| 00:05 | This is lecture 11 of neuroscience and began talking about neural transmission. We |
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| 00:12 | several important topics. We covered the of acetylcholine and the neuro muscular junction |
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| 00:20 | the vagus nerve and the cardiac Ah And we described this experiment, |
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| 00:31 | spoke about two types of synopsis that present in neurons. The chemical |
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| 00:38 | which is the vesicles release across the class, and electrical synopsis and electrical |
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| 00:47 | as we understood, allow for immediate of currents across the cells that contain |
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| 00:53 | gap junctions. It's very, very when you want to synchronize large circuits |
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| 01:00 | large numbers of neurons because by stimulating neuron you can actually engage the entire |
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| 01:07 | . It's very important because you can it in a very fast fashion. |
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| 01:11 | no synoptic delay in chemical transmission. discussed without neurotransmitter to travel across synaptic |
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| 01:18 | and bind to the post synaptic There's a synaptic delay of few |
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| 01:24 | You don't have that delay with the junctions, electrical communication apart from small |
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| 01:32 | and ions, currents that flux between cells. You can also have small |
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| 01:38 | that passed through the gap junctions. gap junctions are always open but sometimes |
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| 01:43 | can be more open and the small that pass through these gap junctions could |
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| 01:49 | even secondary messengers such as cyclic which is a secondary messenger in neurons |
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| 01:57 | in many other cells. So very functions and there are certain advantages and |
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| 02:05 | junctions again would be very important for synchronization of neuronal networks when you want |
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| 02:10 | neuronal network to synchronize and response to input. Then without delay, that |
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| 02:16 | can travel electrical information between the allowing for that synchronization. Let's review |
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| 02:24 | differences between the two synopsis, the of the synopsis that we've discussed, |
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| 02:31 | muscular junction and the important things that discussed about neuro muscular junction is that |
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| 02:38 | individual vertical will contain a quanta of molecules of this. In this case |
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| 02:45 | acetylcholine molecules and in this case acetylcholine are excitatory so settle colon was inhibitor |
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| 02:54 | the heart and slow down the heart , slow down the heart muscle |
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| 02:59 | But in the skeletal muscle it actually the contraction. And that's because to |
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| 03:06 | molecules from The packet that contains to 4000 quanta of these chemical |
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| 03:16 | two of acetylcholine molecules need to bind one acetylcholine receptor, personal piccoli And |
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| 03:24 | release of these quantum molecules of 2,004,000 Can now engage anywhere between 1000 to |
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| 03:34 | post synaptic acetylcholine receptors. These nicotine receptors, ion the tropic receptors. |
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| 03:43 | these receptors that you find are acetylcholine that are nicotine IQ. Because nicotine |
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| 03:52 | buy into them and he needs to single protein molecules to bind in order |
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| 03:58 | this channel to open when this channel it's going to conduct sodium inside and |
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| 04:05 | going to conduct potassium on the So it's a ligand gated channel and |
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| 04:10 | ligand gated channel, that's what's going cause this very large and played |
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| 04:18 | This employee potential is typically a deep of About 70 mil evolves or |
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| 04:27 | And then um played potential always crosses threshold for action potential generation in the |
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| 04:35 | cells, turning on the prolonged action . And that action potential is mediated |
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| 04:42 | the channels that are located lower within junction. All falls. The voltage |
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| 04:48 | sodium channels involved, educated calcium channels potassium channels that will be involved in |
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| 04:54 | cardiac action potential production. And cardiac potential is much longer in duration than |
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| 05:00 | action potential will be discussed in their . So this is a very high |
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| 05:06 | synapse 1 - one. There's a , there's employee potential very powerful. |
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| 05:13 | means that every time there is a release there's going to be employed |
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| 05:18 | There's going to be action potential in muscle or contraction or twitch of a |
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| 05:24 | . Very highly reliable synapse. very large response from the single |
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| 05:32 | And you want that you need that you also don't need any complications |
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| 05:37 | There's no inhibition at the level of muscle. Remember? So at the |
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| 05:42 | of the muscle here skeletal muscle, single colon is either exciting that muscle |
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| 05:46 | contract or there is no single colon the opposing muscle and that muscle is |
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| 05:52 | . Where is the inhibition? It's the spinal cord. So remember the |
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| 05:58 | tendon reflex circuit. So this is very simple synopsis. There's no inhibition |
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| 06:05 | . it's only excitation it's only acetylcholine receptor, it's always very large |
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| 06:11 | polarization, very straightforward, very reliable . The central nervous synapses activation of |
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| 06:20 | single central nervous synapse typically produces a of about 0.5. No evolves that |
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| 06:29 | call excitatory post synaptic potentials or P. S. P. |
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| 06:34 | So in the C. N. . In the C. N. |
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| 06:38 | you have a different situation. You have this high fidelity synapse and you |
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| 06:43 | a single synapse. The polarizing the Boston topically. Only 0.5 million. |
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| 06:51 | how many synapses we need to activate order to reach the threshold for action |
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| 06:59 | . This is the comparison of neuro junction and you have an employee's |
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| 07:10 | It's about 70 million volts. This E. Pp. In comparison you |
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| 07:18 | a this is E. P. . Of neuro muscular johnson and then |
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| 07:23 | have cns synapses and the E. . S. B. In the |
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| 07:27 | synopsis It's only about 0.5 million volts the threshold for action potential, It's |
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| 07:38 | -45 million volts. So you can them not. You can do the |
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| 07:43 | in the muscle cell. Once the activated you reached action potential because the |
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| 07:48 | of that muscle fiber? Okay in you activate one synapse. Is that |
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| 07:54 | to reach the threshold for action potential in the neurons you have excitatory |
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| 08:00 | P. S. P. Plus. You have inhibitory I PS |
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| 08:07 | . And we will learn about These are inhibitory parts synaptic potentials. |
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| 08:12 | you have both excitation and inhibition. means that you have excitatory neurotransmitters and |
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| 08:19 | and you have an inventory no transmitters receptors. So how many excitatory synopsis |
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| 08:26 | you need in order to reach the value for action potential in the |
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| 08:31 | The math is about 20 million gold with the threshold between resting member and |
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| 08:38 | . 20 million volts. One Half a million volts. So you |
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| 08:43 | at least what 40 active excited tourist to drive the cns neurons to the |
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| 08:54 | . And while you're getting these 40 inputs you might be getting also inhibitory |
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| 09:00 | . So now the situation is a more complex than the C. |
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| 09:03 | S. It's not as reliable. have to have many synopses activated onto |
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| 09:09 | Neuron onto one cell in order for cell To reach the threshold for action |
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| 09:14 | . So you would need to activate synapse to synapses three until you reach |
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| 09:21 | . And this could be activation of 40 synapses. Yeah And this is |
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| 09:34 | one and that's that's a huge significant between these circuits and the muscle. |
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| 09:41 | simple excitatory nicotine receptor driven circuits versus more complex not as reliable uh responses |
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| 09:51 | the C. N. S. would require a lot more of the |
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| 09:59 | . So these are all of the details the neurotransmitter criteria that we covered |
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| 10:05 | neurotransmitter systems that we talked about. recall that in addition to all of |
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| 10:12 | elements that you have listed here. talked about some other very interesting |
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| 10:20 | Those other very interesting elements are So these are gas neurotransmitters, carbon |
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| 10:30 | , not the stock side. We lipid soluble neurotransmitters. The lads |
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| 10:42 | And they can organize and these are lipid soluble. So both of them |
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| 10:51 | lipid soluble. Except these are gasses these are chemicals and the cannabinoids. |
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| 10:58 | we talked about ananda. Yeah my to A G. And we will |
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| 11:06 | back and talk more about and looking . So this is just the first |
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| 11:11 | anandamide Amanda in sound script it means or the feeling of happiness. So |
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| 11:19 | we talked about one of the functions then the cannabinoids is actually the effect |
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| 11:24 | causing overwhelming happiness. This euphoric effect that happens with long distance running and |
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| 11:33 | referred to a lot of times as runner's high. So that is happening |
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| 11:36 | of them. The cannabinoids. We discuss our economic acid. Our economic |
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| 11:46 | is not an endocannabinoid but it's actually the precursors and the canal animals and |
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| 11:52 | breakdown molecules and the phenomenal. It's . It's an important molecule that's also |
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| 11:57 | soluble none of these are going to stored in the vesicles. A lot |
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| 12:04 | them will be produced on demand based the activity or maybe even metabolic demand |
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| 12:11 | metabolic supply things that you eat will your neurotransmitter systems. An example is |
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| 12:19 | may have heard how important it is have a mega through your omega six |
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| 12:24 | acids in your intake diet. And fact maybe it's important to have a |
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| 12:29 | ratio of omega three, omega six omega nine. Why? Because these |
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| 12:35 | acids become precursors to some of these in the brain and other cells in |
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| 12:39 | body such as the economic acid. proper intake of the fat fatty assets |
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| 12:46 | affect the brain chemistry if you may the levels of different chemicals that are |
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| 12:52 | in the brain. So this is molecules that we discussed. We also |
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| 13:02 | that if you look at the I the acid molecules there distributed throughout the |
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| 13:10 | that express Gaba and glutamate are found . But the neurons that express and |
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| 13:17 | serotonin, dopamine, norepinephrine. They located in very specific nuclei in the |
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| 13:24 | stuff. Mhm. And as we acetylcholine, a mean neurotransmitters such as |
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| 13:32 | , they have the bicycles and they released from the vesicles, neural peptides |
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| 13:37 | different or peptides that you see on ride here because they are not stored |
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| 13:43 | the vesicles. The neural peptides are produced on demand when there's heightened levels |
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| 13:50 | activity. There will be a synthesis the top type recourse are here at |
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| 13:58 | ribosome complexes. Roughing the plasmid particular of that the golgi apparatus information of |
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| 14:05 | Secretary Granules and the Secretary Granules will directed to the external terminal. Except |
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| 14:12 | many instances there will not be specially specific as the neurotransmitter of bicycles. |
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| 14:20 | will always be found in there so terminal there will be re synthesized in |
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| 14:25 | external terminal released and re uptake in external terminal. But neuro peptides coming |
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| 14:31 | the samoan demand can actually fuse along external extent and release through the Secretary |
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| 14:40 | so they're not as spatially as specific the neurotransmitters that are stored in the |
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| 14:48 | . And yes you recall when we about parameter cells in the hippocampus was |
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| 14:54 | that some of these parameter cells will express peptides such as C C |
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| 15:00 | Some of them were positive for CCK in him. Criminal cells in the |
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| 15:06 | and others were not the nominal sauce produced glutamate. So you can co |
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| 15:14 | the neurotransmitters that are in the The same cell can co express the |
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| 15:20 | neurotransmitters and neuropathy tides the Haram it'll would co express glutamate and released glutamate |
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| 15:28 | CCK because if some of the prominent will have these neuro peptides molecules they |
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| 15:34 | release through the secretary Granules. in addition to this list we mentioned |
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| 15:42 | other molecules that we will be coming and talking about is a teepee and |
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| 15:51 | So http is not only just an molecule, it's also a neurotransmitter and |
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| 15:56 | core of ATP molecule the denizen. also a neurotransmitter and as we discussed |
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| 16:05 | understanding that I want you to start is that the levels of these chemicals |
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| 16:09 | the brain and the body of flux the flexing as part of the normal |
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| 16:16 | diurnal rhythm. Day night rhythm for , denizen levels the core of the |
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| 16:24 | . ADP dennison levels go up in evening, go up at night and |
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| 16:29 | denizen has a calming effect on the and promotes sleep and in the morning |
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| 16:36 | dentist in levels go down when the bear is running at you, it's |
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| 16:43 | adrenaline, norepinephrine and epinephrine kick in put you in a fight or flight |
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| 16:50 | , which doesn't give you much time think or contemplate the plan of response |
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| 16:56 | big bear coming at you. It's fight or flight. When there is |
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| 17:02 | activity involved appetite, serotonin levels fluctuate serotonin levels change prolonged workout activity, |
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| 17:13 | moderate stress on the south. Physical will increase the levels of under canal |
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| 17:20 | eating some good 30 assets will change levels of some of these chemicals in |
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| 17:27 | brain and the body. These chemicals we're talking about. They represent different |
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| 17:34 | and different behavioral states. Big Final flight serotonin sexual food intake, |
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| 17:45 | all circulating and they're changing but they represent different behaviors and different behavioral |
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| 17:54 | If we just had glutamate which is to be a plus or Gaba, |
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| 18:02 | is minus, we just have plus minus and life is pretty boring. |
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| 18:08 | when you add all of these no no peptides and you can find |
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| 18:15 | release and the production of those means certain parts of the brain but you |
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| 18:19 | can access and Sprinkle all of the cells that express amino acids throughout the |
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| 18:27 | . This is a this is a very interesting system that you have in |
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| 18:33 | brain and it would be boring if was just placed in violence. And |
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| 18:39 | these elements I say they add The color is you know appetite is |
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| 18:47 | color alright, sleepy or awake. the color otherwise plus and minuses. |
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| 18:52 | pretty boring. You can think of and minuses a digital code. And |
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| 18:58 | the analogy code comes alive with all these other neuro peptides, gasses and |
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| 19:03 | cannabinoids that are circulating in the Mhm. So this was your homework |
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| 19:11 | and I just answered your homework So the difference is the synthesis the |
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| 19:16 | and the storage of the to ties the neurotransmitters. And if you look |
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| 19:22 | the neurotransmitter vesicles, there's two things need to happen in order for the |
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| 19:27 | transmission to take place. The first that needs to happen is our forward |
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| 19:32 | action potential has to reach the external . The pre synaptic terminal and when |
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| 19:39 | reaches the pre synaptic terminal, that polarization opens up both educated calcium |
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| 19:46 | So when an action potential reaches the , that deep polarization opens up voltage |
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| 19:52 | calcium channels and calcium influx is necessary order for the vesicles which is a |
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| 20:00 | nous organ. Now, in order this vesicles to infuse with the plasma |
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| 20:07 | of the neuron and release the neurotransmitter into the synaptic cleft. Two things |
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| 20:15 | you don't have an action potential or polarization prison optically you will not open |
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| 20:20 | channels so you will not have neurotransmitter . So you need to have action |
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| 20:26 | . But if you have deep polarization you don't have calcium you also will |
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| 20:32 | see neurotransmitter release. And why would not have calcium? So as an |
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| 20:37 | you have control and you know that a lot of calcium on the outside |
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| 20:40 | the cells compared to the inside. you can experimentally deprive the cells of |
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| 20:46 | and you can stimulate president optical and see in the absence of calcium influx |
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| 20:51 | no particular release. You can also voltage gated calcium channels. So we |
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| 20:57 | blockers, agonists or antagonists for very channels. And when you block voltage |
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| 21:02 | calcium channel and you d polarize present neuron, there's no physical release. |
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| 21:08 | that's because when calcium comes in there this vesicular protein complex and trans membrane |
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| 21:16 | complex it's shown here in a simplified as vesicular for V. Sneer and |
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| 21:22 | membrane is T snares. In reality is what the surface of the vesicles |
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| 21:28 | like. And on that surface there many different kind of a three dimensional |
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| 21:35 | and some of these structures are proteins recognize calcium and they're like calcium |
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| 21:45 | Synaptic synaptic bagman is one of these sensors. So, when the calcium |
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| 21:51 | is in synaptic synaptic hagman says, sense enough calcium. Now this calcium |
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| 21:56 | allow for the protein protein complex to onto each other from both sides to |
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| 22:02 | the bicycle close to the membrane and the fusion of the secure membrane with |
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| 22:09 | neuronal number. When you have the , you'll have neurotransmitter vesicles opening release |
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| 22:16 | the neurotransmitter. Following that, you see that this piece of the number |
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| 22:22 | it's not just it's not that the spits out the bicycle, it actually |
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| 22:28 | this piece of the number as if imagine if you have a lot of |
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| 22:33 | using to the plasma membrane, what going to happen because you're going to |
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| 22:38 | the surface area and when you increase surface area it will actually increase the |
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| 22:44 | properties of the cell too because remember capacitance, the good capacitors have to |
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| 22:50 | a lot of surface area and so this, You just used 200 vesicles |
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| 22:56 | the plasma membrane. How much more the surface area, you added quite |
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| 23:00 | lot. So you can actually measure in capacitance during the vesicular release |
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| 23:08 | And see stepwise changes in capacitance as fuse to the plasma membrane, increase |
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| 23:14 | surface area. And as they they also very shortly after get endorse |
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| 23:19 | toast. So they decrease the surface . So capacitance goes up briefly during |
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| 23:23 | vesicular fusion and released. And then goes back to it's pre release |
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| 23:29 | This is the end of psychosis of vesicles. What happens into the |
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| 23:34 | That's pretty cool too. And in old days when we started visualizing and |
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| 23:42 | The second half of the 20th the membranes, we wanted to really |
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| 23:48 | the channels. We wanted to visualize exhaust psychosis. And so this is |
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| 23:55 | electron microscope picture. You can see these are presumed calcium channels well educated |
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| 24:01 | channels. And you can see how are very densely located along these active |
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| 24:08 | . Pre synaptic zones and during the of the south there is exocet. |
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| 24:15 | sis. So what you're looking at crater you're looking at is the vesicles |
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| 24:20 | came from the cell infused, informed crater. So you're looking into the |
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| 24:26 | secular crater here and the neurotransmitters will released. So showing the proximity of |
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| 24:33 | densities of these voltage gated calcium channels the active zones where you have high |
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| 24:41 | of vesicles that are primed and ready go for the particular release. And |
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| 24:48 | is an electron microscope picture. You see how this is a regular Synaptic |
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| 24:55 | of distance of about 20 nm in , Two cells on the left and |
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| 25:00 | right come very close together in This is that 3.5 nmeter physical |
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| 25:08 | And in this very small physical the gap junction proteins on both |
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| 25:14 | That's where they're formed. And you the formation of these gap junctions. |
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| 25:21 | so this is really nice way to it. And then the next thing |
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| 25:26 | in the second half of the 20th , people wanted to know what exactly |
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| 25:32 | in the plasma membrane. What exactly on the two sides of the plasma |
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| 25:37 | . There was no good way to visualize it life or understand which face |
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| 25:46 | transfer the cytoplasmic or the extra cellular . You know, it's called it |
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| 25:52 | E face or the P phase, one of these plasma membrane layers will |
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| 25:59 | the molecules of interest which ones will in which phase. So there was |
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| 26:05 | technique that was called freeze fracture Now, what you would do as |
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| 26:10 | would take us out and you would it with liquid nitrogen and as you |
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| 26:15 | it with liquid nitrogen, the plasma and all the elements and the plasma |
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| 26:19 | would freeze also. And then you put a little tin little needle, |
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| 26:24 | micro needle next to that piece of plasma number in okay, that you |
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| 26:29 | and you want to know what's in phase versus data phase. So you |
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| 26:35 | place a little needle and it was little bit like a ritual because it |
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| 26:38 | needed the right amount of vibration, of like tapping it the right way |
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| 26:44 | order for the face to split open it's frozen. So you'd have the |
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| 26:49 | plates of the plasma membrane split So people, it was almost like |
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| 26:54 | ritual because people had different ways of it, you know, putting something |
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| 26:58 | the table, walking around, you know, looking if it opened |
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| 27:02 | not, you know, maybe even at it, waving. Has it |
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| 27:06 | needed that little fracture. And once did that little practice, it was |
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| 27:11 | cool because you would have to faces the plasma membrane now open. Now |
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| 27:16 | can understand remember we talked about inside and outside out Patrick's electrophysiology. This |
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| 27:21 | suitable. Also very important. Which of the membrane is holding this |
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| 27:25 | Which one is anchoring that protein? when you split the two, the |
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| 27:29 | that's anchoring should maintain that protein and one that is not, it's not |
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| 27:34 | proteins are on one side versus the side. Which ones are trans |
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| 27:39 | What happens when you rip the membrane and you have trans membrane protein? |
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| 27:43 | it anchored stronger on one side versus other? Why? You know, |
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| 27:47 | has to do with the structure? has to do with this three dimensional |
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| 27:52 | box hill and nitrogenous terminal that a of proteins have. And then we |
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| 27:59 | to see what is happening at the neuroscientists wanted to see what's happening at |
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| 28:04 | synapse with calcium. So this is very interesting technique that so far when |
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| 28:11 | talked about imaging neurons, we talked visualizing neurons with stains and we've discussed |
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| 28:18 | stains. We discussed Golgi stain, stain, you're a Buyten. We |
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| 28:25 | things like immuno history chemistry where you target specific cell markers, antibodies, |
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| 28:32 | that the cells express. You we talked about functional imaging of the |
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| 28:37 | activity. So very briefly mentioned positron tomography when we said that there is |
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| 28:42 | invasive way that you can look and how different brain regions are activated. |
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| 28:47 | so this is a macro scale that looking at. But it's very important |
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| 28:53 | look at the micro scale and visualize at the micro scale and visualize them |
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| 28:57 | the level of a single synopsis. so rodolfo llinas as one of the |
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| 29:05 | South american neuroscientists. He did these where they started using the dye and |
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| 29:15 | this case the dye indicates concentration of ion. So it's an eye on |
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| 29:22 | diet. It's not a self specific , it's not going to reveal the |
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| 29:30 | or morphology of the South, it going to track calcium and wherever there's |
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| 29:36 | in calcium concentration, you're going to this yellow and red signals. And |
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| 29:42 | when rodolfo linas used what are called sensitive dies. That means when calcium |
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| 29:49 | go up that substance that die that in there, it will start blowing |
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| 29:56 | . There's a chemical reaction that allows that calcium ion and increased calcium concentrations |
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| 30:02 | glow stronger in yellow and red and ones that are not regular levels would |
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| 30:08 | in this blue range. So before stimulation, what they reported is that |
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| 30:14 | are these mountain peaks and you can that there's a small peak here in |
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| 30:20 | and red, which indicates the peak of calcium. And you have these |
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| 30:25 | mountains and peaks in those mountains and of calcium concentration of course are located |
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| 30:31 | you have the collections of these presumed gated calcium channels to and during the |
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| 30:39 | . This is what happens to these distinct speaks very spatially confined concentration mountains |
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| 30:48 | calcium related to vesicles. Now you see that instead of one or two |
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| 30:54 | , you have a whole mountain range and this is during the activation. |
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| 30:59 | can see that Calcium concentrations go up a lot of the peak at about |
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| 31:05 | micro mauler during the synoptic vesicles released the signal. So you can see |
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| 31:12 | there's massive influx of calcium and the in the spatial temporal pattern, spatial |
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| 31:21 | the states and time pattern before the and after the activation. So these |
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| 31:29 | levels and these very short flexes of concentrations, pre synaptic aly and necessary |
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| 31:36 | the secular fusion and release. And can image them. and in fact |
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| 31:41 | is even a technique that will allow fusion of a single vesicles. It's |
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| 31:47 | epic fluorescent. You can track a of the single vesicles all life and |
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| 31:51 | how the packet of a single vesicles released in the synapse. Really, |
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| 31:56 | cool technique that just focuses in on 10 nanometers of space in the focal |
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| 32:02 | epi fluorescence and allows you to visualize at least. But before that we |
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| 32:08 | the static visualization you would stimulate the , you would fix it, put |
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| 32:13 | under electron microscope and see before stimulation after stimulation you would study the |
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| 32:20 | you know, location of these proteins they're located using freeze fracture. And |
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| 32:25 | you would start looking at the functional at the level of a single synopsis |
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| 32:30 | it's ionic changes such as calcium, ions can be traced also. So |
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| 32:36 | are sodium sensitive dyes, not just sensitive dies, there's also voltage sensitive |
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| 32:44 | which will show a change of voltage the whole neuron and is a collection |
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| 32:50 | multiple ion signaling. There's very different of visualizing these things. This really |
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| 32:57 | us about the dynamics from neuron to is a great book. If somebody |
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| 33:02 | a neuroscience, it's from the fourth that I took this figure from. |
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| 33:07 | it's a really cool book that I like very much now in neurons we |
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| 33:17 | this kind of a particular release that be either full or partial. And |
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| 33:24 | I put cns synopses versus neuromuscular This diagram is really for the cns |
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| 33:32 | remember if you have quantum release of or you have quantum release of molecules |
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| 33:37 | the cns too. It's just that the uh neuro muscular junction is very |
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| 33:45 | powerful with that template potential that's very large. But if you have the |
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| 33:51 | conditions and there you have the early that produces the vesicles vesicles loaded with |
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| 33:58 | , it gets to be into this here needs a little bit of energy |
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| 34:04 | a teepee and other factors. In for this fully filled vesicles to be |
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| 34:09 | and primed but not released. So like sitting at the dock ready to |
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| 34:15 | off. And if you have calcium then you have a recognition between the |
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| 34:21 | protein complex have a fusion but if is not enough calcium coming in and |
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| 34:29 | can happen sometimes because you may have changes in the extra cellular calcium concentration |
|
| 34:35 | whatever reason, maybe we have slurped a little bit too much of it |
|
| 34:38 | the moment. You don't have that calcium that came in. So instead |
|
| 34:43 | a full fusion to the right you release a little bit of that neurotransmitter |
|
| 34:49 | you run back away into this doctor prime position. So this is just |
|
| 34:55 | and wrong. This just comes in . Makes a little popular little kiss |
|
| 35:01 | then runs back away. It doesn't fully. It doesn't release the entire |
|
| 35:06 | packet. Okay so okay with this does not happen in the neuro muscular |
|
| 35:16 | . That does not happen. Okay if you have enough calcium that comes |
|
| 35:22 | you will have a full fusion have neurotransmitter release. Then molecules that surround |
|
| 35:30 | membrane they're referred to as Claritin molecules like this plasma membrane of the vesicles |
|
| 35:36 | is being recognized as you've been used something. You must be a used |
|
| 35:41 | . I'm gonna Claritin you with this Claritin coach and the cell pre synaptic |
|
| 35:49 | is gonna know that you're an empty call because you have the Claritin code |
|
| 35:54 | it's gonna Acidifying you. Gonna bring with a lot of energy A. |
|
| 36:00 | . P. A lot of Plus protons inside the Mexico. Um |
|
| 36:05 | some instances it may have to go the early end of cell. Get |
|
| 36:11 | re synthesized as an organ. Now as an organ now and plays back |
|
| 36:17 | in the pre synaptic terminal and it's little bit longer time period to do |
|
| 36:22 | . And in most cases the faster is not good to the early end |
|
| 36:27 | zone. But as it gets acidified this vesicles acidification actually becomes also a |
|
| 36:37 | mechanism also driving it's a proton driven of the neurotransmitter neurotransmitter uptake and now |
|
| 36:45 | have again a filled their transmitter that be docked and primed and ready to |
|
| 36:50 | released. And so the cycle when stimulate the central nervous synopsis and you |
|
| 36:57 | neurotransmitters and you have a very strong that you shock the whole synapse and |
|
| 37:03 | release many many of these vesicles they and you'll get with each fusion you'll |
|
| 37:10 | a stronger response and stronger response and response. This isn't C. |
|
| 37:15 | S. Okay so you'll keep increasing response. With with with each |
|
| 37:23 | And what happens then how long does take for the self to reconstitute the |
|
| 37:32 | Cause repositioned the vesicles. Primary doctor you Joel to really shocked the cell |
|
| 37:40 | that cell released a lot of a lot of vesicles fused. That |
|
| 37:46 | is about 10-15 seconds to recover. if you exhaust synaptic transmission, if |
|
| 37:54 | checking synaptic transmission, you want to it about every 10-15 seconds because this |
|
| 37:59 | how long after a very strong simulation takes it to rebuild the whole |
|
| 38:06 | Now if you just released one or packets that's a different story because you |
|
| 38:10 | have 20 maybe hundreds of packets sitting dr in front. But if you |
|
| 38:16 | all of those hundreds of packets and a strong response Then it will take |
|
| 38:22 | 10-15 seconds to rebuild that some So when people do electro physiological studies |
|
| 38:29 | sample the cells or they stimulate and the post synaptic responses. That stimulation |
|
| 38:37 | typically every 10-15 seconds because you want give the cell a full time for |
|
| 38:43 | to rebuild physiologically to test how it ready to release more neurotransmitters poisoning, |
|
| 38:54 | release. What's in your book? interests section, bacteria, spiders, |
|
| 39:05 | , and me and you. So do we talk about that? Because |
|
| 39:16 | there is physiological processes there's usually nature surround us and nature can interfere with |
|
| 39:23 | physiological processes. We can block we can boost them and then as |
|
| 39:29 | find out things from nature, You 80% of the pharmaceutical drugs you have |
|
| 39:35 | the market is because Some 2000 years , some 300 years ago. Some |
|
| 39:43 | years ago some crazy shaman, some , somebody in the woods with herbs |
|
| 39:49 | making concoction and it helped from something everybody knew that this concoction was from |
|
| 39:57 | . So in the 60s and 70s develop these techniques called high performance liquid |
|
| 40:03 | and H. B. L. . Allowed us to separate individual |
|
| 40:08 | individual active elements, chemicals in these and these plants that we were together |
|
| 40:15 | thousands of years. So all of sudden it's like oh I found this |
|
| 40:20 | in this concoction. Now we know it does, Guess what follows next |
|
| 40:27 | trials, A billion dollars, 90% , 90-95% of pharmaceutical drugs and trials |
|
| 40:41 | 95% of neuro drugs fail at clinical three trial it takes billions of dollars |
|
| 40:51 | get through clinical stage Clinical one clinical to get to three then you |
|
| 40:59 | So What's the percentage one in 20 in 40 the drugs that from these |
|
| 41:08 | , these botanicals then they actually become . They become something approved for the |
|
| 41:13 | of something. So most of the we find things in spiders, in |
|
| 41:17 | , in snakes we get poisoned, see the reaction. Then we |
|
| 41:21 | well what if I isolate this Can I use it? Like roderick |
|
| 41:25 | use the spider toxins. Can I it? Is it going to be |
|
| 41:30 | ? What can I use it And you can use it for |
|
| 41:33 | studying the structure and function and also therapeutic treatments if you understand both. |
|
| 41:41 | so we're going to talk a little about clostridium botulinum and you're invited to |
|
| 41:46 | Botox party. So this is uh billion dollar beauty industry where you would |
|
| 41:57 | to get a Botox injection and you a glass of champagne served. And |
|
| 42:04 | you get the injections for Botox you also get fillers injected. So it |
|
| 42:11 | make our eyebrows really big. You , eyelids really big, your lips |
|
| 42:16 | fat. Um So it's I guess a part of the beauty enhancement for |
|
| 42:24 | . Sometimes it spoils the look. what is going on? And why |
|
| 42:30 | it clostridium botulinum? And why is a Botox party. So have you |
|
| 42:35 | heard of botulism. So it comes bacteria and that can't food and you |
|
| 42:44 | get pretty serious poisoning from from botulism this toxin that is produced as botulinum |
|
| 42:55 | in the bacteria and the bad bad food. And there's botulinum toxin. |
|
| 43:02 | these little sharky's here And so you botulinum toxin B. D. E |
|
| 43:09 | . G botulinum toxin E botulinum toxin . One the different variations subtypes of |
|
| 43:16 | bunch of unknown toxin. But what actual island toxin? Does it binds |
|
| 43:22 | shark ist bind to the protein protein and chew up the protein protein complex |
|
| 43:28 | it stops the vesicular fusion so there's acetylcholine release. So essentially if you |
|
| 43:38 | with the protein protein complex and that's botulinum toxin does you will interfere with |
|
| 43:44 | vesicular release. What is the point injecting Botox sin to make yourself more |
|
| 43:53 | . Well the reality is that as move your muscles your muscles move your |
|
| 43:58 | and with age you start forming So how do the muscles move? |
|
| 44:05 | a civil code and release. There's of the muscles. You're moving your |
|
| 44:08 | there smiling and it causes wrinkles and don't like that. Some people. |
|
| 44:13 | how do you get rid of You stop the civil colon release and |
|
| 44:18 | fusion and then you put fillers? the fillers fill up the space it |
|
| 44:22 | out the wrinkles and botulinum toxin or stops the vesicular release and stops the |
|
| 44:30 | of the skin and the wrinkling and why a lot of times you will |
|
| 44:34 | him or whatever tv shows housewives of or new york or whatever. Orange |
|
| 44:41 | whenever, wherever they are or other kind of a beauty plastic surgery |
|
| 44:46 | You'll see that when people come out Botox treatments you have difficult fun moving |
|
| 44:53 | from the Poland expression themselves. It's they're having a hard time because there |
|
| 45:01 | enough of the a single colon. there isn't enough of the muscle |
|
| 45:05 | You need to contract the muscles in . Do you move your mouth? |
|
| 45:08 | telling your muscles and all of that now you have basically impeded with |
|
| 45:14 | And so for a while while the concentration control concentration of Botox wears |
|
| 45:20 | People may have difficult time with some the motor functions like moving the lips |
|
| 45:25 | such. And so this is for purposes. But anybody know that Botox |
|
| 45:32 | also an approved treatment for something else a neurological disorder. You know it |
|
| 45:44 | . How the marshals is extremely isn't he? Always it that injecting |
|
| 45:51 | is not kill you because you have known concentrations and you're doing localized in |
|
| 45:59 | of it. So instead of a intake that you would eat a lot |
|
| 46:04 | something, it's about the concentration, the same as with pharmaceutical drugs? |
|
| 46:10 | perfect example is opiates? Why do have opiate um epidemic. Now, |
|
| 46:17 | do we have so many people dying opioids and fentaNYL. Because the act |
|
| 46:23 | does the active dose effective dose the dose of complete pain is this big |
|
| 46:32 | opiates and fentaNYL And the deadly does only this big It's only 3-4 times |
|
| 46:39 | the effective dose and that's the So if you took three or four |
|
| 46:44 | your breathing center shut down you're If you take one dose you may |
|
| 46:50 | some pain and be okay and your rate or your breathing may slow down |
|
| 46:55 | little bit and that's what happens. you don't cut off at high concentrations |
|
| 47:00 | whole breathing system. So it's you can say it's controlled and it's |
|
| 47:05 | to the point where it's also approved approved treatment for migraines. So this |
|
| 47:16 | everything, there's nature, there's beauty there is also therapies that that you |
|
| 47:22 | use it for. So there's Botox directions that are FDA approved treatments |
|
| 47:29 | And this plastic or beauty treatments they not not technically like a D. |
|
| 47:36 | . Approved procedure but you're supposed to substances that are FDA approved. And |
|
| 47:40 | is one of the margins. So you can see that there is a |
|
| 47:47 | complex, there's trans membrane complex, protein protein complex and you can interfere |
|
| 47:55 | the civil colon release with Botox. widow um spiders will contain venom that |
|
| 48:06 | also interfere with the Seattle colon It's one of the deadliest spiders that |
|
| 48:12 | lives around us in texas. I an acquaintance. His father died from |
|
| 48:18 | bite of that spider in the back the neck. Within two days he |
|
| 48:23 | in the hospital, it was like pussy mess and within 3.5 days he |
|
| 48:27 | and he was just working in the when he got bit by that |
|
| 48:33 | So these things around Taiwanese cobra will the substance called alpha bangalore toxin. |
|
| 48:41 | spider snake venoms will contain the toxins it can target pas synaptic acetylcholine |
|
| 48:48 | So you have the whole system, have the release system and you have |
|
| 48:51 | possum optic receptors. So you can with the release using these substances like |
|
| 48:57 | , like a Black Widow venom, then you also can interfere with post |
|
| 49:03 | receptors. So many different substances toxins in nature or pharmaceuticals will it will |
|
| 49:09 | different parts of this pathway. We synthesize things that are not quite |
|
| 49:17 | organophosphates and they will see in the slides are still Colin nestor is |
|
| 49:28 | So they're both actually they're used in uh and they used a certain form |
|
| 49:36 | organophosphates that Alzheimer's medication too. So learn about that in a few |
|
| 49:44 | We'll see if we get to Okay. Alright, so we're making |
|
| 49:52 | good progress here. A lot of will come together in the last lecture |
|
| 49:59 | week is on the neurotransmitter systems that overview these systems one more time. |
|
| 50:05 | if you recall neurons will be receiving synopsis with glue dramaturge IQ. And |
|
| 50:15 | you know to be receiving inhibitor synopsis are Gabor urgent. And so if |
|
| 50:21 | recording from this neuron here and that receives glutamate it will produce an |
|
| 50:30 | P. S. P. Excited the boston athletic potential. The soul |
|
| 50:38 | gaba, it will produce it Dsb with the inhibitory personal potential. |
|
| 50:48 | remember that neurons can receive hundreds of of these synopsis. The response of |
|
| 50:54 | neuron will depend on what the receptors carries. And with area. |
|
| 51:01 | And what happens is during the deep . During the E. P. |
|
| 51:08 | . P. You have an influx sodium coming in and this influx of |
|
| 51:18 | here this influx of sodium causes the polarization. This is the outside of |
|
| 51:25 | south. This is the inside as know there's high levels of sodium chloride |
|
| 51:29 | the outside and then the following phase the PSP is because potassium ions are |
|
| 51:37 | to be easy flexing. So the phases sodium going in and this is |
|
| 51:46 | block out similar to action potential. this is a synaptic potential. So |
|
| 51:51 | a graded potentials post synaptic potential action was all are known. This is |
|
| 51:56 | and potential is graded because depending on number of synapses activated, the size |
|
| 52:03 | this potential will depend. So it's potential when you look at an action |
|
| 52:09 | and the cell repeats action potential and overlay these action potentials one over the |
|
| 52:20 | And the selfies 200 500 of them always be the same. So it's |
|
| 52:29 | or not. But for the PS you can get a smaller your |
|
| 52:33 | largely a PSP. Or even a PSP. Each one of these |
|
| 52:39 | each one of these increments increases means means an additional synapse activated? Remember |
|
| 52:46 | one Cns synapses only half a So if you have an Ep sp |
|
| 52:53 | only half a million volt. That you're just activating. Once announced releasing |
|
| 52:57 | an applicant if you're seeing the multiple that happened or evolved, it's multiple |
|
| 53:05 | is your relation. Mhm. This an E. P. S. |
|
| 53:09 | . That gets recorded posting optical in are transmitter gated ion channels. So |
|
| 53:17 | happens is when glutamate gets released, will bind to this channel and will |
|
| 53:27 | that excited to report synaptic potential P. S. P. |
|
| 53:33 | The difference. I'm sorry I. . S. P. S. |
|
| 53:38 | . Difference because when Gaba is released Gaba will bind to its own wagon |
|
| 53:51 | channel and it's going to conduct chloride so influx of positive charge here sodium |
|
| 54:03 | the deep polarization influx of negative charge through Gaba receptors causes hyper polarization. |
|
| 54:16 | will also be great and depending on many inhibitory the testicle packets, how |
|
| 54:20 | inhibitory synapses are activated. So excitation deep polarization, positive inputs coming in |
|
| 54:30 | glutamate receptor channels and inhibition is chloride in negative charge through Gaba receptor |
|
| 54:42 | The PSP which his I. S. P. We have two |
|
| 54:48 | of synaptic transmission whenever glutamate binds to receptor and that receptor is also channel |
|
| 55:01 | and also this are referred to as of tropic. They are receptor channels |
|
| 55:08 | conduct ions. So they have ion tropic channels were involved in ion a |
|
| 55:14 | or direct signaling. So binding of directly through that receptor channel causes the |
|
| 55:20 | of ions directly through that channel metabolic signaling is the fact that many |
|
| 55:27 | the same ones that we're talking about and Gaba and also the mean |
|
| 55:32 | They'll also bind to the receptors that G protein coupled receptors. So the |
|
| 55:39 | of that neurotransmitter Ligon such as Instead of opening the channel is actually |
|
| 55:46 | to activate the G protein complex. the catalysis activation of the G protein |
|
| 55:53 | can now target enzymes can target protein . Ion channels in the plasma membrane |
|
| 56:04 | turn on. Secondary messenger cascades can change the transcription factors and transcription properties |
|
| 56:11 | the South through the secondary messengers. in ii on the tropic signaling, |
|
| 56:17 | have binding of the molecule and the open and measurable tropic signaling. You |
|
| 56:23 | binding of the molecule. The channel opens. But instead activists ju protium |
|
| 56:32 | mhm which activates secondary messengers. So neurotransmitter different effect in the same |
|
| 56:44 | We'll talk about that different same neurotransmitter effects in different cells. We're already |
|
| 56:50 | with that same neurotransmitter acetylcholine as inhibitory cardiac muscle and excitatory in skeletal |
|
| 56:58 | We also know that I wanna tropic Colin is excited, formidable tropic signaling |
|
| 57:03 | be inhibitory. It can be opposing other through the same neurotransmitter chemicals through |
|
| 57:11 | same molecules. And in general this how the neurotransmitter systems work. So |
|
| 57:18 | is a system that I want you be fully responsible for knowing the synthesis |
|
| 57:22 | breakdown and all of the details that talked about. It's like it's sort |
|
| 57:26 | our poster child for all of the neurotransmitter systems. There's a seal Colin |
|
| 57:33 | a single colony in and synthesize when have a sealed away and ko'd the |
|
| 57:40 | and they come together and they This is how you remember calling this |
|
| 57:45 | transfer race. That's the chat. they chat they form calling. See |
|
| 57:53 | have a single choline and choline acetylcholine loaded up into the vesicles. Sydell |
|
| 58:00 | gets released on deep polarization. Person a civil calling combined to in the |
|
| 58:10 | now outside the neuro muscular junction. now adding a letter of complexity in |
|
| 58:15 | C. N. S. Acetylcholine iron a tropic receptor channels and it |
|
| 58:22 | also find memorable traffic acetyl coa then protein coupled receptors. So we didn't |
|
| 58:31 | that in the skeletal muscle there's no tropic signaling in the skeletal muscle because |
|
| 58:36 | want skeletal muscles to contract and do it says to do. Because otherwise |
|
| 58:40 | say pick up this thing and I'm trying to pick it up and you're |
|
| 58:44 | neurological problems so settle Colin is loaded . It's released advance to the receptors |
|
| 58:53 | it doesn't stick around the synoptic laughed the synaptic cleft that gets broken down |
|
| 59:00 | a single colonists to race seal. histories will break it down into Colin |
|
| 59:07 | acetic acid and Colin will be co back with sodium into the pre synaptic |
|
| 59:17 | . Where with the help of chat the civil co. A. It |
|
| 59:22 | re synthesize the civil coding molecule. . So it stays at the Exxon |
|
| 59:31 | terminal. So those projections have come the brain stem, let's say. |
|
| 59:35 | dump a pseudo colon in the That little colon gets recycled in the |
|
| 59:41 | . All terminals. There's a civil neurons gets re synthesized here at the |
|
| 59:48 | of the central terminal. So when talked about Alzheimer's disease, I said |
|
| 59:56 | may still have that page that you tracking the symptoms and the pathology, |
|
| 60:02 | hallmarks of the pathology of Alzheimer's And one of the most common Alzheimer's |
|
| 60:09 | are a settler colonist erase inhibitors or necessaries inhibitors. Or if you watch |
|
| 60:19 | sometimes you'll hear commercials, especially towards population drug commercials. That will say |
|
| 60:27 | you on sin medications? Not as am. But see I am like |
|
| 60:32 | Esther is inhibitors because there might be cross effect with colonists inhibitors if you're |
|
| 60:39 | them. So Colin nestor is What do they do? And why |
|
| 60:44 | you target a single Colin? So turns out that acetylcholine cells and acetylcholine |
|
| 60:51 | in the CMS is the most sensitive system In Alzheimer's disease that gets affected |
|
| 61:01 | . Okay, so this is really and interesting because I said I want |
|
| 61:06 | to start thinking about neurotransmitters. They through the day. They also mean |
|
| 61:11 | behavioral states. If you upset the of chemical transmission, if you upset |
|
| 61:17 | balance of synthesis recycling of a single molecules, if you eliminate acetylcholine |
|
| 61:23 | you have a neurological condition have a disorder. So chemical imbalances also are |
|
| 61:31 | of neurological disorders but different neurological disorders be linked to different chemical imbalances. |
|
| 61:41 | when you're talking about depression and treating , you're talking typically about serotonin ergic |
|
| 61:47 | and serotonin systems. When you're talking Alzheimer's medication and the chemical system that |
|
| 61:55 | affected the first and the most is simple cooling system in the C. |
|
| 61:58 | . S. Right? What The acetylcholine neurons start dying so there |
|
| 62:05 | not enough to settle cooling. So main therapeutic strategy in treating Alzheimer's disease |
|
| 62:13 | to prolong or increase the bio availability this acetylcholine molecule in the synoptic left |
|
| 62:24 | if there isn't enough of a single being produced and all of it that |
|
| 62:29 | being produced better bind acetylcholine receptors to a full effect. And if it's |
|
| 62:35 | little bit of it is being released then it's getting degraded, that's not |
|
| 62:40 | cause a strong enough fast synaptic All right, so you introduced a |
|
| 62:49 | colony asteroids inhibitor and you block the of acetylcholine and you prolong the by |
|
| 62:59 | the amount of a civil cold then the duration of time that a single |
|
| 63:04 | can be in the synoptic corrupt, prolongs and increases the ability of this |
|
| 63:11 | signaling through the past in africa Yeah. So now you have another |
|
| 63:19 | of pathology is Colin ergic dysfunction. of Colin ergic neurons in Alzheimer's |
|
| 63:27 | And now you also have a therapeutic , the most common therapeutic treatment. |
|
| 63:34 | It does not cure Alzheimer's disease. does not improve Alzheimer's disease. It |
|
| 63:43 | not improve the symptomology that we're talking . First loss of short term memory |
|
| 63:48 | loss of long term memory, disorientation, inability to take care of |
|
| 63:54 | and then an ability for your brain take care of the body, the |
|
| 63:59 | , the formation of the plaques, formation of the tangles, all of |
|
| 64:02 | pathology. Now you have on top that, death of the colon ergic |
|
| 64:06 | on top of that and on the on anatomical macro scale. You saw |
|
| 64:13 | shrinkage of brain tissues, both the the gray matter but also the white |
|
| 64:19 | tissue. So what does this medication ? Just slows down the progression of |
|
| 64:23 | disease And it's not very effective. then you have to ask yourself a |
|
| 64:33 | if there isn't enough civil Colin produced , how is this going to |
|
| 64:43 | Alright, if there isn't, if cells are dying that produces single colon |
|
| 64:47 | there isn't enough of it produced, is this going to help? It |
|
| 64:52 | a little bit. So it helps stopping the progression of the disease |
|
| 64:58 | It doesn't slows down. It doesn't the progression of the disease. It |
|
| 65:02 | down the progression of the disease. it doesn't develop as fast as severe |
|
| 65:07 | fast. But that's about it. this is the main main Alzheimer's |
|
| 65:14 | there's only one that targets glutamate receptors then the receptors that we'll talk about |
|
| 65:20 | men wanting. But this is the one. So this is good for |
|
| 65:24 | to add on to your therapy. in the previous slide also talked about |
|
| 65:29 | substances that are called organophosphates. So are human made human synthesized. That |
|
| 65:39 | that we didn't isolated from nature but saw what nature produced and then we |
|
| 65:44 | into the lab with chemicals together and to recreate that molecule chemical X. |
|
| 65:49 | organophosphates. Um they're using agricultural fertilizer . Organophosphates are also nerve gasses. |
|
| 66:01 | you've heard potentially of nerve gasses that used in illegal warfare. They're illegal |
|
| 66:08 | as siren S. A. N. Soma. You may have |
|
| 66:15 | of attacks by nerve gasses. The attacks, 1990s, Tokyo Metro. |
|
| 66:24 | gas release. You can look up story. Mm hmm. Chechen |
|
| 66:32 | rubbles taking over the theater in Nerve gasses were released to control them |
|
| 66:39 | also poisoned the people that were locked with them. The hostages. |
|
| 66:46 | look and see what countries like Syria doing. Where you see images of |
|
| 66:53 | villages of the people dying, of animals dying. It's a chemical biological |
|
| 66:59 | . It's the release of the nerve and what the nerve gasses do is |
|
| 67:05 | are civil Colin asteroids inhibitors. So much of a good thing is also |
|
| 67:11 | . And if you have uncontrolled acetylcholine and presence of the civil coding you |
|
| 67:17 | over excitation, You have over contraction when the muscles start contracting too much |
|
| 67:23 | walk into what is called tetanus but cannot contract any longer. So nerve |
|
| 67:28 | is a lot of farms would kill by stopping the contraction of the diaphragm |
|
| 67:34 | and the breathing activity because acetylcholine these organophosphates will prolong the seed alkaline |
|
| 67:44 | there in such a degree that it be too much of it can cause |
|
| 67:49 | can cause epilepsy but three years ago had a special forces medic that was |
|
| 67:55 | my course and he told me about story in Afghanistan and Fallujah where he |
|
| 68:01 | a medic. I was rescuing his that got exposed to the nerve |
|
| 68:07 | So this is something that is happening days. You know, I wouldn't |
|
| 68:10 | surprised that we see some nasty stuff out of Russia and Ukraine because of |
|
| 68:17 | conflict that they started just tonight. don't know if you've heard but there's |
|
| 68:21 | war going on. Russia is invading and the players on the world stage |
|
| 68:29 | are not very good players. Clean . They often reserved to means like |
|
| 68:35 | gasses and nerve gasses. So and you know how it works. So |
|
| 68:40 | will end our lecture, Have a weekend and I will see everyone back |
|
| 68:48 | next |
|
