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Beique - Principles of neurobiology.docx

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Jean- Claude Beique

Principles of neurobiology Beique Lecture 1 The origins of neuroscience People found skulls that contained holes in them that had partially healed. The Egyptians thought that the brain wasn’t important; they would remove it from the nostrils. Hippocrates thought that brain was the seed of intelligence. Aristotle thought it was there just to cool the body. Galen was the doctor for the gladiators, made a bunch of analysis’ of gladiators who received blows to the head, studied sheep as well, came up with cerebrum, cerebellum and ventricles – he admitted the hypothesis that the cerebellum was involved with movement and that the cerebrum was involved with sensation and perception – he was right but his conclusions as to how he came to this were trivial. The Renaissance convinced that the ventricles and the nerves were little hydraulics. Descartes thought that everything that was human was human because of God. 17 and 18 century – found the white and grey matter, they thought that every brain structure had a specific function because they realized that the th colours served different purposes. 19 century – could elicit muscle function with electrical currents, a biological phenomenon could be an electrical phenomenon – so they are not hydraulic systems. Bell and Magendie took the dorsal horn and thought that the roots leading out served different functions, they found that if you cut the ventral part it leads to muscle paralysis, if you cut the dorsal part, the animal is deprived of sensory information (muscle spasms). Flourens wanted to see what would happen if you removed certain parts of the brain. Gall idea that looking at the shape of a head you could determine personality traits – Flourens was totally against this, while he was right, he was also wrong by saying that “all regions participate equally”. Broca – brocas region related to learning. Gages story – involved in formation of explosives, it exploded in his face and a metal rod blew through his skull. Not only was he alive, he was also conscious, this was a perfect lesion in his prefrontal cortex which caused a personality switch, and he became aggressive and such. Natural selection is evident when looking at brains of our common ancestors, the brain has a historical remenance of evolution, it gives credence to the use of animal models. There is very little you can do with the human brain – ethical reasons – in modern science, there’s an inverse reason between what you want to study and what you can study. Thus we study animals. Golgi invented golgi staining in order to view neurons, Cajal wanted to disprove Golgi so copied his work but it worked so they both got the nobel prize. Kuffler and Katz believed that neurons were based on a chemical basis, however Eccles believed it was an electrical basis Lecture 2 Nissl stain labels neurons and not glial cells, it labels DNA so the nucleus. Histology is the study of tissues. We take brain tissue, slice it up and insert the Nissl stain and it will stain the neurons. Where the area is darker, there is a higher density of neurons. When looking at the cortex with the Nissl stain, it is obvious that there are different layers (6). Cell bodies typically found in layer 5 and 6 and send dendrites all the way up to 1. Pyramidal cells are found throughout these layers. Golgi stain will only stain certain cells, good to use when looking at the morphology. Apical dendrites are longer and go upwards. Basal dendrites go downwards. Axons have a constant diameter. Cajal hypothesized that neurons had an ability of plasticity. You can’t see synaptic clefts with light microscopy, but you can see is with electron microscopy because the resolution is better. You can use light microscopy to study the shape of neurons. Neurons are by far the most complicated cells in the body. The number and types of receptors that neurons have in their membrane determines what they do. Membrane proteins will be made in rough ER. Neurons have a huge energy requirement, the making of the gradient costs a lot of energy, high supply of mitochondria. Protein concentration differs depending where it is positioned. The cytoskeleton is not static, they are constantly moving, when you increase the activity, the neurons will increase in number. Axons are not linear; they can have axon collaterals which are protrusions of axons that are travelling to other regions of the body. One neuron can innervate many things. There is no ER in the axon. At a central synapse, you will have 0 to 1 vesicle release by action potential. Anterograde transport is from the nucleus to the terminal. Retrograde transport is from the terminal to the nucleus. Analogue signal is continuous in time. Digital signal is discontinuous in time. Neurons are converters, the dendrites receives all the information from other neurons and has to decide whether to shoot an action potential, this is an example of analogue signal. But the action potential itself is a digital signal, it is all or none, it carries information in time. Neurites are axons and dendrites. Spines are the site of excitatory transmission, but you can also have these transmissions on aspinous axons. Pyramidal cells in the somatosensory cortex and visual cortex are extremely similar. Interneurons are within the cortex but make contacts with their close neighbors, they almost always release GABA. Astrocytes are the main type of glial cells, there are pretty much found all over the brain. The glutamate synapse is the essential transformation of information in the brain. Glial cells participate in this; they activate receptors to clear the glutamate so that if another event enters, the body needs to differentiate between the 2. So glutamate is actively being cleared from synapses by glial cells. Myelin sheaths are made from oligodendrocytes and form concentric circles. Microglia act as phagocytic cells and function with the immune system. Lecture 3 – the neuronal membrane at rest **describe a membrane at a resting potential One of the things that neurons do is that they transmit information via the neural code. This is action potential discharge. Neurons are resting at -60mV. The neural code is the amount of information that is being transferred and this will determine if it should fire an action potential or not. Water is a polar solvent; the ions are not evenly distributed. If we take NaCl and we let it dissolve in water, the affinity for the Cl- molecules has a higher affinity for positive ions (H) than the negative ions (O). In the membrane we have ion channels and they need to be able to differentiate between ions. They can only however recognize different ions when they are in contact with water. To make a transmembrane protein, 5 subunits come together (common) with a hole in the middle forming a pentamere. Protein channels contain distinct termini. Typically the N terminus will be found on the outside and the C terminus on the inside of the lipid bilayer. These channels open and close (gating). Channels are different than gates. Channels allow simple diffusion – passive. Whereas pumps need a concentration gradient – active, require energy. Electricity – resistance is the same as conductance but they are the opposite. Batteries generate power across a resistance. The resistance through a bilayer is infinite. If we put holes in through the bilayer, the current will flow through these pumps. I=gV, if g and V increase then I increases as well, where g = resistance and V = voltage. If you stick an electrode in a neuron, the potential difference will typically give you a negative result, which means that one side of the membrane is more positive than the other side. We know that the inside is less positive (or negative) than the inside. The concentration on either side of the membrane is offset by the concentration of K. because the concentration of potassium is usually higher on the inside of the membrane, it will have the tendency to flow through its pump towards the outside (going down its concentration gradient) which will then make the inside of the membrane more negative. We always refer to an electrical chemical gradient because ions are charged. At this point, the membrane is at equilibrium and this is the resting membrane potential. But there is a constant competing force because the potassium will then want to flow into the cytosol. Equilibrium brings on the driving force which is determined by V -Em ion.f your cell is at equilibrium potential for potassium (-80mV), and we open the potassium channels, the driving force will be 0 because there will be no flow. The equilibrium potential is determined by the charge and the concentration. If you have a combination of monovalent and divalent ions, this can cause an issue with the reversal potential. Know the terms of the Nernst equation. Have a rough idea of the reversal potential. So you have a high concentration of a positive charge (potassium) inside of the cell at a resting membrane potential. The resting membrane potential of the cell is going to go towards -80mV. For sodium, you have a higher concentration on the inside of the cell, if you have a pump that is more permeable towards sodium, then the resting membrane potential will be 62mV. Potassium channels are almost always open and sodium channels open for short periods of time. All of the behaviour of neurons is determined by the concentration of ions which can be determined with the Nernst equation. For calcium, there is less calcium than potassium outside the cell. Sodium and calcium have similar behaviours, when the channels open; the potential will want to go towards the reversal. For chloride, the concentration is higher on the inside than the outside (opposite of K, but similar to Ca and Na) but the reversal potential is similar to K – this is because Cl is an anion. The sodium-potassium pumps are slower than the ion channels and they require energy. 70% of the brains consumption of ATP is due to these pumps. They pump 3 Na ions out and 2 K ions in at the same time. So when that sodium pump is open for that split second, pushing sodium out, this also cause potassium to enter. When potassium channels are open, the conductance is high. Sodium at rest is 0. A depolarization occurs when there is added potassium on the outside of the cell – it gets less negative. If you give someone an excessive amount of potassium, this will cause a depolarization and this will kill someone. Glial cells (astrocytes) buffer changes in potassium. Lecture 4 – action potential Hodgkin and Huxley had access to squids in which they could use to study electrophysiology. The giant squid has a giant reflex axon, and bc they were so big, they were experimentally favorable. The studies they performed on the squid ended up being very similar to the human. These guys built oscilloscopes to view action potentials. An action potential starts off when the neuron is depolarized, but the neuron starts off in its resting potential. The depolarization is caused by a current, once, and only when it meets its threshold, will an action potential occur. Action potentials are non-linear. Once the depolarization reaches its threshold, an overshoot will occur, which is an all or none result. Following this, there will be undershoot which will fall underneath the resting membrane potential. This process takes about 3ms to 1ms. To view action potentials artificially, we can insert electrodes which inject current. Direct current injection will cause several action potentials. If we were to block sodium channels, the neurons will act more like a passive structure (similar to injecting current in a blob of lipid), therefore there won’t be any depolarization beyond threshold, and therefore there will be no action potentials. Voltage dependant channels are active conductors. Firing frequency reflects the magnitude of the depolarizing agent. So if we add a little bit of current, threshold won’t be reached so it will plateau at around -70mV. The more current you inject, the cell will give rise to a linear firing action potential. Membrane and conductance can be used interchangeably. Using the Nernst equation, g determines the conductance. If the conductance for potassium is 0, there will be no action potential. If we open up gk, we want to know how much potassium will flow in; this is determined by the conductance and the driving force. At rest, your conductance for potassium is much higher than sodium. Once there is depolarization, the conductance for sodium surpasses the conductance for potassium. Once it reaches the peak, we have mechanisms that will bring it down, this is necessary because the information needs to be transferred very quickly. The mechanism used is the opening of potassium channels (differ from resting potential), the membrane potential will want to go to equilibrium of potassium which is -80mV therefore it will drop. Eventually the sodium channels will close which will cause the hyperpolarization or undershoot. Some of the potassium channels will close and we will go back to resting membrane potential. When putting an electrode in a neuron, you have 2 options, voltage clamp or current clamp. For voltage clamp, the amp clamps the cell at a certain voltage and keeps it there. So if you clamp it a -40mV, then all the sodium channels will open, but the clamp needs to do something in order to keep it at -40mV. Looking at the structure of the ion channels, they contain pore loops which confer specificity. Somehow, in their structure, there is a voltage sensor that is able to transduce potential difference in some sort of physical movement in order for the charges to go through. The voltage sensor is embedded in the membrane so that when there is charge accumulation around the membrane, there is a tiny movement by S4 which allows the ions to pass through. The membrane of the channels are sensitive to the size of the hydrated ions (K is bigger than Na). When studying these channels, you can insert electrodes and pick the conductance and observe the behaviour of these channels. When you put the conductance to -40mV, the sodium channels open for a very brief period of time, but do not open again because they are gated and will thus be blocked. This is due to the fact that there is a refractory period, so during depolarization, they cannot be re depolarized. There are a variety of toxins implicated in voltage-gated sodium channels. For example, a toxin coming from a buttercup, aconitine, lowers the activation threshold. Because this is more easily obtained, more action potentials will fire. The pump is responsible for making the Ek at -80mV at resting potential. Once the action potential has reached its peak, the potassium channels open in response to the depolarization, as do sodium, however they are delayed. The use of this is to rectify the membrane – it wants to go back to equilibrium. The absolute refractory period occurs when sodium channels are inactivated, they are gated. The relative refractory period occurs during undershoot phase. During undershoot, it is more difficult to reach the firing potential threshold which is the relative refractory period. When sodium channels open and sodium rushes in, this is current. Potassium channels open longer and slower than sodium. So K is responsible for rectifying the action potential. Lecture 5 L5 – Synaptic Transmission Synaptic transmission • Information transfer at a synapse • 1897 – Charles Sherrington – coined term synapse • Chemical and electrical synapse o 1921 – Otto Loewi – Vagusstoff – acetylcholine; saline from one frog heart preparation slowed another heart in another bath o 1959 – Furshpan and Potter – first example of a clear electrical synapse in a crayfish Types of Synapses • Direction of information flow o One direction – neuron to target cell o First neuron – presynaptic neuron o Target cell – postsynaptic neuron • Electrical synapses – very fast transmission • Chemical synapses – majority of synapses in brain o Somewhat slower, generates postsynaptic potentials (PSPs) o Synaptic integration – several PSPs occurring simultaneously to excite a neuron (causes action potential) Electrical synapses • Gap junction o Channel – 1 connexon from both cells form the channel for ions to pass through  Connexon – formed by 6 connexins • Cells are said to be electrically couples o Flow of ions from cytoplasm to cytoplasm – no delay in time when measuring electrical synapses between cells Chemical synapses The neuromuscular junction (NMJ) • Studies of NMJ established principles of synaptic transmission – multiple synapses off of axon attaching to muscle Soup vs. spark – Katz – basic principles of synaptic transmission CNS synapses (examples) • Axodendritic – axon to dendrite – primary synapses • Axosomatic – axon to cell body – mainly inhibitory synapses • Axoaxonic – axon to axon – can modulate excitability of axons • Dendrodendritic – dendrite to dendrite – rare and specialized • Grays type I – asymmetrical, excitatory – postsynaptic terminal is thicker then presynaptic • Grays type II – symmetrical, inhibitory Chemical synapse structure: • Post synaptic density – receptors filled with scaffolding proteins between pre and post synaptic terminals o Contains the neurotransmitter receptors which convert the intercellular chemical signal (neurotransmitter) into an intracellular signal (action potential) in the postsynaptic cell o On glutamate excitatory synapses – grays type I Principles of chemical synaptic transmission • Basic steps o Neurotransmitter synthesis o Load neurotransmitter into synaptic vesicle – takes energy o Vesicle fuse to presynaptic terminal o Neurotransmitters spills into synaptic cleft – following a signal o Binds to postsynaptic receptors o Biochemical/ electrical response elicited in postsynaptic cell o Removal of neurotransmitter from synaptic cleft • Neurotransmitters o Amino acids – small organic molecules – glutamate (excitatory), glycine (mainly inhibitory in spinal cord), GABA(inhibitory) – not used to make proteins so evolution used them to make neurotransmitters o Amine – small organic molecules – dopamine, acetylcholine, histamine o Peptides – short amino acid chains (proteins) stored in and released from secretory granules – dynorphin, enkephalins • Neurotransmitter synthesis and storage o Amines, amino acids, peptides – need to be synthesized and stored – happens in vesicle  Precursor molecule with synthetic enzymes make neurotransmitter and package them in vesicles which are waiting and ready fro release • Neurotransmitter release o Exocytosis – process by which vesicles release their contents o Mechanism  Proce
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