WEBVTT 00:00:02.279 --> 00:00:06.400 Today's episode is all about excitation, also 00:00:06.400 --> 00:00:11.160 known as excitatory neurons. Excitatory neurons 00:00:11.160 --> 00:00:16.239 are part of this push -pull system of excitatory 00:00:16.239 --> 00:00:20.780 and inhibitory neurons. Of course, excitation 00:00:20.780 --> 00:00:26.140 is activation or start or go signals. We've recently 00:00:26.140 --> 00:00:29.260 covered a few episodes on the inhibitory side, 00:00:29.980 --> 00:00:34.960 the inactivating. or stop signals. Those are 00:00:34.960 --> 00:00:40.380 episodes. Episode 76, parvalbium interneurons 00:00:40.380 --> 00:00:44.359 and the autistic phenotype. Remember, parvalbium 00:00:44.359 --> 00:00:47.960 interneurons are the most common inhibitory type 00:00:47.960 --> 00:00:52.140 of neuron. These are very fast acting and often 00:00:52.140 --> 00:00:55.619 the autistic phenotype has a deficiency or a 00:00:55.619 --> 00:01:00.539 lack of in key areas such as the anterior insula. 00:01:00.729 --> 00:01:04.629 the ACC, the dorsolateral prefrontal cortex, 00:01:05.150 --> 00:01:10.810 and the thalamic reticular nucleus. Episode 82, 00:01:11.670 --> 00:01:15.569 sonic hedgehog and inhibitory neurons in autism. 00:01:16.829 --> 00:01:21.769 Episode 83, thalamic reticular nucleus or the 00:01:21.769 --> 00:01:27.450 TRN, sensory gating and autism. In addition, 00:01:27.810 --> 00:01:31.349 we have episodes four and five. a two -part series 00:01:31.349 --> 00:01:35.530 about just general excitation and inhibitory. 00:01:36.569 --> 00:01:41.150 The reason is this. The recent episodes are zooming 00:01:41.150 --> 00:01:45.310 in to cover the specific cells and their roles 00:01:45.310 --> 00:01:49.189 within the autistic phenotype. There is a significant 00:01:49.189 --> 00:01:53.510 battle between this excitation and inhibition 00:01:53.510 --> 00:02:01.260 imbalance. Excitatory Neuron are primarily pyramidal 00:02:01.260 --> 00:02:06.560 neurons. And they release glutamate, the brain's 00:02:06.560 --> 00:02:09.860 main excitatory neurotransmitter, to activate 00:02:09.860 --> 00:02:17.560 postsynaptic neurons via AMPA and NMDA receptors. 00:02:19.180 --> 00:02:23.360 Remember the spatial relationship of AMPA and 00:02:23.360 --> 00:02:28.330 NMDA on the postsynaptic area. of the synaptic 00:02:28.330 --> 00:02:33.229 cleft. These neurons drive neural activity and 00:02:33.229 --> 00:02:36.550 promote information transmission and are critical 00:02:36.550 --> 00:02:41.449 for sensory, cognitive, and motor functions. 00:02:42.650 --> 00:02:46.069 Remember, overall, the human central nervous 00:02:46.069 --> 00:02:50.090 system, the brain, has three main types of neurons, 00:02:51.009 --> 00:02:55.849 sensory neurons, interneurons, and motor neurons. 00:02:57.000 --> 00:03:01.719 In the autistic phenotype, excessive excitatory 00:03:01.719 --> 00:03:05.800 activity contributes to an elevated excitation 00:03:05.800 --> 00:03:11.560 inhibition ratio. And this leads to sensory hypersensitivity, 00:03:12.139 --> 00:03:16.219 of course, cognitive deficits. The primary one 00:03:16.219 --> 00:03:20.439 here is a lack of adaptive responses, not being 00:03:20.439 --> 00:03:24.259 able to adapt properly or with a large toolbox, 00:03:24.259 --> 00:03:30.039 if you will. in the social world. And also repetitive 00:03:30.039 --> 00:03:33.599 behaviors. This black and white, these rigid 00:03:33.599 --> 00:03:37.199 thinking, the fixated interests that are so called 00:03:37.199 --> 00:03:42.439 abnormal in intensity or focus. This EI imbalance 00:03:42.439 --> 00:03:47.500 contributes to these things. Overall, I don't 00:03:47.500 --> 00:03:51.240 know, I can't comment on if the Autistic Phenotype 00:03:51.240 --> 00:03:57.370 has an abundance of excitatory neurons. and or 00:03:57.370 --> 00:04:01.810 a lack of inhibitory neurons. Now I know this, 00:04:01.909 --> 00:04:05.370 the data are impressive on this. And based off 00:04:05.370 --> 00:04:10.330 of the Reza Shadmir episode about the cerebellum 00:04:10.330 --> 00:04:15.530 and the parv albium data, there are a lack of 00:04:15.530 --> 00:04:19.009 inhibitory neurons, especially the parv albium 00:04:19.009 --> 00:04:22.790 interneuron and the purgenji cells of the cerebellum. 00:04:22.990 --> 00:04:27.970 There are indeed. a lack of those. I am unsure 00:04:27.970 --> 00:04:31.949 if it's enough, if that's adequate enough to 00:04:31.949 --> 00:04:35.149 cause this imbalance. Because another region 00:04:35.149 --> 00:04:38.870 of interest is this, that hypo -connectivity 00:04:38.870 --> 00:04:42.689 with distal connections of the brain, such as 00:04:42.689 --> 00:04:45.209 the superior colliculus to the frontal eye fields 00:04:45.209 --> 00:04:49.430 or the dorsolateral prefrontal cortex, there's 00:04:49.430 --> 00:04:52.649 distal connections in the human brain and the 00:04:52.649 --> 00:04:55.600 autistic phenotype struggles with that as well. 00:04:57.100 --> 00:04:59.639 So the main cell type here in the excitatory 00:04:59.639 --> 00:05:03.439 neurons is pyramidal neurons. This is characterized 00:05:03.439 --> 00:05:08.639 by its shape, large triangular and extensive 00:05:08.639 --> 00:05:12.220 dendritic trees and long axons for long range 00:05:12.220 --> 00:05:15.459 connectivity. Now if you're wondering why it 00:05:15.459 --> 00:05:17.879 is called pyramidal neurons it's because they 00:05:17.879 --> 00:05:21.060 are it's nothing creative. It's nothing special 00:05:21.060 --> 00:05:25.259 here. They just look like a pyramid. These excitatory 00:05:25.259 --> 00:05:31.439 neurons act on those AMPA receptors and NMDA 00:05:31.439 --> 00:05:35.300 receptors. This is glutamate. And those are both 00:05:35.300 --> 00:05:38.980 ionotrophic receptor types, very fast. They're 00:05:38.980 --> 00:05:42.360 faster than metabotrophic, which is glutamate 00:05:42.360 --> 00:05:46.180 receptors. Mglu are one through five. These are 00:05:46.180 --> 00:05:49.939 more modulatory. Now you might ask, and you ought 00:05:49.939 --> 00:05:53.199 to ask, What are these excitatory neurons? How 00:05:53.199 --> 00:05:55.540 are they different than the excitatory neurons 00:05:55.540 --> 00:05:58.839 of neuromodulators such as acetylcholine and 00:05:58.839 --> 00:06:02.680 dopamine? Remember dopamine has two receptors 00:06:02.680 --> 00:06:06.560 that are excitatory and three receptors that 00:06:06.560 --> 00:06:10.720 are inhibitory. And of course we have excitatory 00:06:10.720 --> 00:06:13.819 dopamine and inhibitory dopamine. These are a 00:06:13.819 --> 00:06:18.720 little bit different. Glutamate transmits information 00:06:18.720 --> 00:06:22.399 in a fast like a light switch type of activity 00:06:22.399 --> 00:06:28.300 here. It just it's instant. Neuromodulators determine 00:06:28.300 --> 00:06:31.720 the processing. They modulate the excitability 00:06:31.720 --> 00:06:36.500 to keep firing or keep paying attention and these 00:06:36.500 --> 00:06:41.759 happen seconds to minutes versus the one millisecond 00:06:41.759 --> 00:06:46.620 to 10 milliseconds of the AMPA and NMDA receptors. 00:06:48.040 --> 00:06:52.319 The modulators are like a volume control. Or 00:06:52.319 --> 00:06:56.279 if you have a adjustable light switch, we can 00:06:56.279 --> 00:07:01.019 determine the lighting. The modulators are state 00:07:01.019 --> 00:07:04.800 setting, determines your brain state, and determines 00:07:04.800 --> 00:07:09.680 attention, motivation, and salience. So really 00:07:09.680 --> 00:07:12.720 the process is these excitatory and inhibitory 00:07:12.720 --> 00:07:16.579 neurons acting fast, within 1 to 10 milliseconds. 00:07:16.920 --> 00:07:20.819 And then neuromodulators are on the scene within 00:07:20.819 --> 00:07:25.519 10 to 30 seconds. And then, if we really want 00:07:25.519 --> 00:07:28.939 to get into it, hormones are activated about 00:07:28.939 --> 00:07:34.079 30 seconds on scene. Okay, with the pyramidal 00:07:34.079 --> 00:07:37.160 neurons, there are little subtypes here. Layer 00:07:37.160 --> 00:07:41.360 2 and 3 pyramidal neurons facilitate cortico 00:07:41.360 --> 00:07:44.899 -cortical connectivity. So for example, visual 00:07:44.899 --> 00:07:48.949 cortex 1 to the dorsolateral prefrontal cortex. 00:07:49.730 --> 00:07:53.009 It's one of the most distal connections in the 00:07:53.009 --> 00:07:55.990 brain, from the very back of the brain all the 00:07:55.990 --> 00:07:59.449 way to the front of the top. That's the dorsolateral 00:07:59.449 --> 00:08:04.649 part. And then layer five and six pyramidal neurons. 00:08:05.149 --> 00:08:07.850 These project to subcortical structures such 00:08:07.850 --> 00:08:11.990 as the thalamus, the striatum, thalamic reticular 00:08:11.990 --> 00:08:16.589 nucleus and so forth. hippocampal pyramidal neurons, 00:08:16.970 --> 00:08:22.589 or in CA1 and CA3, similar, very similar to the 00:08:22.589 --> 00:08:25.509 inhibitory neurons that we discussed. This is 00:08:25.509 --> 00:08:29.610 critical for memory. And we also have granule 00:08:29.610 --> 00:08:33.929 cells. These are dentate gyrus of the hippocampus 00:08:33.929 --> 00:08:39.409 cerebellar cortex and excitatory inputs to inhibitory 00:08:39.409 --> 00:08:43.690 neurons. Remember, excitatory neurons and inhibitory 00:08:43.690 --> 00:08:48.789 neurons can act on each other. The synaptic properties 00:08:48.789 --> 00:08:54.490 here, the high synaptic plasticity via NMDA -dependent 00:08:54.490 --> 00:08:57.509 long -term potentiation. These are huge for learning. 00:08:57.690 --> 00:09:00.929 We'll cover learning shortly. And long -term 00:09:00.929 --> 00:09:05.529 depression. This is modulated by BDNF. We'll 00:09:05.529 --> 00:09:08.710 talk a little bit about brain -derived nootropic 00:09:08.710 --> 00:09:13.970 factor in a bit. some brain regions associated 00:09:13.970 --> 00:09:17.490 with the pyramidal neurons, the cerebral cortex 00:09:17.490 --> 00:09:20.350 of course. Now pay attention to this because 00:09:20.350 --> 00:09:24.590 these are very similar. They are identical to 00:09:24.590 --> 00:09:29.009 the inhibitory neuron episode. So the dorsolateral 00:09:29.009 --> 00:09:33.830 prefrontal cortex, the ventral medial prefrontal 00:09:33.830 --> 00:09:41.230 cortex, the orbital frontal cortex. the anterior 00:09:41.230 --> 00:09:45.129 cingulate cortex. Those are all very popular 00:09:45.129 --> 00:09:47.950 in the podcast. We've discussed each one of those 00:09:47.950 --> 00:09:53.149 regions. And the sensory cortices, primary, the 00:09:53.149 --> 00:09:57.129 visual cortex one, and the subsequent layers. 00:09:59.309 --> 00:10:05.210 Somatosensory cortex, remember S1. And the primary 00:10:05.210 --> 00:10:10.610 auditory cortex, A1. We've discussed V1, S1 and 00:10:10.610 --> 00:10:16.110 A1 and the inhibitory neuron episode. The insular 00:10:16.110 --> 00:10:19.409 cortex as well, the anterior insula especially 00:10:19.409 --> 00:10:23.950 and the posterior insula. The insula is a very 00:10:23.950 --> 00:10:29.090 popular region of mine and of the podcast. Very 00:10:29.090 --> 00:10:33.570 important. It's very privileged. And the temporal 00:10:33.570 --> 00:10:37.230 cortex, especially the superior temporal gyrus. 00:10:37.409 --> 00:10:40.289 Remember the Decoding the brain. How reading 00:10:40.289 --> 00:10:43.929 works in autism and dyslexia. We talked about 00:10:43.929 --> 00:10:49.710 the STG in quite detail. Inferior temporal cortex. 00:10:50.149 --> 00:10:55.190 Huge for object recognition. And then the hippocampus. 00:10:55.250 --> 00:11:02.970 The CA1 and CA3. And the dentite gyrus. And then 00:11:02.970 --> 00:11:07.519 the amygdala. The basolateral amygdala. is heavily 00:11:07.519 --> 00:11:11.740 populated with excitatory neurons and the cortical 00:11:11.740 --> 00:11:15.059 amygdala, more for social behavior. Now, hard 00:11:15.059 --> 00:11:18.200 stop here. The days of saying this region is 00:11:18.200 --> 00:11:22.340 responsible for this, this region equals this 00:11:22.340 --> 00:11:26.039 action, this behavior, this feeling, et cetera, 00:11:26.259 --> 00:11:30.440 are over. Neuroscience has switched off of that 00:11:30.440 --> 00:11:34.379 for great, great reason. It's more about neuro 00:11:34.379 --> 00:11:38.419 correlates, networks. pathways, connections, 00:11:38.980 --> 00:11:43.639 and so forth. Oftentimes even, such as this amygdala 00:11:43.639 --> 00:11:47.519 example that we're using. Yes, it's fear, but 00:11:47.519 --> 00:11:51.139 it's also the opposite of that. It is not about 00:11:51.139 --> 00:11:55.539 the region. It's about the network and connections. 00:11:56.779 --> 00:12:01.980 The amygdala is often the biggest misnomer, especially 00:12:01.980 --> 00:12:06.700 with this so -called fear center. That term oversimplifies 00:12:06.700 --> 00:12:10.519 its complex role in emotional processing and 00:12:10.519 --> 00:12:13.659 does a disservice to its broader functionality. 00:12:14.039 --> 00:12:16.240 And this is what we're going to cover right now. 00:12:16.580 --> 00:12:20.039 It is a huge misnomer. While it's true that the 00:12:20.039 --> 00:12:23.019 amygdala is critical in detecting and responding 00:12:23.019 --> 00:12:27.139 to threats, rapid processing sensory cues to 00:12:27.139 --> 00:12:30.480 trigger fear responses like an increased heart 00:12:30.480 --> 00:12:34.100 rate or freezing. It is not solely detecting 00:12:34.269 --> 00:12:38.429 Fear. This misnomer stems from early neuroscience 00:12:38.429 --> 00:12:42.389 research, particularly studies on fear conditioning, 00:12:43.070 --> 00:12:46.730 which highlight its role in associating stimuli 00:12:46.730 --> 00:12:51.350 with danger. However, the amygdala's involvement 00:12:51.350 --> 00:12:54.549 spans a wide range of emotional and cognitive 00:12:54.549 --> 00:12:57.610 processing, making the so -called fear center 00:12:57.610 --> 00:13:01.929 tag misleading. It's more accurate to view the 00:13:01.929 --> 00:13:06.929 amygdala as an emotional hub. Hub is a very good 00:13:06.929 --> 00:13:11.509 term and it's evaluating the significance of 00:13:11.509 --> 00:13:14.789 experiences and coordinating the brain's response 00:13:14.789 --> 00:13:19.850 to both positive and negative stimuli with fear 00:13:19.850 --> 00:13:23.870 being just one piece of that puzzle. And remember 00:13:23.870 --> 00:13:26.090 everything we've discussed recently about brain 00:13:26.090 --> 00:13:30.450 waves sometimes called frequencies or oscillations. 00:13:31.720 --> 00:13:34.740 The amygdala's functions are very diverse and 00:13:34.740 --> 00:13:38.340 they encompass emotional processing, memory enhancement, 00:13:39.259 --> 00:13:44.720 reward evaluation, and social behavior. The amygdala 00:13:44.720 --> 00:13:49.460 assesses the emotional weight of stimuli, whether 00:13:49.460 --> 00:13:53.799 it's a joy for something you like or you want, 00:13:54.059 --> 00:13:58.080 you need, you love, or the thrill of a potential 00:13:58.080 --> 00:14:03.129 reward. or some sort of social connection. And 00:14:03.129 --> 00:14:06.070 this is integrating sensory input with internal 00:14:06.070 --> 00:14:11.190 states, like mood or hunger. For instance, it 00:14:11.190 --> 00:14:14.309 activates during rewarding experiences, such 00:14:14.309 --> 00:14:18.029 as eating or social bonding. And it's interacting 00:14:18.029 --> 00:14:20.730 with the brain's reward system, including the 00:14:20.730 --> 00:14:25.169 ventral striatum, which in large part, the nucleus 00:14:25.169 --> 00:14:28.549 accumbens. The nucleus accompanies the ventral 00:14:28.549 --> 00:14:32.730 striatum in its very large brain region and dopamine 00:14:32.730 --> 00:14:38.529 pathways. The amygdala strengthens memories tied 00:14:38.529 --> 00:14:43.909 to significant events, both positive and negative. 00:14:45.289 --> 00:14:47.429 And it makes these moments like remembering a 00:14:47.429 --> 00:14:51.190 pleasant first thing, first experience of a certain 00:14:51.190 --> 00:14:55.730 stimuli or a near -miss accident more vivid. 00:14:56.059 --> 00:15:00.720 It kind of stamps these. In addition, the amygdala 00:15:00.720 --> 00:15:05.460 decodes social cues like facial expressions to 00:15:05.460 --> 00:15:10.899 gauge trust or affection. And it also collaborates 00:15:10.899 --> 00:15:14.759 with regions like the prefrontal cortex and hippocampus 00:15:14.759 --> 00:15:19.820 to regulate emotions and contextualize the experience. 00:15:21.000 --> 00:15:24.259 One thing that really throws this misnomer gives 00:15:24.259 --> 00:15:27.850 it strength, I should say. is the so -called 00:15:27.850 --> 00:15:31.830 low road versus high road. And this is very true. 00:15:32.590 --> 00:15:36.870 If you see a snake and you instantly jump back, 00:15:37.230 --> 00:15:41.230 you're startled, you're alert, so forth. That's 00:15:41.230 --> 00:15:43.690 the amygdala kind of lighting up because the 00:15:43.690 --> 00:15:47.250 visual sensory makes a quick stop at the amygdala 00:15:47.250 --> 00:15:51.009 for these things. And that's the low road. But 00:15:51.009 --> 00:15:54.409 then eventually you think, oh, not a venomous 00:15:54.409 --> 00:15:57.659 snake. that's not a copperhead that's a water 00:15:57.659 --> 00:16:01.480 snake and then that's the high road kind of providing 00:16:01.480 --> 00:16:06.279 context based off of memory based off of the 00:16:06.279 --> 00:16:11.639 living organism really to say no need for startle 00:16:11.639 --> 00:16:17.919 no need for this fear and by the way a copperhead 00:16:17.919 --> 00:16:21.600 and water snakes are very similar they have this 00:16:21.600 --> 00:16:27.710 black shape The Copperhead, this shape is in 00:16:27.710 --> 00:16:31.509 the shape of a Hershey Kiss, a triangle. And 00:16:31.509 --> 00:16:34.769 the Water Snake, it's more of a tornado, so it's 00:16:34.769 --> 00:16:38.070 a upside down triangle. Or even sticking to the 00:16:38.070 --> 00:16:40.990 theme of the episode, we could call it a pyramid, 00:16:41.769 --> 00:16:46.110 based off of the pyramidal neuron. Hershey Kiss, 00:16:46.250 --> 00:16:52.399 Copperhead. Tornado, Water Snake. Okay, we were 00:16:52.399 --> 00:16:55.059 talking about brain regions, and I need to pivot 00:16:55.059 --> 00:16:59.179 back. It's hard sometimes. So we finished up 00:16:59.179 --> 00:17:04.119 the amygdala there. And also the striatum, the 00:17:04.119 --> 00:17:07.579 caudate, and the putamen. So that's the dorsal 00:17:07.579 --> 00:17:10.319 striatum. Remember the basal ganglia, the input 00:17:10.319 --> 00:17:13.099 centers of the basal ganglia. That's our go -no 00:17:13.099 --> 00:17:17.960 -go area. It's modulating response types. And 00:17:17.960 --> 00:17:21.450 also the ventral striatum. that we just mentioned, 00:17:21.710 --> 00:17:25.069 the nucleus accumbens. Pyramidal neurons are 00:17:25.069 --> 00:17:29.210 dense in these three regions. The thalamus, of 00:17:29.210 --> 00:17:33.910 course, the thalamus. Relay neurons and the lateral 00:17:33.910 --> 00:17:36.769 geniculate nucleus, so remember vision, you should 00:17:36.769 --> 00:17:40.450 know that's vision. The ventral basal complex, 00:17:40.769 --> 00:17:44.349 which is VB, we'll talk more about that momentarily. 00:17:44.930 --> 00:17:49.009 And the somatosensory. In addition in the thalamus, 00:17:49.109 --> 00:17:54.240 the medial. Geniculate nucleus. This is auditory. 00:17:55.380 --> 00:17:58.660 And the medial dorsal nucleus for cognitive and 00:17:58.660 --> 00:18:02.900 emotional processing. And the cerebellum for 00:18:02.900 --> 00:18:06.779 those granule cells. And this is the excitatory 00:18:06.779 --> 00:18:10.500 inputs to purgenji cells. Okay, I know that's 00:18:10.500 --> 00:18:13.079 a lot of nomenclature, a lot of dense neuroscience 00:18:13.079 --> 00:18:16.559 and brain regions. But they're all very relevant 00:18:16.559 --> 00:18:20.119 here. They're all important. if you wanna understand 00:18:20.119 --> 00:18:22.799 certain phenotypes, like the autistic phenotype. 00:18:24.180 --> 00:18:26.359 So the receptors, let's touch a little bit more 00:18:26.359 --> 00:18:33.140 on the receptors, AMPA. These are very fast excitatory 00:18:33.140 --> 00:18:38.359 transmissions, such as I was touched, and they 00:18:38.359 --> 00:18:43.619 use sodium, potassium, and they are activated 00:18:43.619 --> 00:18:48.539 one to five milliseconds. The NMDA receptors 00:18:48.539 --> 00:18:53.779 use sodium potassium plus the calcium. These 00:18:53.779 --> 00:18:57.420 are critical for synaptic plasticity to long 00:18:57.420 --> 00:19:00.759 -term potentiation and long -term depression. 00:19:02.259 --> 00:19:05.000 Remembering the texture of what was touched. 00:19:05.700 --> 00:19:10.279 ANPA will say, I was touched. NMDA will say, 00:19:10.680 --> 00:19:13.640 oh, I recognize that texture. I know what touched 00:19:13.640 --> 00:19:18.849 me. and NMDA are slower. They open at roughly 00:19:18.849 --> 00:19:23.390 10 milliseconds and stays open for longer, 50 00:19:23.390 --> 00:19:28.049 to 200 milliseconds. And also the M -glutamate 00:19:28.049 --> 00:19:33.049 receptors, M -Glu -Glu receptors, one through 00:19:33.049 --> 00:19:38.450 five. This modulates excitability and plasticity 00:19:38.450 --> 00:19:43.410 via G protein coupled signaling. These are metabotropic. 00:19:43.609 --> 00:19:47.190 receptors. They are slower than the two previously 00:19:47.190 --> 00:19:52.470 mentioned ionotropic receptors. And some interactions 00:19:52.470 --> 00:19:58.190 here. These excitability receptors receive inhibitory 00:19:58.190 --> 00:20:02.849 inputs from GABAergic interneurons, the parvalbium 00:20:02.849 --> 00:20:07.789 interneuron, the somatostatin inhibitory neuron, 00:20:07.910 --> 00:20:12.349 and the basal active intestinal peptide, the 00:20:12.349 --> 00:20:16.769 calbindian, in the chalretinin and the purgenji 00:20:16.769 --> 00:20:21.210 cells, all of those inhibitory neurons that we 00:20:21.210 --> 00:20:26.410 previously discussed. This is via GABA -A, B, 00:20:26.410 --> 00:20:31.589 and C receptors. A general role here for these 00:20:31.589 --> 00:20:36.089 excitatory neurons and receptors to drive neural 00:20:36.089 --> 00:20:40.589 activity for sensory processing, especially visual 00:20:40.589 --> 00:20:46.269 cortex 1, somatosensory cortex 1 and auditory 00:20:46.269 --> 00:20:50.670 cortex 1 and for cognitive functions especially 00:20:50.670 --> 00:20:54.670 in the dorsolateral prefrontal cortex for emotional 00:20:54.670 --> 00:20:57.990 regulation some regions of interest here are 00:20:57.990 --> 00:21:01.910 the anterior insula and the amygdala and the 00:21:01.910 --> 00:21:06.109 motor control remember the striatum and the cerebellum 00:21:06.109 --> 00:21:10.250 they also facilitate synaptic plasticity for 00:21:10.250 --> 00:21:15.099 learning and memory, huge. And they generate 00:21:15.099 --> 00:21:19.480 gamma oscillations from the 30 to 80 Hertz range. 00:21:19.960 --> 00:21:23.259 Remember, these are activating, telling us to 00:21:23.259 --> 00:21:28.759 go. In coordination with parvalium interneurons. 00:21:29.839 --> 00:21:32.480 In the autistic phenotype, there's an excessive 00:21:32.480 --> 00:21:36.640 excitability, excitatory activity in the sensory 00:21:36.640 --> 00:21:41.109 cortex. especially the visual cortex one, the 00:21:41.109 --> 00:21:45.029 somatosensory cortex, and the auditory cortex. 00:21:45.029 --> 00:21:49.349 We've covered this in great detail. This is due 00:21:49.349 --> 00:21:54.250 to brain -derived nootropic factor -driven synaptic 00:21:54.250 --> 00:21:57.309 enhancements and reduced inhibitory control. 00:21:58.650 --> 00:22:01.670 And this elevates that gamma power, and it drives 00:22:01.670 --> 00:22:08.059 sensory hypersensitivity. This impaired EI imbalance 00:22:08.059 --> 00:22:12.160 in the dorsolateral prefrontal cortex and the 00:22:12.160 --> 00:22:17.660 anterior insula reduces gamma synchrony and contributes 00:22:17.660 --> 00:22:21.279 to cognitive and social deficits. Especially 00:22:21.279 --> 00:22:25.200 remember those distal connections. It's a big 00:22:25.200 --> 00:22:32.980 mismatch, a timing mismatch. Overactive corticostriatal 00:22:32.980 --> 00:22:37.400 thalamic cortex circuits especially the orbital 00:22:37.400 --> 00:22:41.920 frontal cortex in the striatum amplify repetitive 00:22:41.920 --> 00:22:46.660 behaviors remember the basal ganglia is involved 00:22:46.660 --> 00:22:52.339 there so what is the neurobiology and the purpose 00:22:52.339 --> 00:22:57.980 this evolutionary aspects of excitatory neurons 00:22:57.980 --> 00:23:03.500 information transmission is huge synaptic plasticity 00:23:03.680 --> 00:23:08.119 These so -called network activations. This is 00:23:08.119 --> 00:23:12.000 now and the future of neuroscience. Networks. 00:23:13.339 --> 00:23:16.599 And the thalamic reticular nucleus interaction. 00:23:17.660 --> 00:23:21.859 So excitatory inputs from cortical layer visual 00:23:21.859 --> 00:23:26.000 cortex 1 pyramidal neurons to the thalamic reticular 00:23:26.000 --> 00:23:30.779 nucleus modulate sensory gating and oscillatory 00:23:30.779 --> 00:23:34.779 activity. It has to be a healthy balance here. 00:23:34.799 --> 00:23:38.339 Just think about this push -pull tactic. So what's 00:23:38.339 --> 00:23:41.059 the difference between typical and the autistic 00:23:41.059 --> 00:23:44.700 phenotype with the excitatory neuron functions? 00:23:45.640 --> 00:23:48.859 In large part, it's the get up and go, the activation 00:23:48.859 --> 00:23:52.680 versus inactivation, orchestrating which regions 00:23:52.680 --> 00:23:57.019 to turn on in addition with those neuromodulatory 00:23:57.019 --> 00:24:00.720 cells. It's all a network here, an orchestra. 00:24:02.160 --> 00:24:05.839 modulating movements and understanding, processing, 00:24:06.819 --> 00:24:08.980 understanding your environment and what you're 00:24:08.980 --> 00:24:12.019 going to do when you encounter these things in 00:24:12.019 --> 00:24:16.740 the environment. And also with the brainwaves. 00:24:16.740 --> 00:24:20.339 Remember the different brainwaves here. Each 00:24:20.339 --> 00:24:24.140 wave range has different functions that has a 00:24:24.140 --> 00:24:30.200 lot to do with brain states, bodily states. The 00:24:30.200 --> 00:24:32.569 autistic function here. Let's start with the 00:24:32.569 --> 00:24:37.809 sensory cortices. V1, S1, and A1. So the hyperactivity. 00:24:37.990 --> 00:24:42.430 You can all understand the hyperactivity. Excessive 00:24:42.430 --> 00:24:45.970 excitatory activity due to the enhanced pyramidal 00:24:45.970 --> 00:24:52.049 neuron firing and the reduced parvalbum and somatostatin 00:24:52.049 --> 00:24:55.950 inhibition. This must be a healthy balance. You 00:24:55.950 --> 00:24:59.509 have to activate and inactivate. Activation and 00:24:59.509 --> 00:25:05.500 inactivation happen simultaneously. An elevated 00:25:05.500 --> 00:25:08.960 gamma power. Increased gamma power, especially 00:25:08.960 --> 00:25:13.740 in that 30 to 80 Hertz, and V1, S1, and A1 is 00:25:13.740 --> 00:25:16.700 very much a huge thing with the autistic phenotype. 00:25:17.480 --> 00:25:21.900 This hijacks the sensory processing. What are 00:25:21.900 --> 00:25:24.599 you paying attention to in the environment or 00:25:24.599 --> 00:25:29.400 even within yourself? This is huge. This is why 00:25:29.400 --> 00:25:32.299 the autistic phenotype has that attention to 00:25:32.299 --> 00:25:36.819 detail. Remember the tree bark example and the 00:25:36.819 --> 00:25:40.559 visual thinking. I believe episode two of visual 00:25:40.559 --> 00:25:44.440 thinking. Think about a tree. Do you see the 00:25:44.440 --> 00:25:48.559 tree or do you see specific details about different 00:25:48.559 --> 00:25:51.859 trees? And in large part this is a source of 00:25:51.859 --> 00:25:55.819 the visual thinking as well. This imbalance of 00:25:55.819 --> 00:25:59.019 excitatory and inhibitory especially those early 00:25:59.019 --> 00:26:04.009 connections. We get stuck. There's so much to 00:26:04.009 --> 00:26:06.450 process right there. The rate of information 00:26:06.450 --> 00:26:11.210 coming in is so fast. But then those distal connections 00:26:11.210 --> 00:26:14.789 are huge. This so -called higher order regions 00:26:14.789 --> 00:26:18.609 of the prefrontal cortex and so forth. Reduced 00:26:18.609 --> 00:26:22.809 activity and synchrony because of this imbalance 00:26:22.809 --> 00:26:26.690 of EI. I can't overstate this enough. If you 00:26:26.690 --> 00:26:29.109 go from point A to point B, and let's say there 00:26:29.109 --> 00:26:32.470 are five stops, that you have to make to reach 00:26:32.470 --> 00:26:35.630 your destination. The autistic phenotype, let's 00:26:35.630 --> 00:26:40.230 say the first two stops, we get there fast. So 00:26:40.230 --> 00:26:44.609 fast versus the typical. But the final destination, 00:26:45.049 --> 00:26:47.490 achieving and reaching that final destination, 00:26:47.789 --> 00:26:50.950 the typicals will get there faster because there's 00:26:50.950 --> 00:26:54.769 the disconnection. It's about the overall point 00:26:54.769 --> 00:27:01.839 A to point B. How we get there differs. For the 00:27:01.839 --> 00:27:06.279 autistic phenotype, it's skewed to the early 00:27:06.279 --> 00:27:09.940 connections. We get there so fast. But the subsequent 00:27:09.940 --> 00:27:13.880 stops. Especially, you know, to the prefrontal 00:27:13.880 --> 00:27:17.680 cortex. You know that's a major region for how 00:27:17.680 --> 00:27:22.440 we evolve and executive functioning. We get there 00:27:22.440 --> 00:27:26.440 slow. And just think about neuroplasticity and 00:27:26.440 --> 00:27:31.140 how we store memories and expectations. How do 00:27:31.140 --> 00:27:34.640 you think this is going to build up with experience 00:27:34.640 --> 00:27:38.059 and over a lifespan? Do you think this is going 00:27:38.059 --> 00:27:42.160 to be stored as pleasant memories? Because mostly 00:27:42.160 --> 00:27:45.400 what we're talking about is the social environment. 00:27:46.380 --> 00:27:51.779 Internally, all good. No problems. It's actually 00:27:51.779 --> 00:27:55.140 a huge benefit here. Remember, the biology that 00:27:55.140 --> 00:27:58.500 gives us autism allows us to be comfortable within 00:27:58.500 --> 00:28:02.980 ourself. That's the huge source or the top source 00:28:02.980 --> 00:28:06.519 of the accelerated learning. We give ourselves 00:28:06.519 --> 00:28:10.920 a chance. There's no internal conflict or barriers. 00:28:12.880 --> 00:28:16.019 So some roles in learning with the excitatory 00:28:16.019 --> 00:28:18.859 neurons. In large part, it has to do with the 00:28:18.859 --> 00:28:21.940 synaptic plasticity. Remember, the brain doesn't 00:28:21.940 --> 00:28:25.400 want to work. It just wants to respond. It responds 00:28:25.400 --> 00:28:28.509 based on what it knows, what kind of connections 00:28:28.509 --> 00:28:31.470 are being made and strengthened within each of 00:28:31.470 --> 00:28:36.529 us. And that will be privileged. The brain doesn't 00:28:36.529 --> 00:28:39.490 want to utilize other connections because that's 00:28:39.490 --> 00:28:43.210 work. You might think about how change is hard 00:28:43.210 --> 00:28:46.369 for the human being, and indeed it's true, but 00:28:46.369 --> 00:28:50.650 think about it from the synaptic view. Look, 00:28:50.650 --> 00:28:53.049 go inside the brain in the central nervous system 00:28:53.049 --> 00:28:56.200 and view it from that perspective. this will 00:28:56.200 --> 00:29:00.019 allow it to make better sense. Whenever we repeat 00:29:00.019 --> 00:29:03.779 things, the so -called cells that fire together 00:29:03.779 --> 00:29:07.579 wire together and the strengthening and the growth 00:29:07.579 --> 00:29:12.079 of synoptic connections, that's the preferred 00:29:12.079 --> 00:29:16.660 choice for the living organism. And then if you 00:29:16.660 --> 00:29:19.799 add in the brain waves, if it's one trial learning 00:29:19.799 --> 00:29:23.859 or gamma or high gamma, it's strengthening these 00:29:23.859 --> 00:29:28.369 connections faster. That's why if you almost 00:29:28.369 --> 00:29:32.150 get into an accident, a near -miss accident, 00:29:32.609 --> 00:29:35.210 that's really heightened and it stamps your memory 00:29:35.210 --> 00:29:38.650 much more than the previous time you drove to 00:29:38.650 --> 00:29:42.190 work and there was no accident or close call. 00:29:43.109 --> 00:29:45.490 The role of the brain -derived neutropic factor, 00:29:45.670 --> 00:29:52.430 BDNF, enhances NMDA receptor function. This is 00:29:52.430 --> 00:29:56.119 in large part the driving mechanism behind this. 00:29:56.299 --> 00:29:59.900 BDNF is so huge, especially in the critical period. 00:30:00.579 --> 00:30:04.460 Whenever children can just learn multiple languages, 00:30:04.460 --> 00:30:08.099 like passively, with no problems, no disruptions. 00:30:08.660 --> 00:30:12.059 In large part, BDNF is modulating that. It allows 00:30:12.059 --> 00:30:15.420 it to happen. And if you think about the autistic 00:30:15.420 --> 00:30:19.680 phenotype, altered plasticity, there's this so 00:30:19.680 --> 00:30:22.710 -called hyperplasticity. because of the excessive 00:30:22.710 --> 00:30:27.930 BDNF driven long -term potentiation especially 00:30:27.930 --> 00:30:33.329 in V1, S1, and A1. This enhances sensory learning 00:30:33.329 --> 00:30:37.029 leading to superior detailed oriented learning 00:30:37.029 --> 00:30:40.509 like visual pattern recognition but it overall 00:30:40.509 --> 00:30:46.470 reduced flexibility. In the hippocampus overactive 00:30:46.470 --> 00:30:52.099 CA1, CA3 pyramidal neurons Due to that reduced 00:30:52.099 --> 00:30:55.980 somatostatin and peripheral albium inhibition, 00:30:56.140 --> 00:31:00.200 impaired pattern separation. This creates a rigid 00:31:00.200 --> 00:31:03.440 memory encoding. Remember, these are all the 00:31:03.440 --> 00:31:06.680 same areas that we discussed in the inhibition 00:31:06.680 --> 00:31:12.039 episodes. Drosolateral prefrontal cortex impairment, 00:31:12.700 --> 00:31:17.039 a reduced EI imbalance in this brain region impairs 00:31:17.039 --> 00:31:20.880 working memory and associative learning. And 00:31:20.880 --> 00:31:23.759 this contributes to that cognitive inflexibility 00:31:23.759 --> 00:31:27.960 as well. The dysfunction in the thalamic reticular 00:31:27.960 --> 00:31:33.680 nucleus, an impairment of parvalbian inhibition 00:31:33.680 --> 00:31:37.440 in the visual and somatosensory and auditory 00:31:37.440 --> 00:31:42.000 sectors, allows for excessive sensory input back 00:31:42.000 --> 00:31:45.579 up to the cortex. Remember the thalamic cortical 00:31:45.579 --> 00:31:49.680 pathway, enhancing sensory learning but overwhelming 00:31:50.009 --> 00:31:54.670 cognitive circuits. In the limbic sector of the 00:31:54.670 --> 00:31:59.210 TRN has a deficit because of the reduced dorsolateral 00:31:59.210 --> 00:32:05.130 prefrontal cortex excitatory activity. This appears 00:32:05.130 --> 00:32:10.309 attention and dependent learning. In the autistic 00:32:10.309 --> 00:32:14.369 phenotype some strengths here is enhanced sensory 00:32:14.369 --> 00:32:19.380 learning in those early visual, somatosensory, 00:32:19.400 --> 00:32:23.279 and auditory networks. This is superior attention 00:32:23.279 --> 00:32:28.539 to detail. Some challenges, though, are impaired, 00:32:29.400 --> 00:32:33.099 creating inflexible, the lack of adaptive responses, 00:32:33.880 --> 00:32:37.720 and leads to context -dependent learning. Just 00:32:37.720 --> 00:32:42.000 tell us. Just be specific type of thing. So also 00:32:42.000 --> 00:32:45.259 think about repetitive behaviors here and social 00:32:45.259 --> 00:32:50.450 deficits as well. and OCD -like behaviors. OCD 00:32:50.450 --> 00:32:54.769 and the autistic phenotype share some very similar 00:32:54.769 --> 00:33:00.009 neural circuitry. Overactive excitatory inputs 00:33:00.009 --> 00:33:04.910 in the corticostriatal thalamic cortex circuit. 00:33:05.549 --> 00:33:09.049 Due to the reduced inhibition control, this amplifies 00:33:09.049 --> 00:33:12.609 habitual learning and drives repetitive patterns. 00:33:13.390 --> 00:33:16.859 Something as similar as tics, tourettes is over 00:33:16.859 --> 00:33:21.279 excitation. We've talked about stereotypy. It's 00:33:21.279 --> 00:33:24.339 a misnomer as well. It's like, it's defined. 00:33:24.400 --> 00:33:26.759 If you look up the definition of stereotypy or 00:33:26.759 --> 00:33:31.660 stereotypy, it will say purposeless behavior. 00:33:32.000 --> 00:33:35.019 But there is very much a purpose of why these 00:33:35.019 --> 00:33:40.000 repetitive behaviors and stemming and OCD like 00:33:40.000 --> 00:33:43.000 tendencies, tics, tourettes, there's a purpose. 00:33:43.039 --> 00:33:46.099 There's a reason. these things are happening. 00:33:47.339 --> 00:33:52.440 Humans just define things so loosely without 00:33:52.440 --> 00:33:57.420 even considering. So let's wrap up with the push 00:33:57.420 --> 00:34:02.480 -pull analogy here. The goal signal explanation 00:34:02.480 --> 00:34:06.180 of this push -pull. Excitatory neurons act as 00:34:06.180 --> 00:34:08.980 the brain's goal signal, and this drives neural 00:34:08.980 --> 00:34:12.679 activity to initiate and propagate information 00:34:12.679 --> 00:34:19.260 processing. Glutamate releases via AMP or NMDA 00:34:19.260 --> 00:34:23.099 receptors, and this depolarizes post -synaptic 00:34:23.099 --> 00:34:28.260 neurons. While increasing, they're firing probability 00:34:28.260 --> 00:34:33.860 and promoting, one, sensory processing, cognitive 00:34:33.860 --> 00:34:40.039 processing, emotional processing, and motor output. 00:34:41.480 --> 00:34:46.119 V1, S1, and A1 so visual, tactile, that touch, 00:34:46.699 --> 00:34:50.480 and auditory stimuli. Cognitive processing, especially 00:34:50.480 --> 00:34:54.460 in the prefrontal cortex. Pyramidal neurons support 00:34:54.460 --> 00:34:58.860 attention and working memory. The emotional processing 00:34:58.860 --> 00:35:03.000 centers. The basolateral amygdala is huge here 00:35:03.000 --> 00:35:06.840 and the anterior insula drive emotional responses. 00:35:07.380 --> 00:35:10.539 What are you paying attention to? There's a reason 00:35:10.539 --> 00:35:13.599 why the insula is part of the default mode network 00:35:13.599 --> 00:35:19.639 and the salience network. Motor output. The dorsal 00:35:19.639 --> 00:35:23.019 striatum and even the ventral striatum with reward 00:35:23.019 --> 00:35:27.539 learning. Then the cerebellar. These are motor 00:35:27.539 --> 00:35:30.820 movements. Remember the dorsal striatum is our 00:35:30.820 --> 00:35:34.539 input area and this will regulate and determine 00:35:34.539 --> 00:35:40.050 action selection. In typical brains, this goal 00:35:40.050 --> 00:35:45.130 signal is balanced, acting as a stop -slow signal. 00:35:46.030 --> 00:35:49.070 You have limitations on how fast you can go. 00:35:51.590 --> 00:35:54.210 In the autistic phenotype, that excessive goal 00:35:54.210 --> 00:35:58.670 signal and the BDNF -driven excitatory enhancements 00:35:58.670 --> 00:36:03.769 and the reduced inhibition amplify everything. 00:36:04.780 --> 00:36:09.300 The 2003 paper from Rubenstein and Mike Merzenich, 00:36:09.539 --> 00:36:12.900 who studies neuroplasticity, is a good foundation 00:36:12.900 --> 00:36:17.739 to start with with this EI imbalance. An EI push 00:36:17.739 --> 00:36:21.639 -pull analogy here is the push, the excitation. 00:36:22.800 --> 00:36:27.179 Pyramidal neurons in the cortex and the thalamus 00:36:27.179 --> 00:36:31.139 push neural activity forward, driving sensory 00:36:31.139 --> 00:36:34.699 cognitive and emotional processing. The pull 00:36:34.699 --> 00:36:39.260 system here, however, the inhibition, those inhibitory 00:36:39.260 --> 00:36:42.559 cells and the purgenji cells pull this back. 00:36:42.980 --> 00:36:46.079 It's a brake system. Collectively, they're working 00:36:46.079 --> 00:36:50.619 as bumpers on, let's say, a bowling alley. And 00:36:50.619 --> 00:36:55.619 this is all one, depending on the context and 00:36:55.619 --> 00:36:59.699 living organism dependent. Depending on what 00:36:59.699 --> 00:37:03.440 the living organism is thinking, wanting, liking. 00:37:03.690 --> 00:37:08.369 trying to accomplish and so forth. I have something 00:37:08.369 --> 00:37:11.349 exciting. I want to introduce a product unlike 00:37:11.349 --> 00:37:16.210 any other product available. A highlight is the 00:37:16.210 --> 00:37:20.150 product from Daylight Computer Company created 00:37:20.150 --> 00:37:24.610 their product based on these factors. 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You can contact 00:42:47.710 --> 00:42:54.090 me on X at RPS 47586. We can discuss anything 00:42:54.090 --> 00:42:56.849 and everything about autism. I very much appreciate 00:42:56.849 --> 00:43:00.630 your comments and your interactions on X. You 00:43:00.630 --> 00:43:03.650 can check out the YouTube page for all the videos, 00:43:04.150 --> 00:43:08.030 full -length videos, shorts, and clips. You can 00:43:08.030 --> 00:43:15.250 email me info .fromthespectrum .gmail .com. Thank 00:43:15.250 --> 00:43:18.409 you for listening. to From the Spectrum Podcast.