| 00:01 | In Congress is the first lecture we're the visual system. And this first |
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| 00:13 | gets into the very specific song, sensory organ for the visual system and |
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| 00:19 | cellular circuit, you know, specifically the right. So retina in the |
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| 00:26 | of the eye where photo transduction processes . That means that when the light |
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| 00:34 | the dock of the eyeball where retina located, yeah, produces or converts |
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| 00:46 | photons of light into an electrochemical Of course, by chiro complex, |
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| 00:55 | reduces the cyclic GMB presence into regular and it closes Odium channel. So |
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| 01:03 | what's happening at the level of the the rent. However, before we |
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| 01:10 | there, the two articles that I've it for you are really good and |
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| 01:20 | a couple of figures that will discuss little bit out of border of how |
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| 01:25 | presented. OK. Let's try to it. Apparently this computer control mind |
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| 01:43 | let's do so when the information goes the retina, there's a lot of |
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| 01:50 | here that you will understand as we about the visual system over the next |
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| 01:57 | of lectures. When information comes into retina, that information gets communicated to |
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| 02:03 | dorsal lateral nucleus of the. So the first station for visual information |
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| 02:13 | is retina. OK. The second is the dorsal collateral geniculate nucleus which |
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| 02:22 | a part of the. So about to 90 of all of the retinal |
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| 02:34 | everything that leads retina, 80 to innovates dorsal lateral. Another structure that |
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| 02:46 | a small input Uh of about 10 or minus five or so percent of |
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| 02:56 | output is this other structure called C superior colliculus and superior Colliculus has a |
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| 03:12 | of psychic or very fast. I it does not necessarily process the visual |
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| 03:22 | , uh shape, form and but it uses that visual input to |
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| 03:32 | the brain stem. That's where our colliculus lobe is located in the brain |
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| 03:38 | . The thalamus is located inside the in the brain stem. Super Colliculus |
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| 03:45 | these very fast psychotic or jumping eye , psychotic eye movements. Because if |
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| 03:51 | trying to like watch a car racing the track and the only way you're |
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| 03:58 | keep it in focus is if you your head, but even if you |
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| 04:02 | your head, your eye movement is gonna track that in a smooth pursued |
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| 04:09 | and how you have in electronics, it's going to jump and readjust to |
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| 04:14 | sure that it keeps that car that's across the field of view always in |
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| 04:20 | . So these are the sy eye again, more to readjust and to |
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| 04:28 | on the inputs and the uh uh inputs are specifically very important when there's |
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| 04:34 | uh uh so that you can track move eyes in a very fast |
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| 04:42 | No, the other interesting part of is that obviously the thalamic dorsal or |
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| 04:52 | geniculate nucleus receives its input primarily uh uh the, the output from the |
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| 05:00 | goes primarily into the L G But as we learn most of what |
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| 05:05 | G M receives comes from other And in particular, it comes from |
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| 05:13 | . So let's first talk about the information right now, the thump the |
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| 05:21 | cortex. And you can see that is a, a lot of inputs |
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| 05:28 | the that innervate layer 231 and also four in the visual cortex. Also |
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| 05:42 | dear nucleus is surrounded by I stands inhibitory neurons. And it says here |
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| 05:52 | R M, this nucleus is the nucleus and the thalamic particular nucleus surrounds |
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| 06:00 | dorsal lateral genes and is comprised of of the inhibitor into neurons. So |
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| 06:09 | a lot of particular nucleus controls a of activity that is happening in the |
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| 06:16 | . Now, were you seeing the projections here? This is the |
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| 06:22 | So once the output of the which is the retinal gang cells, |
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| 06:29 | are the cells that come out of retina. Once the output and the |
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| 06:33 | gang cells that form the optic nerve out. But these are excitatory inputs |
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| 06:45 | go into the nucleus. So the here indicate excitation and inside the |
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| 07:01 | you also have inhibition. So eyes and these flu neurons here indicate that |
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| 07:07 | is inhibitory neurons also in the relay . In, in the, in |
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| 07:12 | thalamus. The excitatory cells involve the cells and they relay information from the |
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| 07:17 | cortex and they are controlled by the cells in the thalamus. And they're |
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| 07:25 | controlled by thalamic reticular nucleus, inhibitory . The whole brain stem as it's |
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| 07:33 | here also has inputs into the dorsal nucleus. It's a mix I'm excited |
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| 07:40 | the, then the outputs from the G M and green and then red |
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| 07:46 | the excitatory outputs of again, following same kind of a logic how the |
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| 07:54 | cells are excitatory cells typically and how into neurons are typically local network cells |
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| 08:03 | don't set their axons into the cortex . But here rather controlled activity of |
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| 08:10 | level of increase I inhibitory cells. course, in the primary visual |
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| 08:18 | These are the the projections and then output goes back from the visual |
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| 08:25 | Positive exci output goes back into the geno and goes back into the in |
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| 08:36 | . So this is retina to L M is referred to as retina geniculate |
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| 08:44 | , retina geniculate projections from retina to nucleus from thalamus to cortex. It's |
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| 08:53 | cortical or genicular cortic from geniculate nucleus there are other nuclei but from uh |
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| 09:03 | lama cortical to nu nucleus to the and then it moves back around cortico |
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| 09:13 | cortico genius. So from the primary cortex and other cortical areas, it |
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| 09:20 | exciting here. These little triangles are synapses here. So exciting dorsal |
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| 09:31 | So this is the flow of So first, the information is in |
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| 09:36 | retina. Second, the information is the lateral genius and then it's in |
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| 09:43 | primary additional cortex and along each station war on each station, L G |
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| 10:07 | and the cortex, we have neuronal , there are gonna be different neuronal |
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| 10:20 | . We'll look at the neuronal circuit the retina where you have photoreceptors and |
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| 10:25 | you have bipolar cells and retinal gang . We look at the circuit and |
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| 10:29 | G M where you have excited inputs and inhibitory inputs, we won't study |
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| 10:34 | in greater detail, but there are here and in the cortex and then |
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| 10:38 | have the communication. So first of these circuits are comprised of unique subtypes |
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| 10:45 | sounds. If we're talking about we'll discuss the circuit in a second |
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| 10:57 | the south there. Uh retinal ganglion or RGC S is the main output |
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| 11:04 | the retina from the L G The main output are called relay cells |
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| 11:19 | from the cortex. These cells are Ron excitatory songs. So these are |
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| 11:34 | circuits are within and the retina genicular the retinal ganglia sounds genicular cortic or |
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| 11:43 | styles. All of these are excitatory like in the diagram and relay. |
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| 11:50 | cortex is genicular coral and cortex to cells is typically cortico, genicular is |
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| 11:58 | grain cells, the projection of side neurons. So that's sort of a |
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| 12:09 | though now what is inside the the ? This is the overall system. |
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| 12:16 | inside the retina by the retina. have photo receptors, photo receptors are |
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| 12:22 | for photo transduction motor receptors are connected bipolar cells and bipolar cells can be |
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| 12:29 | to gang cells and they're controlled by intermediary, inhibitory cells that are horizontal |
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| 12:38 | and amaro cells. OK. So is the circuit, this is the |
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| 12:44 | circuit that we just discussed. The that comes out and forms the optic |
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| 12:50 | , which is cranial nerve tube is gang the cells, that's the |
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| 12:58 | right. No, the other thing we are interested in is what are |
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| 13:06 | sounds? What are the pathways and between retina, L G M and |
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| 13:13 | and bat. But also what are properties of the cells? And in |
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| 13:20 | case, we're not just interested whether excited or inhibitory, but we want |
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| 13:26 | understand what retina sees what al G sees and what cortical cells see at |
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| 13:32 | primary visual cortex. And we refer these as receptive field properties. There |
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| 13:40 | a point by point representation. When look at the outside map, there's |
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| 13:45 | pond that looks at that tree in retina. There is a point in |
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| 13:50 | retina that looks at this other There's a point in my retina that |
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| 13:54 | at the screen over there, there's point in my retina that looks at |
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| 13:58 | other screen. So we have this of the outside world. How does |
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| 14:05 | perceive this outside world map? And turns out that both rein and L |
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| 14:12 | M, the receptive field properties are we call concentric on and off center |
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| 14:22 | . How does that come about? this extends to both L G M |
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| 14:26 | well. So this is what retina for the visual input that it |
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| 14:33 | It has this kind of a structure a lot of the photo receptors are |
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| 14:41 | connected through the circuit to gang And what retina sees essentially when it |
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| 14:50 | to the outside world. Retina sees on and off concentric center surround. |
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| 15:01 | don't wanna draw and everything I run of here. OK. So if |
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| 15:15 | see something like this, this is Rena can process. So some of |
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| 15:21 | cells, the receptive fields will be responsive if the beam of light is |
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| 15:28 | the very center and they're called centric cells. And these sticks are action |
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| 15:35 | . So these receptive fields in the which are collections of the photoreceptors connected |
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| 15:40 | ganglion cells will produce the highest number frequency of action potentials when the beam |
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| 15:46 | light is in the very center of receptive field. And then the off |
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| 15:51 | gang cells are going to produce the uh number of frequent of actions with |
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| 15:57 | shaws when the surround is illuminated. when the light is coming in to |
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| 16:05 | eye, it's lighter and darker luminescence . And our retina based on the |
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| 16:14 | , the photoreceptor of the connectivity places of this visual information of luminescence into |
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| 16:22 | round receptive field properties being processed by and having these properties of on center |
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| 16:31 | off center. So on center cell the most action credentials. When the |
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| 16:37 | is on, it produces the least credentials. When the light is in |
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| 16:41 | surround instead of the center and the of action for controls doesn't change much |
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| 16:47 | the entire area in the retina has illumination. So as you can see |
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| 16:55 | , this is a stimulus here. in this situation, the action potential |
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| 17:01 | before the stimulus during the stimulus or the stimulus doesn't change. When the |
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| 17:09 | center surround recept, the field is illuminated which suggests and indicates the |
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| 17:20 | It's coded by what by increase in in the frequency and number of the |
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| 17:31 | potentials. So there is there is difference in contrast and luminescence of |
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| 17:38 | lighter and darker. You will see change in the action potential pattern that |
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| 17:44 | indicate essentially a different illumination of an in your receptive field. But if |
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| 17:51 | is evenly illuminated, like you're looking a white wall, there is not |
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| 17:56 | difference and there isn't gonna be much in action down control frequency as you |
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| 18:03 | staring at the same luminescence uh Basically like these photoreceptors can release |
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| 18:15 | The bipolar sauce really use glutamate and gangrene cells also release gate. Now |
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| 18:27 | can you have excited or neurotransmitter in of these three cells? And you |
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| 18:32 | certain cells producing more action but that cells producing less action. So when |
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| 18:39 | say the devil is the details, devil is in the circuit. And |
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| 18:46 | The bipolar cells in the retina contain types of glutamate synaptic receptors. The |
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| 18:57 | that we discussed and also metabotropic glutamate six, which we we mentioned me |
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| 19:06 | glutamate receptor signaling in the in the the glial cells. And the s |
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| 19:12 | you recall right. So glutamate combined either ionotropic ample kate receptors or metabotropic |
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| 19:21 | g protein couple receptors and the tropic receptor channels, the tropic of gco |
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| 19:28 | receptors, it turns out when glutamate to a. So if this neuron |
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| 19:36 | excited and it releases glutamate, it depolarize the itself and this is sign |
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| 19:46 | . So the positive here stands for conserving, not excited during it's all |
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| 19:52 | during. But here it's sine meaning that if this neuron is |
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| 19:58 | if it releases glutamate, this neuron with amine interceptors is going to be |
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| 20:06 | . However, however, it says soft center bipolar cell is hyper |
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| 20:10 | So you're not telling us the I'm telling you the truth because what |
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| 20:16 | is in the dark, the membranes hyper polarized of the photoreceptor cells depolarized |
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| 20:28 | there is influx of sodium. I'm sorry. OK. So it's |
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| 20:32 | The resting number and potential is minus in neurons and here it's like minus |
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| 20:38 | minus 40 in the dark. And the light, this eppo couple cascade |
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| 20:46 | the sodium channel and there is hyper . So if this is sign concerning |
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| 20:53 | there's depolarization, there's depolarization here. in the life, this photoreceptor we |
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| 20:58 | know in the light, this photoreceptor sodium channel and hyper polarizes. So |
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| 21:07 | the light, this cell doesn't release , it's hyper polarized and therefore the |
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| 21:13 | center cell is also hyper polarized. because it has a glutamate release |
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| 21:20 | it's not conserving synapse. That means this is hyper polarized. There isn't |
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| 21:24 | be any glutamate released. And this subject gangl cell is also gonna be |
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| 21:28 | polarized. That means that the cell center by and off central gang |
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| 21:35 | they're not reacting to the stimulus on center and they're acting through this tropic |
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| 21:43 | . But here it's the opposite. is the sign and inverting synapse. |
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| 21:49 | there's depolarization and photoreceptor. This is polarization. This is sign concerning. |
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| 21:56 | there's hyper polarization then this is hyper . But in the light, this |
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| 22:03 | is hyper polarized. That means that no glutamate release. And if it's |
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| 22:07 | opposite, so if this is hyper , that means this is depolarized. |
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| 22:13 | a tropic cascade, there's no this is depolarized and the centric gang |
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| 22:18 | . So is depolarized. So that that this cell is communicating to this |
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| 22:24 | receptor through this cascade. And when light is on and the sounds are |
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| 22:29 | gang and cell will be excited. this gangle cell that's communicating to the |
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| 22:34 | photoreceptor but through a a in the , it's gonna get hyper polarized, |
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| 22:40 | gonna be off. So then you'll , well, how when is this |
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| 22:44 | cell gonna be because you're gonna have photo receptors inside this bucket that comprise |
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| 22:50 | receptive fields. Ok. Hundreds of , thousands of them that process one |
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| 22:56 | of information of your retina. And so then maybe it's gonna be |
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| 23:04 | to the off center gang itself through a another pathway and it's gonna |
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| 23:11 | located on the other area. This horizontal cells are, they have gap |
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| 23:25 | in between them. So electrical junctions connect them. If you recall, |
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| 23:31 | learned the rules for inhibition, feed feedback inhibition. So this is an |
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| 23:37 | of sine conserving synapse plus from So when photoreceptor is depolarized, that |
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| 23:45 | horizontal cell is depolarized, but it feedback projections. And because it's an |
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| 23:53 | cell, it will not hyperpolarize the photo of actors. So there is |
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| 24:00 | additional layer of control by the horizontal and also by the amari cells. |
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| 24:08 | and they allow for the circuits to perceive a broad area of retinal illumination |
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| 24:18 | together through the gap branches to connected networks or segregate into the active zones |
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| 24:27 | inhibition of the visual stimuli that are certain areas of the retina. |
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| 24:36 | And by releasing Gava on the they control cone release of glutamate because |
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| 24:43 | inhibiting photoreceptors and we have rod and photoreceptors, but inhibiting the photoreceptors will |
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| 24:52 | those photoreceptors releasing glutamate if it's in dark because you polarize from the |
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| 25:03 | these outputs of the retinal ganglion there are on off retinal ganglion cells |
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| 25:09 | we describe based on the receptive field . And then there are also, |
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| 25:17 | you stain the retina retinal ganglion we'll see that some of these cells |
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| 25:22 | very small. They're called parvo in and other retinal gang cells, they |
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| 25:29 | large in size, they're called magno . So the Parmer itself have small |
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| 25:36 | fields because there's they're small. So uh synoptic connectivity is not, you |
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| 25:43 | , to be as spatially as they have slower conductance because they're smaller |
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| 25:49 | size. And by that virtue, are less sensitive to, to low |
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| 25:55 | or to low light. And in case, we're looking at the |
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| 25:59 | So we're really talking about contrast cells large, fast conducting and they're more |
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| 26:09 | to low contrast. So, apart the receptive field properties, we also |
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| 26:14 | these anatomical distinctions of atom and And in addition to those two, |
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| 26:21 | also have non MP types of And this is based on anatomical and |
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| 26:27 | differences. The non MP type of are, they don't either, |
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| 26:34 | they don't qualify to be either P M cells and their projections are different |
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| 26:40 | we've learned where they spatially project into , into the, into the |
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| 26:48 | When we get to the central of course, this kind of a |
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| 26:56 | fuel properties and this kind of a luminescence and contrast perception of the outside |
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| 27:03 | is not gonna cut it for us . And we have the circuits, |
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| 27:08 | south, the inputs and the outputs generate quite complex receptive few properties in |
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| 27:17 | primary visual cortex where it allows us receive everything that we do from complex |
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| 27:23 | patterns, to motion, to color shapes interactions and even stability of visual |
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| 27:33 | . Uh So part of it is , right? What we understand about |
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| 27:39 | outside world is those engrams that got . So we can a good example |
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| 27:47 | me of an ingram is when you a car, can you tell it's |
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| 27:53 | and model? Wow, you get in the air and that's really |
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| 27:57 | But can you do that? So an end ground? And can you |
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| 28:02 | it from a distance, not by at the name or can you do |
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| 28:08 | at the distance and then you'll see there is maybe, uh, you |
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| 28:13 | use certain vehicles because they kind of alike and the manufacturers with each other |
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| 28:18 | certain shapes, But generally you learn and then once you learn it, |
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| 28:24 | can recognize it and you can track plans are pulling up pretty well and |
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| 28:31 | lose the shape, the color or size of the vehicle. Not gonna |
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| 28:37 | that because the vehicle is pulling up increased in size by 10 times over |
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| 28:42 | , it was really small. So but that happens in the central processing |
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| 28:48 | happens in the primary visual cortex in higher uh sentence as well. |
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| 28:54 | this says development of road and retinoic pathways. Why do we care about |
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| 29:03 | when we talk about retina genicular I'll tell you several reasons why we |
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| 29:09 | about rodents and why it's a really system to understand the early development of |
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| 29:19 | genicular objections. And what and how changes over the first really three weeks |
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| 29:28 | postnatal life. Postnatal is after, birth, I have this blank slide |
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| 29:37 | mean, draw some things, the good and um what we may do |
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| 29:48 | instead open the figures in the, the two articles. So I it |
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| 29:55 | him and explain the things that So all right down. OK. |
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| 30:29 | what, what what is this? what were we doing? This is |
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| 30:37 | one of my publications with my It's called lots of binocular responses and |
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| 30:47 | retinal convergence during the period of retina axon segregation loss. That's easy binocular |
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| 31:05 | with binocular is one eye or two , bi is two eyes, reduced |
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| 31:11 | convergence. So we're talking about these from the retinal that first converge and |
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| 31:17 | there's a reduction in this convergence onto thalamus during this development period. Uh |
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| 31:25 | there is anatomical segregation of these axons these symbols. This is what I |
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| 31:32 | as a as a graduate student at S U. And we injected at |
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| 31:40 | time, we injected uh some simple Into the, into the eye. |
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| 31:50 | the point of this figure is that P2, when we inject it and |
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| 31:55 | into one eye, this is the lateral nucleus was almost everywhere. We |
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| 32:04 | see these contralateral stains. So we right eye and looked in the opposite |
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| 32:14 | . And then at P three, was still all over this nucleus. |
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| 32:21 | then P seven, it started getting , the zone, the nucleus started |
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| 32:27 | larger because it's growing. But the for contralateral injections, you know this |
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| 32:33 | qula injections is getting smaller At P , it got even smaller. This |
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| 32:41 | the boundaries of the whole nucleus, sort of looks like a para shape |
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| 32:46 | the tail of the para piece is body of the. So the P |
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| 32:52 | , the whole model of the was with contralateral inputs. That P |
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| 32:57 | there was a very clear zone, zone became even smaller than P |
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| 33:04 | He stands for postnatal day. So days after birth, seven days after |
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| 33:11 | , 13, 19. So we're at the first three weeks of |
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| 33:18 | we're looking at the first three weeks development because this period in rodents is |
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| 33:24 | to as a critical period of And during the critical period of development |
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| 33:30 | where there is the highest amount of . And in fact, this is |
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| 33:37 | common in the brain that in the brains at first projections are going everywhere |
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| 33:46 | a lot of neurons are interconnected with neurons. This shows that the projections |
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| 33:53 | one eye are innervating the entire But anatomically, it gets much smaller |
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| 34:01 | gets segregated to a very specific what call contralateral. So, OK, |
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| 34:10 | by this ipsilateral area. Uh but this is the lateral area surrounded by |
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| 34:17 | contralateral zone. So AP seven quadrilateral the lateral, if you superimpose the |
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| 34:29 | . Yeah. And at P you can see a very clear Ipsilateral |
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| 34:37 | surrounded by the contralateral zone. there's a significant amount of overlap between |
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| 34:43 | red and the green size. And it's much smaller. So we show |
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| 34:50 | anatomical that there is an anatomical There's anatomical reshaping of the contralateral if |
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| 35:00 | lateral zones and the lateral geniculate nucleus the developing road. And this is |
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| 35:10 | percent area. You can see that a lot of overlap, especially developing |
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| 35:20 | the third week of age crossed, are overlaps. So cross is |
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| 35:28 | uncrossed isil lateral and the overlap between two. And the important thing here |
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| 35:34 | that you can see that there's a of area in yellow that indicates overlap |
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| 35:39 | the area and projections from the two . And that decreases significantly into the |
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| 35:45 | week of life was named on Then uh we had a really cool |
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| 35:57 | in which we isolated L G M we would pop out L G M |
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| 36:02 | these developing rats and mice also. we would stab the cells with electrodes |
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| 36:10 | sharp electrode recordings. So these are electrode recordings and the reason why we |
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| 36:16 | sharp is because we could penetrate deep the tissue because they're blind recordings. |
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| 36:23 | the difference between the whole cell and intracellular and the sharp electrodes. And |
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| 36:29 | not advantage. So you can stick deep into the tissue. You are |
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| 36:33 | visualizing the cell, you're doing it a what is called blind fashion. |
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| 36:38 | instead the listening to the uh audio they're looking at the changes in the |
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| 36:46 | traces from the silo. It's a technique, but that's how we are |
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| 36:51 | of penetrating into the L G M the surface. This uh bar is |
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| 36:58 | micrometers. So you can see that is this, for example, is |
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| 37:02 | 60 to 80 micrometers into the And you can go even deeper. |
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| 37:08 | during the experiments, I would have dye inside the electrode by assigning |
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| 37:14 | I would fill the cells. So after experiment, I could look and |
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| 37:19 | what cells I recorded from to make I reported from relay cells in this |
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| 37:24 | . And if I didn't, then would have to, you know, |
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| 37:27 | in a different experimental batch or data batch. And then we would look |
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| 37:32 | confirm that these are the cells, we would also do recordings. |
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| 37:41 | And so we would stimulate contralateral optic . And in this case, this |
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| 37:47 | a really cool setup that I developed a graduate student where I preserved both |
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| 37:57 | nerves and the and the fibers that over in one side of the L |
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| 38:06 | M. So in this L G , I had hip C projections coming |
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| 38:12 | the retina and I also had contra from the other side that were preserved |
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| 38:20 | I would cut the nerves right cut the nerve right behind the |
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| 38:25 | So I have both inputs and I isolate only one L G M on |
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| 38:30 | side. So I had this basically nerves going into L G M and |
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| 38:37 | is one of a kind preparation that many people replicate it, it's quite |
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| 38:45 | . And you really have to do early age when they got to B |
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| 38:48 | 18, I had very limited amount time because once you isolate the uh |
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| 38:56 | nucleus, nucleus, guess what oxygen penetrate all the way through these |
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| 39:03 | you're having an in vitro preparation of whole nucleus. That's why in a |
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| 39:09 | of in vitro preparations, it will slices that are approximately 303 150 maybe |
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| 39:14 | micrometers thick. And the reason for is because you're keeping it in the |
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| 39:20 | spinal fluid solution that is being so that oxygen supplies the neurons and |
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| 39:26 | them alive. Now you put a of the brain that's one centimeter in |
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| 39:33 | . OK. So you cannot you can penetrate 50 maybe 100 micrometers |
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| 39:39 | in inside. In fact, there studies that show that the core of |
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| 39:43 | 305 50 micrometer slide is the core about 100 micrometers is is hypoxic of |
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| 39:50 | actual slide. So now you can you have one centimeter and they did |
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| 39:55 | well. They did really well when were developing this postnatal age of like |
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| 40:03 | three would be my earliest recordings to 10. They did really well. |
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| 40:10 | when I was doing my dissertation, needed additional experiments. And I noticed |
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| 40:17 | somehow when I sat up one time the morning, Like really early at |
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| 40:25 | , Then I got my best eight hours later four pm. And |
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| 40:31 | noticed that several times that I don't what it is. Maybe it's the |
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| 40:36 | , maybe it's the acclimation to the . I would always get the best |
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| 40:42 | physiological responses. So then I got a different schedule and all that is |
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| 40:49 | like to work in the lab when would leave because I would have the |
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| 40:54 | space to myself. I can jam music, the one that I like |
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| 41:01 | I can work. And basically, just, you know, nothing |
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| 41:06 | but work kind of like the, I would do that and I realize |
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| 41:13 | like leaving like, you know, , leaving late 11 o'clock midnight. |
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| 41:23 | , and a lot of the times would come in, then I would |
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| 41:26 | up the surgery and, you I say, well, so I |
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| 41:29 | to or I should wait for four five hours. So it devised the |
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| 41:33 | that actually I would leave around midnight I let it sit over there. |
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| 41:40 | we'll leave at two AM or we start to arrive before I left. |
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| 41:44 | so when I came in the following at 9, 10, whatever, |
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| 41:49 | eight hours later, just start the . So I didn't want it. |
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| 41:54 | was really productive. And then after E I would analyze the data, |
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| 41:59 | look here we are doing the recordings the cell recordings. E N |
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| 42:07 | These are synaptic response is by These are binocular responses. So I |
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| 42:15 | either one nerve contralateral lateral and I these cells. So I stopped many |
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| 42:21 | cells of these cells. You stab lot of these cells and they're like |
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| 42:28 | subtle. You stop. A cell one responsive, stimulate on a good |
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| 42:35 | , a good day eat cells. response from 8, 7 out of |
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| 42:42 | eight cells, I would analyze this bi molecular, all of those eight |
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| 42:48 | and P seven, about a half them or so would be binocular. |
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| 42:57 | then I did the recordings of P . All of them are there's a |
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| 43:03 | of cells. So then we come this area here which is an interesting |
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| 43:10 | . And you can see that these still binocular at P 10, P |
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| 43:18 | , P 13. And then the they become strongly monocular. So that |
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| 43:28 | that I am stabbing was still in , what do we call it this |
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| 43:34 | zone or this zone? This its lateral patch here, I'm in this |
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| 43:39 | zone. So I'm expecting that at older age, I'm only gonna get |
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| 43:45 | response from one, not the other I can't really stab the right down |
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| 43:52 | deep into the zone. So, when we all of these hundreds of |
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| 43:57 | at different days, you can Wow, look at that number of |
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| 44:03 | and equal 35 By molecular and equals of molecular. So 35-15, that's |
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| 44:15 | cells so that's probably 10 days of in one column here. These two |
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| 44:22 | for experiment. All right. But is very clearly showing how the cells |
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| 44:28 | binocular dominant, binocular dominant. And at the third week of age, |
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| 44:34 | switch and they become monocular Domb in , we're looking at this contralateral |
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| 44:41 | Now, we did some really other experiments about graded potentials and we published |
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| 44:47 | paper with uh moa mo five review you don't fix it. Thank |
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| 45:02 | OK. Let's go back into this here because this paper again, kind |
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| 45:12 | uh uh reminds us and shows us interesting things. Now, why did |
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| 45:19 | say you want to care about, know, studying and rodents and some |
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| 45:25 | have a very late development systems. if you have a development and anatomy |
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| 45:32 | segregation of the inputs of the lateral postnatally, that means that you can |
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| 45:38 | a lot of experimental manipulations if it happens in the womb prenatally, which |
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| 45:45 | lot of things happen prenatally and form the form prenatally, the connections that's |
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| 45:53 | to influence it. You're not talking embryonic manipulation or pregnant rodent manipulation. |
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| 46:04 | if you have a system that you track, you can manipulate, whether |
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| 46:09 | a whisker system or this retina geniculate , what is happening here you're having |
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| 46:19 | , functional and anatomical plastic. It's here that first of all, you |
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| 46:26 | this very large ipsilateral zone in this area And then that zone becomes very |
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| 46:37 | in the 3rd and after the 3rd of life. So look at what's |
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| 46:43 | here. There's so much structural plasticity reshaping taking place from two large, |
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| 46:51 | block just overlapping each other into one small block surrounded by, by, |
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| 46:57 | mono monocular zone here. Yeah, 12, P 12 is over. |
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| 47:11 | that's significant. That means that even eyes closed, these animals are born |
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| 47:19 | our eyelids closed. And then P , the eye was open. So |
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| 47:26 | is refinement, anatomical functional refinement that's during the first 12 days of |
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| 47:35 | But after that, that explains a of different changes, structural and functional |
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| 47:41 | take place into the third week of . They're getting direct axial rays of |
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| 47:47 | rather than ambient light that can still through the islands. Uh there are |
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| 47:56 | waves. So even before the photo are functional, there are retinal waves |
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| 48:05 | are happening. This shows you the activity as it is related to this |
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| 48:10 | of development. And M L G . So if you have waves, |
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| 48:17 | are repeating themselves across the red and sending these uh uh wavelike information into |
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| 48:26 | L G M in the absence of visual input that answers the question. |
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| 48:33 | how come there are still changes happening ? And it's not that ambient light |
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| 48:40 | through the island. It's a mechanism we refer to a lot of times |
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| 48:45 | a pattern generator that is built in these networks of circuits, especially during |
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| 48:52 | development. And we have pattern generators different parts of the body in different |
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| 48:58 | . Your heart is a pattern it generates action and the heart |
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| 49:04 | It's a pattern generator, breathing a pattern generator. But you also |
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| 49:12 | these patterns and these spontaneous, they're to spontaneous retina waves or spontaneous spinal |
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| 49:22 | waves, they're referred to spontaneous because is no visual input, stimulating the |
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| 49:28 | . There's no SOMA sensory input at the spinal cord. But these developing |
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| 49:36 | will produce these patterns of activity. will generate and replicate these patterns in |
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| 49:44 | uh cycles. Some of them will slower, some of them will be |
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| 49:50 | and only following the eye opening of retina, you will see visual responses |
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| 49:57 | you'll see a lot of visual responses during this period of segregation, anatomical |
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| 50:05 | and this visual responses. But going Kind of a stabilized and reach some |
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| 50:11 | of a steady state in what you call a maturely developed or now |
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| 50:19 | they, they can, you they can be called adults. Rodents |
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| 50:23 | be called adults after about 6-8 weeks life. Uh So they're already now |
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| 50:31 | instead of developing services. Now, else is going on retinol conversion? |
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| 50:42 | this is just a lot of really information convergence. Uh Where's rental |
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| 50:54 | The wiring diagram illustrating the pattern of convergence of the den drive of a |
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| 51:00 | neuron. So these are contralateral c I in green, there is a |
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| 51:10 | gang uh cells, they're all So it's not inhibition, it's later |
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| 51:17 | and they're projecting onto this relay neuron is in the G M. So |
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| 51:25 | relay neuron shows here as 12345678 S . That's a lot of synapses. |
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| 51:37 | a lot of convergence, Uh contralateral sil lateral onto one neuron. |
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| 51:47 | Now and at first you are having P SPS. So this is rental |
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| 51:54 | and you have a lot of exci . So you get these E P |
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| 51:58 | and because these E P SPS are , remember it said that a single |
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| 52:02 | P S P is about half a size, they're graded controls. So |
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| 52:06 | more synapses you activate the uh higher E P S P you have |
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| 52:17 | Then you also generate during this uh , these alive plateau potentials alive or |
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| 52:26 | five calcium mediated queau potentials. So you stimulate, now there's a |
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| 52:34 | stimulate, stimulate, stimulate, If you repetitively stimulate the contralateral and |
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| 52:42 | lateral inputs, the relay cell will with these Alpi controls. And it |
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| 52:50 | you that receptive field structure also during development is not very anatomically segregated. |
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| 53:04 | happens later, later, we get in the in the thalamic circuit that |
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| 53:12 | plateau was making it to the circuit we get a lot less of the |
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| 53:19 | olympics. So now we're down to silla Olympics and we're down to three |
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| 53:26 | lateral inputs and one of them is , which means that this is probably |
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| 53:34 | active one. This is activity dependent , the synapse that is active, |
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| 53:39 | becoming larger, more efficacious, maybe has L T P already between these |
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| 53:46 | cells. These are becoming smaller. , in the third week of line |
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| 53:55 | , you now lost the ipsilateral liquids . Into this relay cell. You |
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| 54:01 | almost 1-1 excited to re open. one gang cell to one relay cell |
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| 54:11 | you also have this inhibition which lets forward inhibition. Now what you're seeing |
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| 54:23 | here, this is E P S and it's a lot of people organizations |
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| 54:28 | in the early stages that can produce very large alti plateau potential. But |
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| 54:36 | the E P SDS are followed by SDS Because now we have functional inhibition |
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| 54:46 | this retinal circuit. And then inhibition strong enough 1-1 almost now because if |
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| 54:53 | have one inhibitory input, one exci , so now you have to stimulate |
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| 54:59 | lot and you don't reach this plateau natural because of the inhibition presence there |
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| 55:07 | also some changes that are associated with alive Gaussian channel function and expression. |
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| 55:15 | at this stage, you have very nice anatomical segregation of receptive field structures |
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| 55:26 | we've discussed and this centers around fashion the level of lateral gear makes |
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| 55:39 | right. When everything is overlapping everywhere the retina, the retina may have |
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| 55:45 | concentric on and off fields that are specific. But if the projections are |
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| 55:52 | everywhere in the L G M, it's gonna be spatially the interpretation of |
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| 55:58 | visual stimulus of that luminescence, it's gonna be great. And only when |
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| 56:05 | get the segregation of these inputs and get the Convergence from multiple inputs into |
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| 56:14 | an almost 1-1 communication. We have very precise map in the lateral nuclear |
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| 56:22 | field map, which also tells you LGM and relay cells still have this |
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| 56:30 | centers around on of receptive field property . So this is going up into |
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| 56:45 | cortex, some other beautiful stains and detailed studies of these inputs. But |
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| 56:58 | would be the the biggest that I you to focus on. If we |
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| 57:02 | use this uh this figure here, a lot of information, but I |
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| 57:09 | it puts everything in perspective really well we talk about the circuit, we |
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| 57:14 | about activity, we talk about red activity, red milk convergence, poop |
|
| 57:21 | that L G and then receptive field as a function of this first three |
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| 57:26 | of development called critical period of It's a period when we have the |
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| 57:34 | plasticity, we have the correct chemical or a specific chemical environment. And |
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| 57:47 | that encourages the refinement, the anatomical structural, as well as functional refinement |
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| 57:55 | the connectivity in the processing of the activity. So I spent about five |
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| 58:02 | of my, of my life on and this review is my, my |
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| 58:11 | phd Moor William. It's a terrific of the development form and function of |
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| 58:19 | mouse visual follows so written, Judicate follows. In fact, a lot |
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| 58:25 | experiments are if, if you look in this paper, there's a lot |
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| 58:31 | experiments that we are talking about. we talk about convergence, you see |
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| 58:38 | E P SPS. So would very raise the stimulus intensity by 5%. |
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| 58:48 | stimulate the fiber, stimulate the fibers I get a little jump here in |
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| 58:53 | second synapse is activated with stronger 3rd, 4th 5th. So this |
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| 59:00 | actually has five inputs, contralateral, , the lateral inputs, a contralateral |
|
| 59:08 | , three of the lateral limps. what, what with that diagram show |
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| 59:13 | convergence is this work actually of stimulating seeing how many grad increases you get |
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| 59:21 | that post response. OK. These monocular cells, these are monocular |
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| 59:28 | Again, this is excitation followed by very strong inhibition. And then what |
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| 59:35 | is that you can raise the stimulation . 10 2030, 40% doesn't |
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| 59:41 | You're still just getting one single So not single contralateral input and three |
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| 59:49 | the lateral uh the single in contralateral three contralateral monocular cell. So this |
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| 59:59 | a number of inputs each cell can on a postnatal day. So you |
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| 60:07 | see that in uh on average, can receive 9-10 inputs in the first |
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| 60:12 | of life. And then it goes to three. And in some |
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| 60:19 | just the one, there is 1-1 fatality that is shown in this diagram |
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| 60:27 | . So it goes from many inputs a few inputs to just one or |
|
| 60:35 | couple of them. This is exactly we saw experiment. So it's a |
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| 60:41 | set of experiments because we use immunochemistry tracing and looking which also contralateral its |
|
| 60:52 | . Uh We used uh specialized preparation two optic nerves. Um We used |
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| 61:03 | to count and show the the number inputs that are being received and you |
|
| 61:10 | , early versus late developmental stages. it all uh supports the hypothesis also |
|
| 61:18 | the refinement of the receptive field properties the Yeah. So please uh know |
|
| 61:30 | , these, these two uh figures particular figure two and figure three and |
|
| 61:37 | three may look a little bit like right now. But don't worry because |
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| 61:41 | will be talking about a lot of projections uh and other information that will |
|
| 61:48 | you boost your knowledge sharing. So look at this another classical experiment uh |
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| 62:01 | deprivation. And this is another reason certain systems are easy to manipulate. |
|
| 62:10 | can wiggle the whis card. You wiggle the hair cell and the cochlea |
|
| 62:17 | invasive surgery. But you can literally the whisker that's connected to a single |
|
| 62:25 | here than the manipulation. Of you can close the hears of deprived |
|
| 62:29 | sound. You can close the eyes deprive these rodents of vision and knowing |
|
| 62:36 | you have this process of refinement of and functional refinement that happens in the |
|
| 62:42 | three years of life, Knowing that animals open their eyes at 12 days |
|
| 62:48 | age. And then by the time two months of age are pretty much |
|
| 62:55 | . Now, you understand all of , what what happens if there is |
|
| 63:01 | deprivation period in a critical period? happens if there is an injury to |
|
| 63:06 | system during the critical period? If are telling us that there is the |
|
| 63:12 | amount of plasticity in the system, should also infer that there is the |
|
| 63:20 | capability for that system to repair itself it smells plastic. Once things are |
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| 63:27 | and they can't change as easily. repair is also uh not as easy |
|
| 63:33 | adult brains. And the doctor, is an experiment in which we learned |
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| 63:40 | most of the projections from the thalamus a the cortical projections. Now from |
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| 63:48 | thalamus into the cortex, these projections with the eye to the thalamus and |
|
| 63:56 | it goes into the cortex all the here to the primary visual cortex. |
|
| 64:03 | have these projections from one I. at about one month of age, |
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| 64:12 | suit your one eyelid, He deprived animal of vision of one and three |
|
| 64:20 | later, you open the suture and month later. So you say I |
|
| 64:26 | competed with the system development for three during this crucial time of development. |
|
| 64:31 | gonna see if it's going to have effect that they don't. And I'm |
|
| 64:36 | test it by shining the light in eye and recording how the eye that |
|
| 64:44 | closed. Contralateral eye are the cortex still responsive to con contralateral eye. |
|
| 64:52 | you can see that there's a reduction function, lateral eye responsive compared to |
|
| 64:57 | eye that remained open of Sola. there's a bias in the cortex. |
|
| 65:02 | , during this development period, if deprive sensor information, there's a bias |
|
| 65:07 | dedicate cortic malar and space for the and open eye. And that persistence |
|
| 65:17 | no, if you have the same , but instead of three days, |
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| 65:25 | suture the island for six days and you open the isle and then one |
|
| 65:31 | later, you stimulate the suture, , contralateral and you stimulate the un |
|
| 65:39 | dye and your cortex is not responsive the either of suture. That means |
|
| 65:48 | this period of six days during critical of development of sensory deprivation. In |
|
| 65:54 | case, visual deprivation has permanently altered functionality and the structure. So these |
|
| 66:04 | the inputs that would come out of L G M and go into the |
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| 66:09 | forming these very bushy A. So and this is from the deprived |
|
| 66:16 | Now, you can see that these and this is just short term monocular |
|
| 66:21 | . Just after this short term, day deprivation, you already have a |
|
| 66:28 | change, a structural change that projections are coming from the muscle cortex. |
|
| 66:38 | this is after, after the eyes been over Now, it tells you |
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| 66:45 | important it is that if you have critical period of development and the deprivation |
|
| 66:50 | very short for three days, it's fairly good chance for it to |
|
| 66:54 | There will be a bias to another that was open. But if you |
|
| 66:59 | it for long term, there is recovery finally. So this is happening |
|
| 67:05 | , you know, with obviously right one month eyes open at P |
|
| 67:10 | So these are already open eyes you stimulated it already change the projections |
|
| 67:16 | we talked about. So, but still have the ability to impede with |
|
| 67:22 | lot of cortical projections now and how cortex is reacting. Now, the |
|
| 67:29 | thing I wanna show, I didn't for a while. It should be |
|
| 67:55 | so the way that it was uh experiments were done, the first were |
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| 68:04 | uh the retina would be isolated and would be placed on microelectrode array. |
|
| 68:15 | first, this is the retina is you place it on multi electrode array |
|
| 68:26 | like 300 400 electrodes. And we e electrical waves. S not me |
|
| 68:37 | where we had optical imaging techniques, can image as a kid. We |
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| 68:46 | about how you can image calcium, you can image voltage. So there's |
|
| 68:52 | ways in which you can image. so it was noted that before the |
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| 68:58 | see even functional, there are these waves of activities that read as active |
|
| 69:07 | in the retinal circuits that are being and they're being reproduced and they're being |
|
| 69:14 | and regenerated. And that these spontaneous are incredibly important with this normal |
|
| 69:23 | And this anatomical refinement, structural and refinement of retina to the to the |
|
| 69:29 | M. So there were a further that if you block these waves, |
|
| 69:34 | don't get that at the. Uh uh and and so this is just |
|
| 69:41 | example, not maybe an older Uh I may have to open an |
|
| 69:51 | but if you see waves and oh maybe that's the best one so |
|
| 70:02 | . But equivalent kind of a uh that you're seeing here, the fluorescent |
|
| 70:09 | here, equivalent kind of waves will produced in many different structures during the |
|
| 70:15 | development. And we don't necessarily understand they come above the patterns. We're |
|
| 70:23 | to understand the cells that are And we understand that in retina, |
|
| 70:28 | a lot of cool anergic signaling early . That's very important for the sea |
|
| 70:34 | that helps these waves and help them them. But that all of these |
|
| 70:39 | . So spontaneous processes at the level the uh retina and retinal waves and |
|
| 70:47 | the active sensory processes during this critical of development. At the early |
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| 70:53 | they're all very plastic and change a . I think I'm done with time |
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| 71:00 | with this lecture and we'll continue on |
|
