |
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| 32:33 | they have DVH, they will produce . So all three of these neurotransmitters |
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| 32:43 | from the common precursor and you can it's very simple relax reactions of oxy |
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| 32:48 | Coh oxidation. Uh over here adding three group on top of that. |
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| 32:57 | you have to have enzymes inside those in order to be able to synthesize |
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| 33:01 | dopamine or norepinephrine. So, if don't have that synthese or transferase or |
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| 33:08 | . You cannot make that molecule. again, when you're gonna use |
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| 33:11 | you know, as the chemistry you're wanna find and target, potentially these |
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| 33:20 | transaxial lais or decarboxylase enzymes dopamine. have two major areas that produce |
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| 33:29 | So we're gonna focus on dopamine uh this slide, ventral tegmental VT A |
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| 33:36 | substantial mi ventral bt A intervascular region Sophal on this region, mostly in |
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| 33:45 | frontal lobe. These mesac cortical limbic system, dopamine ergic projections from |
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| 33:54 | The substantial Migra axons will projected to . Striatum is involved in initiation of |
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| 34:05 | motor commands and complex motor commands. motor cortex is the one that is |
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| 34:11 | to command my spinal cord to move right hand. OK. That's motor |
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| 34:17 | command. But if I have a sophisticated thing I'm gonna do to recall |
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| 34:24 | really cool something like that. That of that motor command is gonna get |
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| 34:33 | upon from the side. Motor cortex just gonna say though, you |
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| 34:40 | over there you'll learn um spin your hand like this, you know, |
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| 34:46 | and um right. So motor cortex telling me what to do, but |
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| 34:50 | command is stored inside of me, ? I remember how to cast the |
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| 34:55 | when I see it. So the has a lot of these sequences of |
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| 35:01 | motor commands. So the striatum doesn't the signal to spinal cord, move |
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| 35:05 | muscle, the striatum sends that signal the motor cortex. The motor cortex |
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| 35:11 | moving this muscle, that muscle, muscle left hand right hand, it |
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| 35:18 | the initiation of voluntary movements. Degeneration substantial Niagra degeneration of dopamine igic |
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| 35:29 | Uh depletion of dopamine or loss of cells is a cause of Parkinson's |
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| 35:38 | So, acetylcholine, we talked about disease and we talked about therapies, |
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| 35:44 | about cholinesterase inhibitors, talking about dope system. We're talking about Parkinson's |
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| 35:54 | One of the symptomologies of Parkinson's disease inability to control your movements. |
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| 36:02 | quite common, even in the definitions the first chapter of Parkinson's disease, |
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| 36:07 | a motor disorder that is affected by loss of degeneration of dopamine. But |
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| 36:14 | symptomology, we talk about tremors and will see Parkinsonian tremors is a pretty |
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| 36:23 | symptomology. When people are trying to up a cup of coffee or tea |
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| 36:29 | something. And they experience these they really can't control the, the |
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| 36:34 | at all and they cannot execute certain so they cannot drink and things like |
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| 36:40 | . When we talk about brain we will look at the clinical case |
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| 36:44 | deep brain stimulation of how stimulating these like substantia, nigra can stop the |
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| 36:52 | in Parkinson's patients. And obviously, you're talking about medications, a lot |
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| 36:57 | these medications for Parkinson's disease are gonna to do something with dopamine function with |
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| 37:05 | receptor function, with dopamine ergic trying to boost the dopamine activity which |
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| 37:12 | going down in this particular disease. . So that's substantial Igra. And |
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| 37:20 | talk about imaging techniques and we'll come to this deep brain stimulation for Parkinson's |
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| 37:25 | . It's a really cool technique where get implanted in people's brains and they |
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| 37:31 | there permanently and they get turned on control the abnormal movements of Parkinson's |
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| 37:39 | Norepinephrine. You have production of locus , the blue nucleus, the blue |
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| 37:46 | . Once you cut the brain tissue , this locus Aurelius turns blue with |
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| 37:52 | , it's really cool. So you're brain slices, you're making red |
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| 37:58 | you gonna come out and as you through this area, it's gonna sit |
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| 38:02 | oxidized a little bit, it's gonna turning blue right in front of your |
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| 38:05 | almost. That's why it was called crius for blue. So axons that |
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| 38:11 | out, they innervate cerebral cortex, thalamus cortex broadly throughout cortex. Innervating |
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| 38:18 | cortex will affect visual function, parietal , parietal frontal and so on. |
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| 38:27 | , innervation of thalamus is your sensor , hypothalamus learn. There's a lot |
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| 38:32 | uh activities, olfactory bulbs, midbrain and spinal cord. So massive |
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| 38:39 | , uh innovation from one nucleus covering cortex, covering the value and the |
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| 38:45 | port. The function is regulation of t arousal, sleep wake cycles. |
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| 38:53 | this is all time when you're sleeping not attentive. Typically you're also not |
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| 38:59 | when you're sleeping. So it's controlling things learning and memory. It's very |
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| 39:05 | in coding of new information. So not just one molecule, just not |
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| 39:11 | . It's a combination and interaction of different chemicals and transmitters that are responsible |
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| 39:16 | normal memory functions. It's uh uh and pain that is associated regulation of |
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| 39:25 | and pain, mood and brain So a lot of different functions, |
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| 39:32 | of norepinephrine is new, unexpected nonpainful stimuli. What is a painful sensor |
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| 39:41 | , a bruise or cut on your ? It goes through the nose de |
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| 39:47 | . It's not a sensor system. 20 maybe I think or something like |
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| 39:54 | , we'll get to it. But it's not painful sense of stimuli but |
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| 40:02 | . So what are those? Those big bears running out, dude and |
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| 40:09 | have no time to think about So your flight or fight response kicks |
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| 40:17 | . And I always say I'm not what to do with the bear. |
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| 40:19 | think maybe you're supposed to stand So you have this, you |
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| 40:23 | urgency to do something norepinephrine kicking in you're supposed to just stand still |
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| 40:28 | You know, it's, it's pretty , but that would be the the |
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| 40:33 | or something unexpected, something that is life threatening and very quick reaction. |
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| 40:40 | once norepinephrine kicks in things speed up a very uh interesting phenomenon that quite |
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| 40:48 | few people report is if you have been in a car accident and most |
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| 40:54 | us have been hopefully minor ones, things kind of slow down. So |
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| 41:02 | , it's almost like the seconds become and whatever happened in that time span |
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| 41:08 | probably a fraction of a second. , you, it's almost like you |
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| 41:12 | recall every single thing that happened within . It seems so long because you |
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| 41:17 | so attentive to every single thing that happening within that one second. And |
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| 41:24 | the perception of time also could be influenced when you are in the middle |
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| 41:30 | these, you know, reaction times expected stimuli freefall. For example, |
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| 41:37 | things and time perception also changes um when you're exposed to these unexpected |
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| 41:46 | So when we look at the modulation when we look at the control of |
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| 41:53 | again, it's the same story, will get released and norepinephrine will get |
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| 42:00 | update and back into the presynaptic terminal will get released and dopamine will get |
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| 42:08 | back into presynaptic terminal re uploaded and again. So, uh drugs of |
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| 42:15 | like cocaine and also amphetamines, they with the reoping of norepinephrine and |
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| 42:26 | That's why people refer to them as because they increase the amount of centrally |
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| 42:35 | in your brain or and dopamine. are also of course, pharmacological manipulations |
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| 42:44 | the transporters that will be used for . But that's important to know where |
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| 42:49 | of the most common illicit drugs that also methyl thyro alpha methyl thyro can |
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| 42:57 | the synthesis in these. So this something that can impair the production of |
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| 43:04 | or dopamine. This is something that block the reuptake, right. So |
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| 43:11 | what it does. It blocks the of dopamine and increases the available |
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| 43:18 | And in the synoptic left inside the , uh and uh kind of erases |
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| 43:26 | personalities by doing. So, it stimulates dopamine release too. So it |
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| 43:34 | the reuptake and stimulates dopamine release. you have a double whammy effect of |
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| 43:39 | much dopamine in the system. Serotonin from T Toan turkey is very high |
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| 43:51 | turkey and the dark meat in, particular. So you ever wondered why |
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| 43:56 | everybody so happy at Thanksgiving dinner? everybody happy at the family dinners all |
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| 44:02 | time? So everybody gets sleepy and of a drowsy and makes you wonder |
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| 44:08 | it the amount of food you ate Thanksgiving is like picking out, you |
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| 44:12 | , I can't walk or is it getting so much tryptophan from the dark |
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| 44:17 | ? Because some people just go through dark meat off the plate. You |
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| 44:20 | , what do I need? And you generate five HTP and then five |
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| 44:25 | gets decoyed into five hydroxytryptamine, which serotonin. So if you have a |
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| 44:33 | of that precursor Tryon, you can more serotonin. It's a little bit |
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| 44:38 | a joke because you're eating it. not really putting it in your for |
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| 44:41 | but part of it will probably penetrate the gut, it regulates mood, |
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| 44:48 | behavior and sleep serotonin. So mood the first thing that comes out when |
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| 44:54 | said dopamine, what was the first that came out, came out motor |
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| 45:00 | and I said acetyl Colline, the thing that came up number. |
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| 45:06 | So you see how these different memory motor function, mood, |
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| 45:14 | wake cycle attention, they all mediate behaviors. They kind of have one |
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| 45:20 | behavior. They take over mood, only one motor, but they all |
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| 45:26 | . They all interact and have influence , on each other and have influence |
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| 45:31 | the brain as a whole too. not like one system is active, |
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| 45:36 | one is on. They actually have work together to waken. The sleep |
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| 45:39 | have to work together the attention, lack of the attention have to work |
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| 45:44 | these molecules cycle in the increase. is an example of activity dependent increase |
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| 45:52 | unexpected stimulus. So if there is bear running at you, it's not |
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| 45:56 | much norepinephrine in your system. The is running at you. Boom, |
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| 46:00 | of a sudden it gets released and all throughout the brain and more of |
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| 46:05 | is being synthesized to supply more of release. So innervating many areas same |
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| 46:16 | no adrenergic. So look at the spinal cord very diffusely throughout the |
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| 46:22 | Cerebellum, spinal cord, very diffusely the cortex because of its anatomical uh |
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| 46:30 | and overlap. They're also going to overlapping in their function. And |
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| 46:35 | they'll be very intricately involved. Both these system, no epi and serotonin |
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| 46:40 | into the uh control of the sleep cycles and also mood because you're a |
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| 46:47 | , you're 10 that this is in different kind of mood serotonin will |
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| 46:51 | you can make you a little bit relaxed. So that's, that's |
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| 46:56 | regulating the mood states. If you and together with an oric system, |
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| 47:02 | comprise what is called the ascending reticular system. This ascending reticular activating system |
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| 47:10 | very active and starts sending synchronized slow of activity to help you fall |
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| 47:17 | So those chemicals will come together more up in serotonin and certain levels in |
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| 47:23 | that reticular system that will have broad in the whole brain. That's when |
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| 47:28 | start getting sleepy, you kind of like I'm a little bit sleepy. |
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| 47:30 | the next thing you're out, you , it's not like I'm sleeping more |
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| 47:34 | more sleep, more sleepy. It's you're sleepy and then you're out, |
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| 47:38 | is kind of a little unconscious that what happened to you. That's because |
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| 47:42 | get massive release of these molecules throughout cortex and it tunes you now into |
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| 47:48 | sleep cycle. Ok. So most you have heard of Ssris, which |
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| 47:58 | selective serotonin reuptake inhibitors, which are antidepressant drugs. And you will hear |
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| 48:05 | lot about SSRS. So let's talk Ssris, FLUoxetine, FLUoxetine, right |
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| 48:13 | is a selective serotonin reuptake inhibitor. , FLUoxetine will target selectively serotonin. |
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| 48:20 | block the reuptake of serotonin. You more serotonin serotonin mood molecule. Some |
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| 48:27 | will say happy molecule. So block increase serotonin, happier tricyclics or other |
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| 48:36 | . It's a type of drug, will target both no pi and serotonin |
|
| 48:44 | . So this is maybe more mood . This might be more correlated with |
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| 48:51 | and sleep cycle and attentiveness. It be affecting both of these systems. |
|
| 48:59 | , ma O inhibitor. And this a uh diagram from your book that |
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| 49:04 | don't like very much. So I this diagram. And what happens is |
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| 49:10 | once serotonin gets released by the it binds the serotonin receptor by synoptic |
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| 49:19 | metabotropic surface. It gets transported. have taken back into the presyn here |
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| 49:27 | MA O is mono oxidase that breaks down and breaks down these molecules and |
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| 49:36 | they can get re synthesized back into serotonin uh and reload it again. |
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| 49:44 | there's two pharmacological controls here that are first one is blocking the reuptake. |
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| 49:55 | second one is inhibiting the breakdown of . In both cases. In this |
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| 50:02 | , you'll have more serotonin in the by blocking Ma O, you'll have |
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| 50:07 | serotonin in the presynaptic termin. And this is something that is uh really |
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| 50:18 | and is emergent in this field and that we've known about for a while |
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| 50:23 | is these drugs can take time to effect. The antidepressants has ized. |
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| 50:32 | may take 23 weeks to have a effect of it on an individual. |
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| 50:40 | you're changing this whole system? You're the release properties, you're changing how |
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| 50:45 | of this chemical is available. If talking about ma O inhibitors, you're |
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| 50:51 | the metabolism inside the cell. This not something that happens over, you |
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| 50:56 | , seconds and minutes of time, that is a long time. That |
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| 51:01 | a long time. Some of these , uh severe societal depression, anxiety |
|
| 51:07 | societal tendencies, these things need to fixed fairly fast. They cannot wait |
|
| 51:14 | weeks, a lot of times they need instant something now. So people |
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| 51:21 | looking into ketamine sprays that uh that an MD A receptor for immediate suicide |
|
| 51:30 | . All right. And so those again, they're great for therapeutic |
|
| 51:36 | but it's not something that acutely, , depressed, not happy. |
|
| 51:40 | I took the pill, you it's a whole process and it's |
|
| 51:43 | you know, when you look at drug commercials for weight loss, for |
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| 51:48 | , combined with the exercise and a diet, this pill will do A |
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| 51:53 | and Z. So does that mean you just pop the pill? And |
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| 51:57 | not happy now, I'm not Now, exercise and diet, sleep |
|
| 52:03 | , social interactions, all of these are gonna play, play a part |
|
| 52:07 | it. Now, the other line here says LS DC IB mushrooms and |
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| 52:15 | interacts with serotonin signal. That's something is emergent. Again, we have |
|
| 52:21 | this for a while. LSD is acid. LSD is a recreational acid |
|
| 52:29 | . A Lucifer drug, cyber magic mushrooms. Sure. Everybody heard |
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| 52:35 | them. They're even legal in some and some cities and Coyote, which |
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| 52:41 | culturally and traditionally used in, Mexico and a lot of times it's |
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| 52:46 | as a, a rite of passage in growing up, especially for adolescent |
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| 52:53 | and boys as they turn into And a lot of cultures, it's |
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| 52:57 | part of the ritual to go through psychedelic experience or a trip. And |
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| 53:03 | the longest time, people thought it just the hippies, you know, |
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| 53:06 | just want a trip, wear long , bell bottoms, listen to Grateful |
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| 53:12 | and, you know, see visions front of them and hug trees, |
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| 53:15 | know, tree hugger. So, um as always certain things emerge that |
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| 53:23 | hippies would go to a concert and some mushrooms and then they go back |
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| 53:27 | work and they're really happy for like weeks. And it was like, |
|
| 53:30 | wrong with you, man? You , like all depressed and like it's |
|
| 53:33 | concert, I want to, you , OK. Well, what we're |
|
| 53:39 | now is really interesting, especially the mushrooms. There are clinical trials, |
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| 53:44 | Johns Hopkins and Harvard Universities that are at these substances as antidepressants that are |
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| 53:53 | at these substances, especially psilocybin as addiction substances. So the clinical trials |
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| 54:00 | that one use of psilocybin mushroom which is a FDA approved therapy protocol |
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| 54:06 | is done under supervision. So not the festival, not tripping hugging |
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| 54:11 | but somewhere in a facility with the known doses amounts that help because when |
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| 54:20 | put people in that state, they either have a very happy trip or |
|
| 54:25 | , horrible trip too. But that's of the experience actually living through horror |
|
| 54:31 | what makes people feel better on the side too. So what is so |
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| 54:36 | about these treatments with psilocybin mushroom? interesting is it's a one time treatment |
|
| 54:43 | helps people quit nicotine, one of strongest addictions, heroin, another very |
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| 54:50 | addiction or they serve as antidepressants. instead of having this 23 week protocol |
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| 55:01 | you feel an effect and after taking pills every day, Ssris or |
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| 55:07 | Pharma pharmaceuticals, these protocols are different they set up. So the person |
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| 55:14 | a trip for a number of hours they don't take the drugs anymore. |
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| 55:20 | not like they go home and they mushrooms every day now for forever. |
|
| 55:25 | actually don't do that anymore. There's that is happening that is one time |
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| 55:30 | is enough to change these systems. so we're finding out that new synopsis |
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| 55:35 | formed with the use of psilocybin And uh this is becoming more of |
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| 55:41 | kind of a therapy, looked at of a therapy. Even in the |
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| 55:47 | hippie community, people are scratching their like, huh, I've never been |
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| 55:51 | antidepressants but you know, I go this festival once in a while and |
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| 55:57 | I take mushrooms, you know, they, they notice differences. So |
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| 56:03 | is really a margin. It still considered a illegal substance. But there |
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| 56:09 | these experimental emergent protocols that approve and clinical trials that are now showing really |
|
| 56:16 | effects for addiction in particular and So now the issue here with a |
|
| 56:24 | of these drugs and including mushrooms and like that. But with these chemical |
|
| 56:30 | , a lot of issues is that have side effects. Sometimes side effects |
|
| 56:35 | pretty significant and sometimes the medication does agree with an individual. So I'm |
|
| 56:40 | some SSR I my depression is a better but boy, am I |
|
| 56:46 | I have diarrhea and I'm sleeping half the day. You know, |
|
| 56:52 | which one is better? I'm not . So I'm like, I'm |
|
| 56:55 | It's not really doing the thing I'm quit now. It's sr I so |
|
| 57:00 | cannot do that, you cannot drop . It's called weaning off smaller |
|
| 57:06 | smaller dose, smaller dose, smaller , smaller dose 23 weeks ago because |
|
| 57:14 | have to rebuild the whole metabolism release of these neurotransmitters. Ok. So |
|
| 57:21 | pretty promising to me to go on secluded room for eight hours. You |
|
| 57:27 | , and come out and not have do it another half a year or |
|
| 57:30 | , you know, and sure these experimental therapies. But so is ketamine |
|
| 57:36 | anesthesia that is used for depression, that typically needs to be repeated every |
|
| 57:42 | or two months or so. are these new substances, do we |
|
| 57:47 | them really? Well? What's inside the mushrooms are all mushrooms, magic |
|
| 57:52 | the same when you hear the, different kinds of mushrooms and stuff like |
|
| 57:56 | . No, we don't really understand much about them, but this is |
|
| 58:00 | interesting emerging story and it is acting the serotonin system, but we don't |
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| 58:08 | know where and if it's not related interacting with other systems as well. |
|
| 58:15 | . I'm out of time today. , uh, wait for my email |
|
| 58:20 | don't wait, you'll just get it about the quiz on Thursday. And |
|
| 58:25 | hope everyone will be here on It, it, |
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