So, I recently got interested in neuroscience and decided to learn more. Having had no formal training in neurobiology before, I just registered for this course on Coursera.
coursera.org/learn/neurobiolog
Let's see how it goes.

There's only one type of neurons that leaves the central nervous system (CNS) and goes directly to muscles, and that's the motor neuron.
There are a hundred thousand out of 200B neurons in the CNS.
The motor neurons are contained either in the brain stem or in the spinal chord. But, there are no motor neurons in the forebrain.

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Perception -- the conscious perception of sensory inputs, the conscious appreciation of sensory inputs -- depends entirely on the forebrain.
The conscious appreciation of sensory inputs depends on the cerebral cortex.

Homeostasis is a distributed process, which depends on forebrain, brain stem and spinal chord.
The contribution of forebrain to homeostasis is hormonal. The contribution of brain stem is through autonomic changes (changes we are not consciously in control of) as well as through consciously made movements.
Same is true for spinal chord.

Higher Abstract Functions depend entirely on forebrain.

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Neurons have four parts. The first is the cell body, also called the Soma. And this is the part that all cells have, this is cell central.

The cell body has coming out it from a number of dendrites, and these dendrites branch. And they continue to branch. And so, that makes a tree which we call the dendritic arbor or the dendritic tree.

And these dendrites are responsible for gathering in information. They're the sentries. They are the ears of the cell, of the neuron. They're taking in all information. So information is going in to the dendrites.

Axon carries the information along the length of it.

Neurons talk to neurons. But neurons also, go talk to muscles. And neurons talk to glands. And neurons talk to the cardiac, to the heart, to the cardiac muscle and so on.

Source of image: courses.lumenlearning.com/boun

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This is the axon and you can see that it gives off these little terminals, and it also has places where there's just simply a swelling on root. So these are all synaptic, these swellings are synaptic terminals. The long slender projection of the nerve cell is an axon.

Image source: screenshot at 5:44 from coursera.org/learn/neurobiolog

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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'.

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

**Different types of Glia:**

๐Ÿ”ธ 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 and their metabolites.

They also are very important during development. They allow neurons to get to where they have to go during development. 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 .

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 . So, there's a lot of structural and metabolic support that the Astrocytes are providing for neurons.

๐Ÿ”ธ Oligodendrocytes and Schwann Cells: The make myelin in the CNS and the make it in the Peripheral Nervous System. So all these demyelinating diseases will affect either central myelin or peripheral . 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.

๐Ÿ”ธ 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.

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๐Ÿง  Myelin is a fatty wrap that goes around some axons.

๐Ÿ”ธ 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.

๐Ÿ”ธ Now, once we put on , 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.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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 , they can actually jump.

๐Ÿ”ธ And now, if we have a , 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.

๐Ÿ”ธ 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 coursera.org/learn/neurobiolog.

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๐Ÿ”ด Demyelinating Diseases

๐Ÿ”ธ The 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.

๐Ÿ”ธ So the problem is either in the (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 -- or there's a problem in the and its connection to the axon, and in that case you can get a variety.

๐Ÿ”ธ There are a diverse group of hereditary neuropathies called Charcot-Marie Tooth, which are . They're inherited and they typically progress and become worse with time.
๐Ÿ”ธ There's also an acute demyelinating disease called Guillainโ€“Barrรฉ, which typically has a very quick onset, it's inflammatory, and luckily it goes away after a while.

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๐Ÿ”ธ 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'.
๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ–ผ๏ธ Image Source: thoughtco.com/brain-anatomy-me

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๐Ÿ”ธ The 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.

๐Ÿ”ธ In addition, the two regions have very different capacities for repair.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ”ธ Let's look at another virus: herpes zoster.
Herpes zoster is a virus that produces, what's commonly called as, . 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.

๐Ÿ”ธ 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.

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๐Ÿง 

๐Ÿ”ธ One source of brain tumors is metastasis -- which are spreads from other tumors, so for instance, lung tumors.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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 .

๐Ÿ”ธ Glial cells don't have the limits on division that neurons do. So, glial cells can divide and make these tumors. And so, , tumors of glial cells, are the most common type of brain tumor.

๐Ÿ”ธ Another type of brain tumor is the type that comes from a division of meningeal cells, and these are called .

๐Ÿ”ธ And finally, the other major type of brain tumor is are tumors that come from glandular cells.

๐Ÿ”ธ 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 's are fairly common. They account for about 10 to 25% of inter-cranial tumors.

๐Ÿ–ผ๏ธ Image source: images.app.goo.gl/hfXZKhrd7aha

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: 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.
cedars-sinai.org/health-librar

: 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.
pennstatehershey.adam.com/cont

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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: images.app.goo.gl/77CdugW1ym8M

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๐Ÿง 

๐Ÿง  The dura mater, tough mother, is the most outer layer of the meninges, and inside of that layer is the . 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.

๐Ÿง  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.

๐Ÿง  In the , 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.

๐Ÿง  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 . 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.

๐Ÿง  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.

๐Ÿง  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.

๐Ÿง  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.

๐Ÿ–ผ๏ธ Image source: in.pinterest.com/pin/191614159

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โšก Electrical language of cells โšก

โš›๏ธ In a living organism, we don't use electrons. Instead, we use molecules that have a charge, and those molecules are called ions.

โš›๏ธ 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.

โš›๏ธ Let's consider an ion that's positively charged, and let's consider one to be potassium ion (K+).

โš›๏ธ 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.

โš›๏ธ 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.

โš›๏ธ The potassium ion is positive and so there's an electrical force that attracts it into the cell.

โš›๏ธ The potential at which the physical (osmotic) force and the electrical force will be equal is where the membrane is gonna sit.

โš›๏ธ 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).

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

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

โšก 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.

โšก 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.

โšก 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.

โšก So from the resting memory potential (-65mV) to the top of the Action Potential โ€” which happens at around, say, 20mVs or so โ€” 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.

โšก And what carries that Action Potential is: โ€”
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.

โšก 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 โ€”essentially a very nice insulator โ€”called myelin.

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๐Ÿงซ The synaptic terminal has these entities here, which are called synaptic vesicles, and they're small, little organelles.

๐Ÿงซ 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.

๐Ÿงซ And, the neurotransmitter can be any number of a number of different molecules โ€” , , , , , , , , , .

๐Ÿงซ The neurotransmitters are packaged in vesicles. The second thing that's important about this is that we can use the synthesis of a as a therapeutic tool.

๐Ÿงซ So, for instance, Dopamine is missing in .
It's not that dopamine isn't made per say, that's there's a problem with making it โ€” it's that the cells that make it die.

๐Ÿงซ 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.

๐Ÿงซ In the case of Dopamine, what we do to treat in most people with Parkinson's is that we give them the substrate โ€” and so that (drug) is what is commonly known as or .

๐Ÿงซ 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: in.pinterest.com/pin/119627552

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๐Ÿ”ธ 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?

๐Ÿ”ธ There is a cell membrane, but the cell also has a lot of other membranes that are inside. Inside in these things called organelles.

๐Ÿ”ธ 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.

๐Ÿ”ธ What we want to do is we want to make the vesicle fuse to the membrane **only when the action potential arrives** .

๐Ÿ”ธ 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.

๐Ÿ”ธ There is a molecule that suppresses constitutive release within the synaptic terminal.

๐Ÿ”ธ When the action potential comes in, the membrane potential increases and it opens a particular type of ion channel that lets in calcium ions.

๐Ÿ”ธ 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.

๐Ÿ”ธ The release that happens of vesicles that contain neurotransmitters is only when the calcium concentration increases.

๐Ÿ”ธ 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.

๐Ÿ–ผ๏ธ Image source: screen-grab from coursera.org/learn/neurobiolog

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Clostridial Toxins:

๐Ÿ”ธ Botox is one of several clostridial toxins made by clostridial bacteria. And the full name of Botox is actually botulinum toxin.

๐Ÿ”ธ 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.

๐Ÿ”ธ And what happens when calcium comes in is that it changes snare complex's shape. Caยฒโบ changes snare's configuration to being in a straight line. [see GIF]

๐Ÿ”ธ 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.

๐Ÿ”ธ It's the snare pin's sensitivity to calcium that is the final event that allows the vesicle to fuse with the cell membrane.

๐Ÿ”ธ 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.

๐Ÿ”ธ If the snare pin is broken for whatever reason, if that is cut, then release doesn't happen.

๐Ÿ”ธ Nowadays, we use clostridial toxins all the time โ€” 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.

๐Ÿ’‰ 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.

๐Ÿ”ธ 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.

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๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

1๏ธโƒฃ 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.

2๏ธโƒฃ 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).

๐Ÿ”ธ And this is really important for drugs like and . 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.

3๏ธโƒฃ 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]

๐Ÿ”ธ The molecule that the neurotransmitter where degradation is really important is .
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).

๐Ÿ”ธ Acetylcholine is the neurotransmitter that is used by motor neurons. And so, in fact, blocking can be used for therapeutics โ€” in the case of people that are not releasing enough acetylcholine, or don't have enough receptors for the acetylcholine.

๐Ÿ”ธ 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.

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๐Ÿ”ด Receptors

๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ”ธ And which way they travel? Depends on the type of receptor. And so, as it turns out, we have two basic classes of receptors.

๐Ÿ”ธ There are receptors that have an excitatory effect. Any receptor that takes the membrane potential closer to 0 (from -65mV) is an excitatory receptor.

๐Ÿ”ธ On the other hand, if there is a receptor that actually takes the membrane potential away from zero, making it even more negative โ€” thus taking it away from the threshold for the action potential โ€” is an inhibitory receptor.

๐Ÿ”ธ The most ubiquitous excitatory receptor is a a glutamate receptor. And the most ubiquitous inhibitory receptor is a GABA receptor.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ–ผ๏ธ Image source: khanacademy.org/science/biolog

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๐Ÿ”ธ There's a huge class of receptors that don't form a pore and these are called metabotropic receptors.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ”ธ 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.

๐Ÿ”ธ Not only do metabotropic receptors take time to activate for the effect to be seen, but the metabotropic receptor amplifies โ€” 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.

๐Ÿ”ธ 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.

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๐Ÿ”ธ The enteric nervous system is one that's shared throughout the vertebrates. And it lines the digestive track โ€” from the esophagus through the stomach, through the small intestine, And then through the large intestine and down to the anus.

๐Ÿ”ธ And throughout that length, there are intrinsic neurons that sit in the lining in the gastrointestinal tract. And these neurons form the enteric nervous system. And there are about 100 million.

๐Ÿ”ธ These intrinsic neurons form two different plexuses.

๐Ÿ”ธ One of the plexuses, called 'peristalsis', is responsible for pushing the contents of the digestive tract through the pathway from mouth to anus. The other plexuses are responsible for secreting stuff, such as making our feces either more or less watery.

๐Ÿ”ธ The way that this enteric nervous system works is that it's very automatic. This is the most automatic of the autonomic nervous system. We're not doing anything conscious to push the food through, from esophagus to anus. That's all taken care of by the enteric nervous system (ENS).

๐Ÿ”ธ As you may imagine, if you don't have an enteric nervous system, then food doesn't get pushed through. And that actually happens in a disease called Hirschsprung's disease.

๐Ÿ”ธ is identified at birth. So the newborn babies have Hirschsprung's because a section of the GI tract is aganglionic โ€” it has no neurons.
And therefore, it's just contracted. And everything can push down, but it can't push through that contraction. This has to be fixed surgically. Another name for Hirschprung's is . They got in this enlarged colon, because nothing's going through.

๐Ÿ”ธ While the ENS is completely able to do all of this peristalsis stuff on its own, it does interact with the central nervous system. There is information going to the central nervous system โ€” a lot of information. And there's some information coming from the CNS to the ENS. This is all coming to it through the parasympathetics and the sympathetics.

๐Ÿ”ธ The information coming out of the enteric nervous system is about ten times more than the information that's going to the enteric nervous system. The information that comes from the digestive tract is telling us about whether we feel full, whether we just ate a large meal and our abdomen is distended, whether we feel gassy, whether we feel hungry, whether we feel good. It, it is telling us about the state of our GI tract.

๐Ÿ”ธ The information going to the to the enteric nervous system is a way by which our mood can now influence our GI functioning.
And this is the way that if you get very nervous or excited, you may notice a difference in your bowel movements. [ so relatable for me! ]

๐Ÿ”ธ There's an interaction between the way our digestive tract feels and the way we feel emotionally. Not surprisingly many psychiatric diseases are associated with certain GI issues as well.

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๐Ÿ”ด The sympathetic and the parasympathetic systems.

๐Ÿ”ธ These are two different systems, but they both work through two chain neurons. They're both automatic. And they're both motor systems that are targeting three different types of tissues โ€”smooth muscle, cardiac muscle, and glands.
They're working to produce different functional ends.

๐Ÿ”ธ The sympathetic system comes entirely from neurons in the thoracic cord.

๐Ÿ”ธ The parasympathetic system from two places โ€” the cranium through cranial nerves and also from the sacral cord.
And so because of that, this is often called the craniosacral system โ€” the parasynthetics or the craniosacral system.

๐Ÿ”ธ The parasympathetics intervate the heart, and they drive heart rate down. The sympathetics intervate the heart and they drive heart rate up.

๐Ÿ”ธ The parasympathetics come out of the cranium to innervate the eye. And they make the pupil small. And the sympathetics come out and they make the pupil big. So they're working in opposition.

๐Ÿ”ธ So the sacral cord is innervating three tissues โ€” it's innervating the bladder, the colon, and the sexual organs.

๐Ÿ”ธ And the thoracic cord innervates those too, but they do different things. For instance, the parasympathetics are critical to sexual arousal whereas the sympathetics are critical to sexual climax.

๐Ÿ”ธ The sympathetics have a few special places that only they innervate โ€” sweat glands, cutaneous (pertaining to skin) blood vessels, adrenal medulla, piloerection.

๐Ÿ”ธ Sweat glands are turned on by the sympathetic system and there's no turning them off, for instance, by the parasympathetics. The parasympathetics have nothing to do with the sweat glands.

๐Ÿ”ธ The point of the cutaneous blood vessels is whether they are constricted or dilated. And the parasympathetics have nothing to do with that. The sympathetics completely control that.

๐Ÿ”ธ So, for instance, as you're exercising, you build up heat, start sweating, and you also dilate your vessels to release heat into the environment.

๐Ÿ”ธ Another consequence of whether there is more or less blood going to the skin is whether your blood pressure is going to go up or down.

๐Ÿ”ธ So, if you send a lot of blood into your skin, blood pressure will go up and if you constrict your skin blood vessels your blood pressure will go down. And that's a major way in which we control blood pressure.

๐Ÿ”ธ The final tissue that is only innervated by the sympathetics is the adrenal medulla. And the adrenal medulla is the organ the, the gland that pumps out cortisol, a stress hormone which is lacking in people with Addison's disease.

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๐Ÿ”ธ The parasympathetic and the sympathetic systems are commonly known as 'fight or flight' and 'rest or digest' โ€” and that's true, if we were always at full sympathetic tone or at full parasympathetic tone.
That's not the case. Usually, we're somewhere in the middle.

๐Ÿ”ธ We can go sympathetic or parasympathetic according to the needs of the moment, but as we go from being born to old age, we are moving in a steady direction towards more sympathetically dominated.

๐Ÿ”ธ Young kids are very parasympathetically dominated. Now, once you get into older age, the sympathetic domination is going to drive up heart rate and it's going to drive up blood pressure โ€” that sounds like hypertension.

๐Ÿ”ธ Nothing's changed in old people from childhood, except that now they're sufficiently sympathetically dominated that they've encountered this hypertension.

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๐Ÿ”ด Autonomic Pharmacology: Adjusting the PS/S System

๐Ÿ”ธ Instead of as in the skeletal motor system where there's one motor neuron that goes and enervates a skeletal muscle, autonomic systems get to the target by two neurons.

๐Ÿ”ธ The first neuron sits in the central nervous system. We call it the preganglionic motor neuron, and it contacts a motor neuron that sits in an autonomic ganglion.
And in both the case of the parasymptathetic preganglionic and the sympathetic preganglionic โ€” they're both using acetylcholine.

๐Ÿ”ธ So, all motor neurons use acetylcholine. And all motor neurons going to the post-synaptic target โ€” whether it's the skeletal muscle or whether it's a ganglion cell โ€” is going to express a nicotinic acetylcholine receptor. This is a fast ionotropic receptor โ€” it's going to very instantly give a response.

๐Ÿ”ธ The sympathetic preganglionic neuron goes to a ganglionic neuron which expresses this nicotinic acetylcholine receptor.

๐Ÿ”ธ The parasympathetic preganglionic also goes to a ganglionic neuron that expresses a nicotinic acetylcholine receptor. And there, the two systems diverge.

๐Ÿ”ธ In the parasympathetic system, we stay with acetylcholine as our neurotransmitter. The ganglionic neuron sends a post-ganglionic axon, which is an unmyelinated axon that goes to one of the three targets โ€” smooth muscle, cardiac muscle, or gland. And it is going to release acetylcholine.

๐Ÿ”ธ There's a difference between the release of acetylcholine at the terminal of ganglionic neuron and the release of acetylcholine at the terminal of post-ganglionic axon.
And the difference is that the targets (e.g.: smooth muscle) are always expressing as metabotropic (very slow) indirect receptors.

๐Ÿ”ธ They're acetylcholine receptors, but they're muscarinic, as opposed to nicotinic.
Each of these targets is going to express a different muscarinic receptor. The effect is that the transmission is slow.

๐Ÿ”ธ Now, in the sympathetic system, once we get to the ganglion, we switch to norepinephrine (NE).

๐Ÿ”ธ So, norepinephrine is contained in the ganglionic neurons, and they send an axon, and again, an unmyelinated post-ganglionic axon that enervates one of the three targets โ€” smooth muscle, cardiac muscle, or gland.

๐Ÿ”ธ These receptors that receive the message of norepinephrine are also metabotropic, and so therefore, they are also slow.

๐Ÿ–ผ๏ธ Image source: Screen grab from coursera.org/learn/neurobiolog

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๐Ÿ’Š We treat things by either imitating or blocking the post-ganglionic neurotransmitter.

๐Ÿ’Š So, for instance, if we want to imitate a parasympathetic effect, we're going to give a drug that acts like acetylcholine, that acts like acetylcholine at muscarinic receptors.

๐Ÿ’Š If we want to stop a parasympathetic effect, we're going to block a muscarinic receptor.

๐Ÿ’Š So, things that act like a neurotransmitter are called agonists, and things that block the effects of neurotransmitters are called antagonists.

๐Ÿ’Š Secretions are a very parasympathetic effect; we secrete stuff because we're going to go and try and digest stuff.

๐Ÿ’Š And so, if we want to reduce secretions, we're going to try and block the effect of the muscarinic receptors. So, we're going to antagonize that muscarinic receptor.

๐Ÿ’Š The group of drugs that we use, in general, to treat hypertension are called beta-blockers.
They're beta-blockers because they block the beta version of the adrenergic receptors (metabotropic receptors that receive information from norepinephrine are called adrenergic receptors).

๐Ÿ’Š The drugs that act on the parasympathetic system either to mimic it or to block it, they stay peripheral.

๐Ÿ’Š They have no effect on the brain other than an indirect effect.
They might make you feel dry, you'll get dry mouth, dry eyes, and that might make you, put you in a bad mood โ€” but it's not a direct effect. They're not acting on the brain.

๐Ÿ’Š In contrast, drugs that act on the sympathetic system tend to also have psychotropic effects, they also act in the central nervous system.

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๐Ÿ”ด SPINAL CORD INJURY

๐Ÿ”ธ While the sympathetic nervous system is entirely contained within the thoracic cord (all the preganglionic neurons are in the thoracic cord), the parasympathetic preganglionics are split between the brain stem and the sacral cord.

๐Ÿ”ธ And this has one very important consequence โ€” for virtually any spinal cord injury, it doesn't matter where, any lesion that is anywhere near complete is going to isolate the sacral cord.

๐Ÿ”ธ Now, the sacral cord does not make decisions. The spinal cord does not make decisions. It depends on input from the brain.

๐Ÿ”ธ So, for example when an individual wants to wants to void urine, there is a whole part of front, pre-frontal cortex which decides micturation to occur.

๐Ÿ”ธ The sacral cord is responsible for executing micturation, but it's not responsible for making the decision.

๐Ÿ”ธ So, if we have a lesion somewhere in the chord that's rostral (towards the brain) from sacral cord, the sacral cord no longer has instructions from the brain.

๐Ÿ”ธ Under normal circumstances micturition depends on two things:
1๏ธโƒฃ The bladder, which is a smooth muscle, is contracted And it's contracted by neurons in the sacral cord, which is a parasympathetic effect. Parasympathetic neuron contacts a ganglionic neuron in the wall of the bladder, and that ends up contracting the the bladder wall.
2๏ธโƒฃ In addition there's an external urethral sphincter that has to relax in order to let the urine out. And that is a voluntary muscle that your brain controls.

๐Ÿ”ธ Now, in the case of a spinal cord injury, the sacral cord is on its own. So, as the bladder fills up, it starts to contract. It will contract. But this will never relax.

๐Ÿ”ธ And so, what you have is the bladder contracting against a fixed, tight, closed sphincter. This is called "bladder dyssynergia". And it is a huge problem in spinal cord injury.

๐Ÿ”ธ If somebody suffers from a spinal cord injury, a physician is going to make sure, is going to test, whether, the person is able to void urine or not. And if they're not, they're going to need medical intervention immediately.

๐Ÿ‘๏ธ Up in the most rostral part of the thoracic column that provides pregangloinics to the sympathetics, our preganglionics go to the eye. They go to the pupil they go to a few other places, but they also go to this eyelid.

๐Ÿ‘๏ธ The eyelid has two different muscles in it.
It has a muscle which is called "levator palpebrae", which is innervated, is a skeletal muscle and is voluntarily controlled; so, it has a voluntary muscle.
And it has a muscle in the back which is called the "superior tarsus", and the superior tarsus is a smooth muscle.

๐Ÿ‘๏ธ So, the superior tarsus is innervated by the sympathetics. And so, when you're asleep, having very low sympathetic tone โ€” your eye closes.

๐Ÿ‘๏ธ When you wake up, sympathetic tone automatically comes up to some minimum, including a contraction of the superior tarsus, and up comes your eyelid.

๐Ÿ–ผ๏ธ Image source: screen-grab from coursera.org/learn/neurobiolog

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๐Ÿง  The emotion is executed by the autonomic nervous system in large part โ€” not exclusively but in large part. And that in turn, the body-experience influences our emotions.

๐Ÿง  Under normal circumstances memories are made primarily about emotional events.
So, emotion is a great facilitator of memory formation.

๐Ÿง  So, every time we remember something, we actually make that memory again. We make the initial memory and then we reconsolidate that memory.

๐Ÿง  So, using just that information you can now understand why now some health professionals are treating post traumatic stress disorder by exposing individuals with to a trigger in the presence of a beta blocker.

๐Ÿง  The beta blocker is preventing the sympathetic arousal, preventing the heart rate increase, and preventing the blood pressure increase.

๐Ÿง  So now, you've triggered a memory. But the person can't get all worked up about it โ€” their body is unresponsive. We pharmacologically prevented that arousal.
And consequently now, when they remember it, they reconsolidate it without all that body memory.

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@crackurbones This is an amazing writeup!!

I have always tried to rewire painful memories by trying to remember a different version of them. Hoping to you know overwrite them. Or altogether eliminating things from them. Like literally remembering moments with an individual blurred out or pixelated,

I would not recommend it. Constantly visualising a conflicting version of your past really screws things up.

It gave me full blown psychosis. But I cannot say for certain that these visualisations were the reason. Just a hunch

Hey, @Full_marx! Glad to see you again. Long time. I thought you left QOTO.

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@crackurbones Ah no just cutting out distractions and increasing the time I spend learning how to code.

But with this quarantine, time is my bitch so why not.

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