And the anatomy of the neurons is different in appearance. But, it's also different in the sense of what is a neuron connected to, what neurons are talking to it, and what neurons is it talking to. So the inputs and the outputs of each neuron are going to be different.

In addition to the anatomy, the other differences include excitability -- and this is essentially how talkative is the neuron; how much do you have to goad it to get it to say something.
Some neurons are talking all the time; and some neurons are very laconic, very unlikely to speak.

And finally, there's how do they speak? And what we're talking about is the neurotransmitter. What is the neurotransmitter -- or what's the chemical, the substance -- that the neuron uses?

There is also a difference in both speed -- whether is something fast or slow -- or also whether it's affirmative or or negative -- 'yes' or 'no', and how fast does it take you to get to 'yes' or 'no'.

**Glial Cells**
The human brain contains 86B neurons and 85B Glia.

**Different types of Glia:**

🔸 Astrocytes: Astrocytes are really important type of Glia. They're essentially responsible for keeping the environment clean, they're the sanitation worker of the brain. So they are picking up all the refuse that the neurons have let loose including excess ions, excess #neurotransmitters and their metabolites.

They also are very important during development. They allow neurons to get to where they have to go during development. #Neurons are born in one place and they have to go some place else, and what highway did they take? They hitch on a progenitor cell that is going to become an #Astrocyte.

And, in addition when synapses are formed, the synapses are not maintained without some effort, and part of that is that the synapses are enveloped in the processes of #Astrocytes. So, there's a lot of structural and metabolic support that the Astrocytes are providing for neurons.

🔸 Oligodendrocytes and Schwann Cells: The #oligodendrocytes make myelin in the CNS and the #SchwannCells make it in the Peripheral Nervous System. So all these demyelinating diseases will affect either central myelin or peripheral #myelin. They will not affect both -- central or peripheral.

Because they are made by two different types. The Oligodendrocytes in the central nervous system and a Schwann cells in the peripheral nervous system.

🔸 Microglia: #Microglia are the one exception to the rule that
nervous system, that the cells of the nervous system come from Ectoderm. These are actually essentially immune cells coming from the blood lineage. These are immune cells that have invaded into the central nervous system and their job is to be quiet. And if we're healthy and everything goes well, they are quiet. But when there is a problem these microglia react, they try to rectify things, they try and bring some attention to areas of damage and what is emerging is that sometimes they go overboard and they start to participate in making the problem as well as solving the problem.

🧠 Myelin is a fatty wrap that goes around some axons.

🔸 An unmylinated or naked axon can only transfer information at a slow rate. So the rate that it's transfers information is 0.2 to 1 meters per second.

🔸 Now, once we put on #myelin, information transfers much much faster. It can go between 2 and 120 meters per second. If it goes at 120 meters per second, the whole game is over. So very short time, imperceptible to us.

🔸 That information occurs in a 0 or a 1. There's either a point of information or not. **And so it's very much like a computer code**, where what we're seeing is a series of and what's important, the 0s are less important but the temporal pattern of these ones is very important.

🔸 And these 'ones' are actually an action potential, also called a spike. And we talk about firing spikes, neurons fire spikes. So, the timing of these spikes is what carries information.

🔸 The information spikes actually jump. That's what makes it so fast. They don't have to actually be carried through the places; with the #Myelin, they can actually jump.

🔸 And now, if we have a #DemyelinatingDisease, what we're going to end up with is some information that's spread out, because it's slower. And every once in a while, it's going to miss bits.

🔸 The neuron, that we're talking, to is getting a very incoherent message. This is very different from the original message and that is the problem with demyelination. Because axons are demyelinated, the information transfer is very degraded. It's a garbled message and that's a problem.

Image source: Screen-grab from https://www.coursera.org/learn/neurobiology/lecture/B13Z1/myelin.

🔴 Demyelinating Diseases

🔸 The #glialcells that make the myelin are of different types that make it (myelin) in the central nervous system and in the peripheral nervous system. And because of that, people who get a demyelinating disease, get it either in the central nervous system or in the peripheral nervous system -- but not in both.

🔸 So the problem is either in the #oligodendrocytes (and the interaction between the oligodendrocytes and the axon) -- in which case you get a central demyelinating disease, and the most common by far is multiple #sclerosis -- or there's a problem in the #SchwannCell and its connection to the axon, and in that case you can get a variety.

🔸 There are a diverse group of hereditary neuropathies called Charcot-Marie Tooth, which are #DemyelinatingDiseases. They're inherited and they typically progress and become worse with time.
🔸 There's also an acute demyelinating disease called Guillain–Barré, which typically has a very quick onset, it's inflammatory, and luckily it goes away after a while.

🔸 There's a barrier, a fence that is the demarcation between central and peripheral nervous-systems. And that fence is made up of three membranes, and those three membranes are the 'meninges'.
🔸 There are three meningeal layers, and the three layers go from very weak, very tender, the pia, to very tough, the dura and, in between, there's a spidery thing called the arachnoid.

🔸 The only neurons that leave the central nervous system are the neurons that serve a motor function.
They actually go out the meninges and they go into the periphery. In the periphery, there's the peripheral nervous system, and there's also the rest of the body.

🖼️ Image Source: https://www.thoughtco.com/brain-anatomy-meninges-4018883

🔸 The #meninges form a very effective barrier against toxins, viruses, against all sorts of damage, so that the peripheral nervous system tends to be far more vulnerable than the central nervous system.

🔸 In addition, the two regions have very different capacities for repair.

🔸 If you cut an axon in the peripheral nervous system, it can repair itself -- It will reconnect. If there's a traumatic injury to the central nervous system, the same does not happen. So, the ability to repair is far, far greater in the periphery than in the central nervous system.

🔸 A large molecule called botulinum toxin, which comes from spoiled food, can get in and it primarily will affect the peripheral; it will only affect the peripheral neurons. It will not get past the meninges.

🔸 #PolioVirus actually gets in right at the synapse between the motor neuron and the voluntary muscle, and it goes back. It travels back and it does a clever thing -- It gets through the meninges, but it gets through the meninges by getting in through an axon of a motor neuron. And what does it do then? For thanks, it actually kills this motor neuron. So now, that motor neuron is going to die.

🔸 Let's look at another virus: herpes zoster.
Herpes zoster is a virus that produces, what's commonly called as, #shingles. And in herpes zoster, the virus gets into the dendrites of sensory neurons, and it gets transported back inside the axon in these sensory neurons, and then it goes and lives in synaptic terminals. And if all is great, it lives in there and then it never talks again.

🔸 But, under some circumstances, the virus can decide to reproduce and blossom, and it will make copies of itself so that it actually sends it back out. And what you get is a virus all throughout the sensory territory and what you get is a rash.

#BrainTumors 🧠

🔸 One source of brain tumors is metastasis -- which are spreads from other tumors, so for instance, lung tumors.

🔸 The brain tumors are a problem because they exist within the cranium, and the cranium is a fixed, bony container. It can't expand. And as a tumor expands, the cranium is not going to expand. It's going to increase the pressure and we're going to have a problem.

🔸 Neurons don't make tumors because they don't divide at all, and they don't get into this uncontrolled division. So what makes tumors? Well, it's other cell types within the brain. And the primary one that does this are #GlialCells.

🔸 Glial cells don't have the limits on division that neurons do. So, glial cells can divide and make these tumors. And so, #gliomas, tumors of glial cells, are the most common type of brain tumor.

🔸 Another type of brain tumor is the type that comes from a division of meningeal cells, and these are called #meningiomas.

🔸 And finally, the other major type of brain tumor is are tumors that come from glandular cells.

🔸 These glandular cells are not neurons. They're gland cells, and they can divide without control. The other gland that we have in our head is called the pituitary, and these pituitary cells can also divide and that's called 'pituitary adenomas'. These #PituitaryAdenoma's are fairly common. They account for about 10 to 25% of inter-cranial tumors.

🖼️ Image source: https://images.app.goo.gl/hfXZKhrd7ahacDsx9

#PinealTumor: A pineal tumor is a tumor that forms in the pineal gland . The gland is a tiny gland in the middle of your head. It's surrounded by your brain. It makes a hormone called melatonin that affects your sleep-wake cycles. Pineal tumors are very rare tumors. They happen most often to children and to adults younger than 40.
https://www.cedars-sinai.org/health-library/diseases-and-conditions/p/pineal-tumor.html

#HypothalamicTumor: The exact cause of hypothalamic tumors is not known. It is likely that they result from a combination of genetic and environmental factors.
In children, most hypothalamic tumors are gliomas. Gliomas are a common type of brain tumor that results from the abnormal growth of glial cells, which support nerve cells. Gliomas can occur at any age. They are often more aggressive in adults than in children.
http://pennstatehershey.adam.com/content.aspx?productid=117&pid=1&gid=001211

The spinal cord and the brain make up the central nervous system.
Foramen magnum is the hole where the spinal cord comes up, and it joins and continues with the brain.
Image source: https://images.app.goo.gl/77CdugW1ym8Mun6i9

#Meninges 🧠

🧠 The dura mater, tough mother, is the most outer layer of the meninges, and inside of that layer is the #aractnoid. And the arachnoid is the filmy-like substance and it covers the entire surface of the brain. It doesn't invaginate with every hill and valley of the brain.
Pia, the final layer of the meninges, is too fine to be seen.

🧠 The dura is separated from the brain by a layer of fluid, and what that does is that it circles the brain and it in-cases the brain in this bag of fluid. So that, as the brain moves around, it's cushioned -- it can't bang against the skull because it's cushioned by the fluid.

🧠 In the #cranium, the dura is right up against the skull; there's no separation. They can't be separated, except if there's a bleed. And that is a very dangerous situation, that's a medical emergency.
If there's a bleed between the skull and dura. If there's some injury and blood gets in there that's a medical emergency.

🧠 In contrast to the situation in the cranium, where the dura is right up against the bone, the dura in the spinal cord is not up against the #VertibralColumn. So there's a lot of space. It's not up against the bone. And therefore, you can imagine that increasing pressure in the cranium is a much bigger deal.

🧠 If the dura is tough, the dural folds are doubly tough, because they are actually double, double folds -- folds made of two layers of dura.

🧠 There's a fold called the Falx Cerebri, and it goes between the two parts of the brain, between the two hemispheres.
Tentorium is the dural fold that goes between the cerebrum and the cerebellum.

🧠 The most important point of these folds, or one of the benefits of these folds, is that they separate problems, pressure problems, into three compartments.

🖼️ Image source: https://in.pinterest.com/pin/191614159128229061/?lp=true

⚡ Electrical language of cells ⚡

⚛️ In a living organism, we don't use electrons. Instead, we use molecules that have a charge, and those molecules are called ions.

⚛️ So these ions are present within the context of cells. And all cells have what are called cellular membranes, which are made up mostly of fat. It's important to understand that most of a membrane is fat. And this is like a layer of oil surrounded by a couple layers of water.

⚛️ Let's consider an ion that's positively charged, and let's consider one to be potassium ion (K+).

⚛️ This potassium ion is very happy in water, but it can't get through oil. It's not gonna pass through there. So it's gonna bounce off this membrane. And the only way for it to get through is via a special place which we're gonna call an ion channel.

⚛️ The physical force for this potassium ion is to leave the cell because of lower concentration of ions outside the cell than in the cell (osmosis).
But, on the other hand, the cell is actually negatively charged. And outside the cell is grounded.

⚛️ The potassium ion is positive and so there's an electrical force that attracts it into the cell.

⚛️ The potential at which the physical (osmotic) force and the electrical force will be equal is where the membrane is gonna sit.

⚛️ And we have to worry about three ions -- the potassium ion, the sodium ion, which is also positively charged, and chloride ion. And once we take into consideration each of these ions, what we see is that this cell is going to sit at rest at about -70 to -60 millivolts (with respect to the potential outside the cell).

⚡ Neurons sit at a resting membrane potential of about -65 mV.

⚡ Small little potential differences — which are on the order of less than one millivolt up to, say, five millivolts — can travel along the neuron.

⚡ They might travel, but they're going to peter out pretty quickly. So, it's not going to work to simply rely on these small potential changes if we have to go long distances.

⚡ The longest neuron that we possess is a cell that has a cell body right at the base of the spine. And it sends one process all the way down to the toe, and it sends another process all the way up to the medulla.

⚡ Because neurons are so long, we use something called the Action Potential. And the Action Potential goes really far up and comes back down in height. So, it's about 100 mV.

⚡ So from the resting memory potential (-65mV) to the top of the Action Potential — which happens at around, say, 20mVs or so — we're talking about roughly 100 millivolts of difference. And that can get communicated all the way up. That's not going to get lost.

⚡ And what carries that Action Potential is: —
We looked at potassium being in very high concentration in a cell and much lower outside a cell. The reverse is true for sodium.
And so, the sodium comes flooding in, and because it's positively charged, that's what takes the cell up to this very high membrane potential.

⚡ Now the ability for a neuron to communicate using an Action Potential is a slow process unless we add one more thing, and that is an insulator —essentially a very nice insulator —called myelin.

#Neurotransmitters

🧫 The synaptic terminal has these entities here, which are called synaptic vesicles, and they're small, little organelles.

🧫 They're little vesicles made of a membrane; just like the cell has a cell membrane, these vesicles have a vesicular membrane.
The neurotransmitters are within the vesicular membrane.

🧫 And, the neurotransmitter can be any number of a number of different molecules — #Glutamate, #GABA, #Serotonin, #Dopamine, #Acetylcholine, #Glycine, #Norepinephrine, #Epinephrine, #Histamine, #ATP.

🧫 The neurotransmitters are packaged in vesicles. The second thing that's important about this is that we can use the synthesis of a #neurotransmitter as a therapeutic tool.

🧫 So, for instance, Dopamine is missing in #ParkinsonsDisease.
It's not that dopamine isn't made per say, that's there's a problem with making it — it's that the cells that make it die.

🧫 There's something called 'Mass Effect', which means that you take the starting chemical (the substrate) and then through a series of enzymatic processes reaction, through a series of enzymatic reactions, we end up with a neurotransmitter.

🧫 In the case of Dopamine, what we do to treat in most people with Parkinson's is that we give them the substrate — and so that (drug) is what is commonly known as #Sinemet or #Parcopa.

🧫 So we flood the system with substrate, and the goal is to get a little bit of that neurotransmitter out of the system.

Image source: https://in.pinterest.com/pin/11962755239342046/?lp=true

🔸 How do we get the neurotransmitter out of the vesicle and out of the cell and make it able to go and affect another cell?

🔸 There is a cell membrane, but the cell also has a lot of other membranes that are inside. Inside in these things called organelles.

🔸 The fusion between two different membranes happens constitutively. And the challenge for a neuron is to stop that.
We can't have these vesicles fusing with the plasma membrane, with the cell membrane all the time. That would not work.

🔸 What we want to do is we want to make the vesicle fuse to the membrane **only when the action potential arrives** .

🔸 So the key to neurotransmitter release is two things:
1. We're going to suppress constitutive or ongoing release.
2. We are going to link the release that we want in the synaptic terminal to the action potential.

🔸 There is a molecule that suppresses constitutive release within the synaptic terminal.

🔸 When the action potential comes in, the membrane potential increases and it opens a particular type of ion channel that lets in calcium ions.

🔸 These are positively charged ions with two positive charges. And, these calcium ions are going to flood in to the synaptic terminal, and that is going to trigger release.

🔸 The release that happens of vesicles that contain neurotransmitters is only when the calcium concentration increases.

🔸 All that happens when the calcium concentration increases is that the vesicular membrane and the the cell membrane fuse.
And the calcium concentration only increases when the action potential arrives.

🖼️ Image source: screen-grab from https://www.coursera.org/learn/neurobiology/lecture/o4ZMY/neurotransmitter-release

Clostridial Toxins: #Botox

🔸 Botox is one of several clostridial toxins made by clostridial bacteria. And the full name of Botox is actually botulinum toxin.

🔸 The vesicles are held very close to the cell membrane. What holds them? A group of three proteins, two of them anchored in the cell membrane, one of them anchored in the vesicle membrane. This complex is called the snare complex.

🔸 And what happens when calcium comes in is that it changes snare complex's shape. Ca²⁺ changes snare's configuration to being in a straight line. [see GIF]

🔸 So that pushes the vesicle into the plasma membrane and fusion Is inevitable. It takes a lot of energy for them not to fuse, and when they're that close, it's inevitable.

🔸 It's the snare pin's sensitivity to calcium that is the final event that allows the vesicle to fuse with the cell membrane.

🔸 Botox comes in and cuts a particular protein of these proteins of the snare pin. But the clostridial toxins cut a variety of places in these three proteins that make up the snare pin.

🔸 If the snare pin is broken for whatever reason, if that is cut, then release doesn't happen.

🔸 Nowadays, we use clostridial toxins all the time — and we use them for very serious problems, such as focal dystonia, where there is an inappropriate continual contraction of a muscle, and that is a basal ganglia disorder.

💉 So, the Botox is injected at a very low dose, very locally.
And Botox is used for a large variety of treatments of various disorders. It's also used cosmetically.

🔸 And the interesting thing about it's use in cosmetics is that, before the widespread use of Botox, we made our own wrinkles. And what Botox is doing is preventing the motor neuron from releasing the neurotransmitter on to the muscle, and thereby preventing us from actively making our own wrinkles.

🔸 Between two neurons lie the pre-synaptic cell and the post-synaptic cell (cells with the synaptic terminal). They are separated by a short distance called the 'synaptic cleft'.
And the molecules of nerve transmitter are going to make their way from pre-synaptic cell to post-synaptic cell through the synaptic cleft.

🔸 Neurotransmitters need to have a termination, if they are not received by the post-synaptic cell. We use three different mechanisms to terminate the message of a neurotransmitter.

1️⃣ Diffusion: The molecules are simply going to diffuse out if they don't make it to the "ears" of post-synaptic terminal of the receiving neuron. So diffusion is a very effective way to terminate a message.

2️⃣ The second way is through something called re-uptake. And re-uptake is typically in the pre-synaptic terminal. There are channels, or transporters, which take neurotransmitters back up. The neurotransmitters get re-packaged and put back into a new vesicles (which are actually recycled as well).

🔸 And this is really important for drugs like #serotonin and #dopamine. And there are drugs that act on the serotonin and dopamine re-uptake transporters that can be used both therapeutically, for instance, to treat depression.

3️⃣ The third way that we terminate a message is through degradation. And in the case of degradation, what we have is enzymes that sit in the synaptic cleft that are just chewing up neurotransmitters. [GIF]

🔸 The molecule that the neurotransmitter where degradation is really important is #acetylcholine.
So, in case of acetylcholine, there is an enzyme that sits between the pre-synaptic and the post-synaptic cells, eating up acetylcholine, called acetylcholinesterase (AChE).

🔸 Acetylcholine is the neurotransmitter that is used by motor neurons. And so, in fact, blocking #acetylcholinesterase can be used for therapeutics — in the case of people that are not releasing enough acetylcholine, or don't have enough receptors for the acetylcholine.

🔸 We can boost the amount of acetylcholine in the cleft by inhibiting the acetylcholinesterase. And that's useful for people with diseases such as myasthenia gravis.

🔴 Receptors

🔸 The next hurdle is to make sure that the postsynaptic cell receives that message. And it receives the message through a type of multi-protein complexes called receptors.

🔸 The trans-membrane protein-complexes in the cell membrane form a pore, and through this pore, the ions can travel. So, the Potassium ions can go out, the Sodium ions can come in, and Chloride ions can come in.
Normally these receptors are closed and the ions can't come in. But, when a neurotransmitter binds to the receptor, or a couple of neurotransmitter molecules bind to the receptor, the receptors open and the pore becomes available for the ions to travel along.

🔸 And which way they travel? Depends on the type of receptor. And so, as it turns out, we have two basic classes of receptors.

🔸 There are receptors that have an excitatory effect. Any receptor that takes the membrane potential closer to 0 (from -65mV) is an excitatory receptor.

🔸 On the other hand, if there is a receptor that actually takes the membrane potential away from zero, making it even more negative — thus taking it away from the threshold for the action potential — is an inhibitory receptor.

🔸 The most ubiquitous excitatory receptor is a a glutamate receptor. And the most ubiquitous inhibitory receptor is a GABA receptor.

🔸 The neurotransmitter involved that binds to the inhibitory GABA receptor is a GABA molecule. And the neurotransmitter that binds to the excitatory glutamate receptor is glutamate.

🔸 In Myasthenia Gravis, there are antibodies that the body makes by mistake against these acetylcholine receptors. And so, the antibodies destroy acetylcholine receptors. And therefore, the signal is sent from the motor neuron terminal, but it is not received by the muscle.

🔸 We know that the motor neuron terminal can release acetylcholine and we need to stop degradation of acetylcholine. We're going to give acetylcholinesterase inhibitor to try and keep the acetylcholine around longer, so that it can find it's way to the few remaining acetylcholine receptors.

🖼️ Image source: https://www.khanacademy.org/science/biology/human-biology/neuron-nervous-system/a/neurotransmitters-their-receptors

🔸 There's a huge class of receptors that don't form a pore and these are called metabotropic receptors.

🔸 So, metabotropic receptors, like ionotropic receptors, will bind neurotransmitters. But they do not directly lead to an electrical change because this molecule cannot form a pore. Instead, this complex is attached to a G-protein.

🔸 Once the receptor is bound to neurotransmitters, the G-proteins are activated. And they are going to go off and do things like simulating enzymatic reactions, or they're going to bind to other molecules that are in-turn going to simulate enzymatic reactions. So these G-proteins are going to go and do things, but that means it takes time.

🔸 The second thing is that what's the effect of this? Well the effect could be to open a channel, an ion channel somewhere; it could be to close an ion channel. Or it could have no effect on the ion channels. It could just go off and actually elicit a change in the genetic transcription. So it could have an electrically silent effect on the cell. So there is a huge variation in effect.

🔸 Another thing that is different about these metabotropic receptors is that they're incredibly numerous and varied. There are more than 1000 types, while there are less than 10 types of ionotropic receptors.

🔸 Not only do metabotropic receptors take time to activate for the effect to be seen, but the metabotropic receptor amplifies — it goes through many rounds of activating these G-proteins, and so it can have a lasting effect that is pretty difficult to turn off.

🔸 Many of the drugs that we use to treat Glaucoma, motion sickness, arrhythmias, hypertension, asthma, Irritable Bowel Syndrome and so on are acting on G-protein coupled receptors. So this is a very common target for drug development.

@crackurbones and NG2 glia hang around too and contribute to scar formation and immune signaling when they don’t feel like making oligos!