Class 3: The Nervous System Part 2 PDF

Class 3: The Nervous System Part 2 Neuron physiology Receptors & Neurotransmitters Main neurotransmitter systems [email protected] Karim Benchenane Team Memory, Oscillations and Brian states ESPCI – PSL Univers...

Class 3: The Nervous System Part 2 Neuron physiology Receptors & Neurotransmitters Main neurotransmitter systems [email protected] Karim Benchenane Team Memory, Oscillations and Brian states ESPCI – PSL University  How will be organized the course ? Overview of Brain function and exploration the major current questions in neuroscience: transitioning from a bottom-up approach, focusing on concepts like receptive fields, to top-down approach viewing the brain as a predictive machine. Fundamental bases necessary for the study of Neuronal Networks and Behavior Description of the nervous system : physiology of the neuron, antomy, plasticity, main cognitive function (perception, motor, memory, spatial navigation, attention, sleep) For each brain function : properties, anatomy, related-brain activity, effect of lesion, experimental manipulation, related neuronal network activity with related local network activity. Main methods to study Cognitive function with neuroscientific tools ✓ EEG, MEG: main principles, mains evoked reponse, main oscillations, ✓ fMRI, fUS : principle, experimental design, connectivity, ✓ Electrophysiological recording, calicum imaging, fiber photometry ✓ Neuropsychology, lesion studies ✓ Exeprimental manipulation (TDCS, TMS, intracranial stimulation, optogenetics) "Inverted Classroom: Exploring Neuroscience in Societal Controversies »  "Inverted Classroom: Exploring Neuroscience in Societal Controversies" Antidepressant and the MBTI - Personnality tests Opioid crisis serotonin controversy The Myers–Briggs Type Indicator (MBTI) is a pseudoscientific questionnaire that claims to indicate differing "psychological types" (initially descrived by Carl No proof that serotonin is the key player Jung). (adapted from wikipedia) of depression: developing serotonin MBTI is often used in company for drug for depression is wrong managment prupose Non-addictive opiods doesn’t Higher risk of suicide especilly in young But their validity is stronlgy exist even with slow relase people questionned and there are no real Pseudo-adiction doesn’t exist Guilty: Yes/No ? neuroscientific bases to support Guilty : Yes/No ? their existence Guilty : Yes/No ?  "Inverted Classroom: Exploring Neuroscience in Societal Controversies" Antidepressant and the MBTI - Personnality tests Opioid crisis serotonin controversy Inverted Class Instructions for Master of Neuroscience: 1.Assignment: Write a short essay including a 1-page brief as if it were prepared for a trial or a political decision. 2.Topic Selection: Choose 2 topics from the list provided. You will take a 'Yes' position for the first topic and a 'No' position for the second topic. 3.Final Class Debate: The last class will be dedicated to an oral debate. Each group will serve as the jury for the third topic, which will be assigned to another group. 4.Use of Neuroscientific Evidence: Support your arguments with neuroscientific facts learned during this course or through independent research. 5.Class Participation: The last 15-30 minutes of each class will be open for questions to assist you in developing your arguments. Use this time to clarify concepts and gather additional information. The students will argue either in support of or against these ideas, presenting evidence to assess whether the stance taken on each topic is flawed or problematic (guilty) or justifiable and beneficial (innocent). The Neuron (A) Contact-dependent signaling requires cells to be in direct membrane-membrane contact. (B) Paracrine signaling depends on signals that are released into the extracellular space and act locally on neighboring cells. (C) Synaptic signaling is performed by neurons that transmit signals electrically along their axons and release neurotransmitters at synapses, which are often located far away from the cell body. Extremely fast (D) Endocrine signaling depends on endocrine cells, which secrete hormones into the bloodstream that are then distributed widely throughout the body. Many of the same types of signaling molecules are used in paracrine, synaptic, and endocrine signaling; the crucial differences lie in the speed and selectivity with which the signals are delivered to their targets. Extremely fast The Neuron Reaction to the ever changing external world : Need a very fast communication system The Neuron What is a neuron? Secretion at the end of a cable that can be very long. Triggered by an electrical signal propagated along this cable. Substances released (most often at Soma the end of the axon, but sometimes elsewhere): neurotransmitters, various neuromodulators, neuropeptides, hormones, metal Action potentia ions (zinc), ATP, nitric oxide,... l... which is expensive! CNS: ~2% of body mass but mobilizes ~20% of blood flow. The reason: massive use by neurons of ATP-consuming pumps The Neuron Provides energy (ATP) The envelope of the neuron Contains the DNA : program to synthetise all the proteins Synthetize proteins Generates the action potential The Neuron What is a neuron? Secretion at the end of a cable that can be very long. Triggered by an electrical signal propagated along this cable. Substances released (most often at Soma the end of the axon, but sometimes elsewhere): neurotransmitters, various neuromodulators, neuropeptides, hormones, metal Action potentia ions (zinc), ATP, nitric oxide,... l... which is expensive! CNS: ~2% of body mass but mobilizes ~20% of blood flow. The reason: massive use by neurons of ATP-consuming pumps The Neuron Pre-synaptic Flow of information Post-synaptic  The Neuron Chemical synapse Electrical synapse Flow of information  The Neuron Stimulus 1. Fast reaction 2. Various Soma and Action adaptable Flow of potentia information l reaction  The Neuron : A fast reaction device Cell (plasmic) membrane (lipids) Inside Cell Outside  The Neuron : A fast reaction device Cell (plasmic) membrane (lipids) Intracellular Cell Extracellular  The Neuron : A fast reaction device Difference of concentration between the intracellular and the Na+ extracellular media Cell (plasmic) membrane Na+ K+ (lipids) Impermeable to water and ions K+ Extracellular medi is like the ocean with Intracellular salt sodium and Cell Cl- cholride : NaCl Extracellular Cl-  The Neuron : A fast reaction device Difference of concentration between the intracellular and the Na+ extracellular media This difference is Cell (plasmic) really important!! membrane Na+ K+ (lipids) It establishes a Impermeable to water and ions K+ reason for these ions to try to go to where there are less of Intracellular themselves if they Cell Cl- could Extracellular But they can’t Cl- because of the cell membrane is impermeable to ions  The Neuron : A fast reaction device Ion movment through permeable membrane Laws : Chemical Gradient: Ions move from areas of higher concentration to areas of lower concentration, driven by diffusion. This process aims to balance ion concentrations on both sides of the membrane. Each type of ion to try to go to where there are less of themselves if they can Electrical Gradient: Ions move toward regions with an opposite electrical charge (positive ions move toward negative charges, and negative ions move toward positive charges).  The Neuron : A fast reaction device Ion movment through permeable membrane Laws : Chemical Gradient: Ions move from areas of higher concentration to areas of lower concentration, driven by diffusion. This process aims to balance ion concentrations on both sides of the membrane. Each type of ion to try to go to where there are less of themselves if they can Electrical Gradient: Ions move toward regions with an opposite electrical charge (positive ions move toward negative charges, and negative ions move toward positive charges). Osmolarity: Water molecules move from areas of low osmolarity (high water concentration : low ion concentration) to areas of high osmolarity (low water concentration, high ion concntration) through osmosis, aiming to equalize solute concentrations across membranes.  The Neuron : A fast reaction device Ion movment through semi-permeable membrane Laws : Chemical Gradient: Ions move from areas of higher concentration to areas of lower Voltage gradient concentration, driven by diffusion. This process aims to balance ion concentrations on both sides of the membrane. Each type of ion to try to go to where there are less of themselves if they can Concentration gradient Electrical Gradient: Ions move toward regions with an opposite electrical charge (positive ions move toward negative charges, and negative ions move toward positive charges). Voltage gradient Electrochemical graident -> notion of equilibrium The Neuron : A fast reaction device The Neuron : A fast reaction device Difference of concentration between the intracellular and the Na+ extracellular media This difference is really important!! Na+ K+ It establishes a K+ reason for these ions to try to go to where there are less of themselves if they could Cl- But they can’t Cl- because of the cell membrane is impermeable to ions The Neuron : A fast reaction device Ions concentration Difference of concentration Na+ between the intracellular and the extracellular media This difference is really Na+ K+ important!! K+ It establishes a reason for these ions to try to go to where there are less of themselves if they could Cl- But they can’t because of the cell membrane is Cl- impermeable to ions The Neuron : A fast reaction device Na+ Resting potential Neurons have a steady resting potential VM of -50 mV to -80 mV Na+ K+ That is they are negative inside by K+ almost 0.1V Most neurons are permeable to K+ at rest Cl- Cl- The Neuron : A fast reaction device Terminology Na+ Membrane potential VM Na+ K+ K+ 0mV Cl- Depolarization + -50mV Resting potential Cl- Hyperpolarization - The Neuron : A fast reaction device A balance between electrical and concentration forces K+ K+ Concerntration grandient The K+ will have a tendency to leave the cell in order to balance the concentration inside and outide The Neuron : A fast reaction device A balance between electrical and concentration forces 1. K+ channels open K+ K+ Concerntration grandient The K+ will have a tendency to leave the cell in order to balance the concentration inside and outide The Neuron : A fast reaction device A balance between electrical and concentration forces 1. K+ channels open 2. There is more K+ inside so the K+ moves OUT K+ K+ Concerntration grandient The K+ will have a tendency to leave the cell in order to balance the concentration inside and outide The Neuron : A fast reaction device A balance between electrical and concentration forces 1. K+ channels open 2. There is more K+ inside so the K+ moves OUT K+ 3. K+ exit makes VM more K+ negative, slowing K+ exit Concerntration grandient The K+ will have a tendency to leave the cell in order to balance the concentration inside and outide The Neuron : A fast reaction device A balance between electrical and concentration forces 1. K+ channels open 2. There is more K+ inside so the K+ moves OUT K+ 3. K+ exit makes VM more K+ negative, slowing K+ exit 4. K+ stops moving when VM = - 62mV, the Nernst postential of K where concentration and electrical focrese are balanced Concerntration grandient The K+ will have a tendency to leave the cell in order to balance the concentration inside and outide The Neuron : A fast reaction device The Nernst Equation K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in K+ Only the ratio between K+out and K+in is important - for the Nernst potential + VM = -62mV The Neuron : A fast reaction device The Nernst Equation K+ K+ - + VM = -62mV The Neuron : A fast reaction device The Nernst Equation The Neuron : A fast reaction device The Neuron : A fast reaction device The Neuron : A fast reaction device The Nernst Potentials The Neuron : A fast reaction device Na+/K+ pump or NA+K+ATPase : utilizes energy from ATP hydrolysis to actively transport potassium ions (K+) into the cell while expelling sodium ions (Na+) out of the cell. This process helps maintain the electrochemical gradients essential for cellular function. The Neuron : A fast reaction device K+ channel Na+ channel For each ATP hydrolyzed (energy), the Na+/K+ pump transports 3 sodium ions (Na+) out of the cell and 2 potassium ions (K+) into the cell. intracellular extracellular Na+/K+ pump or NA+K+ATPase : utilizes energy from ATP hydrolysis to actively transport potassium ions (K+) into the cell while expelling sodium ions (Na+) out of the cell. This process helps maintain the electrochemical gradients essential for cellular function. The Neuron : A fast reaction device Na+/K+ pump or NA+K+ATPase : K+ channel open : flow of K+ ouside utilizes energy from ATP hydrolysis to actively transport potassium ions (K+) into the cell while Na+ channel open: flow of Na+ inside expelling sodium ions (Na+) out of the cell. This process helps maintain the electrochemical Ca2+ channel open: flow of Ca2+ inside gradients essential for cellular function. Cl- channel open: flow of Cl-+ inside The Neuron : A fast reaction device Ca2+ = 130 mV Na+ = 67 mV Na+K+ATPAse uses energy (ATP) to maintain the resting potential « polarized » So that the neuron is ready to respond to 0 mV stimulation Resting potential -70 mV Cl- = -90 mV K+ = -98 mV The Neuron : A fast reaction device Ca2+ = 130 mV Na+ = 67 mV Na+K+ATPAse uses energy (ATP) to maintain the resting potential « polarized » So that the neuron is ready to respond to 0 mV stimulation If Na+ channels or Ca2+ channels open Depolarization -> Go towards the Nernst potential of Na+ or Ca2+ Resting potential -70 mV Cl- = -90 mV Hyperpolarization If K+ channels or Cl- channels open -> Go towards the Nernst potential of K+ or Cl- K+ = -98 mV The Neuron : A fast reaction device The Nernst Equation EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in is important for the Nernst potential K+ 5 mM K+ - + 100 mM The Neuron : A fast reaction device The Nernst Equation What if we increase extreacellular K+ ? EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in is important for the Nernst potential K+ 20 mM K+ - + 100 mM The Neuron : A fast reaction device The Nernst Equation What if we increase extreacellular K+ ? EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in is important for the Nernst potential 1. Concentration force is reduced K+ 20 mM K+ - + 100 mM The Neuron : A fast reaction device The Nernst Equation What if we increase extreacellular K+ ? EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in is important for the Nernst potential 1. Concentration force is reduced 2. K+ moves into the cell K+ 20 mM K+ - + 100 mM The Neuron : A fast reaction device The Nernst Equation What if we increase extreacellular K+ ? EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in is important for the Nernst potential 1. Concentration force is reduced 2. K+ moves into the cell K+ 20 mM 3. Cell depolarizes K+ - + 100 mM The Neuron : A fast reaction device The Nernst Equation What if we increase extreacellular K+ ? EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in is important for the Nernst potential 1. Concentration force is reduced 2. K+ moves into the cell K+ 20 mM 3. Cell depolarizes 4. Electrical force is reduced to K+ match the new concentration - + 100 mM The Neuron : A fast reaction device The Nernst Equation What if we increase extreacellular K+ ? EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in is important for the Nernst potential 1. Concentration force is reduced 2. K+ moves into the cell K+ 20 mM 3. Cell depolarizes 4. Electrical force is reduced to K+ match the new concentration - -> new equilibrium + 100 mM The Neuron : A fast reaction device The Nernst Equation What if we increase extreacellular K+ ? EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV EK+ = -98mV = RT zF ln ( [100 nM] ) [5 nM] Resting potential -70 mV Cl- = -90 mV K+ = -98 mV The Neuron : A fast reaction device The Nernst Equation What if we increase extreacellular K+ ? EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV EK+ = -98mV = RT zF ln ( [100 nM] ) [5 nM] K+ = -52 mV ( [100 nM] ) Resting potential -70 mV RT [20 nM] EK+ = -52mV = ln Cl- = -90 mV zF The Neuron : A fast reaction device The Nernst Equation What if we increase extreacellular K+ ? EK+ = RT zF ln ( [K+ ] ) [K+ out] in Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV EK+ = -98mV = RT zF ln ( [100 nM] ) [5 nM] New resting potential K+ = -52 mV Depolarization -70 mV Cl- = -90 mV EK+ = -52mV = RT zF ln ( [100 nM] ) [20 nM] -> new equilibrium The Neuron : A fast reaction device Ca2+ = 130 mV Na+ = 67 mV Na+K+ATPAse uses energy (ATP) to maintain the resting potential « polarized » So that the neuron is ready to respond to 0 mV stimulation If Na+ channels or Ca2+ channels open Depolarization -> Go towards the Nernst potential of Na+ or Ca2+ Na+ and Ca2+ will depolarize and excite the neuron Resting potential -70 mV Cl- = -90 mV Hyperpolarization If K+ channels or Cl- channels open -> Go towards the Nernst potential of K+ or Cl- K+ = -98 mV K+ and Cl- will hyperpolarize and inhibit the neuron The Neuron : A fast reaction device The Nernst Equation Na+ Cl- Ca2+ K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in Na+ Cl- Ca2+ K+ Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV Resting potential -70 mV Cl- = -90 mV K+ = -98 mV The Neuron : A fast reaction device The Nernst Equation Na+ Cl- Ca2+ K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in Na+ Cl- Ca2+ K+ Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV What if we increase extreacellular Cl- so that ECl- is exactely -70 mV Resting potential Cl- = -70 mV K+ = -98 mV The Neuron : A fast reaction device The Nernst Equation Na+ Cl- Ca2+ K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in Na+ Cl- Ca2+ K+ Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV What if we increase extreacellular Cl- so that ECl- is exactely -70 mV Resting potential Cl- = -70 mV What happen if I open the Cl- channels? K+ = -98 mV The Neuron : A fast reaction device The Nernst Equation Na+ Cl- Ca2+ K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in Na+ Cl- Ca2+ K+ Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV What if we increase extreacellular Cl- so that ECl- is exactely -70 mV Resting potential Cl- = -70 mV What happen if I open the Cl- channels? K+ = -98 mV Nothing ! The Neuron : A fast reaction device The Nernst Equation Na+ Cl- Ca2+ K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in Na+ Cl- Ca2+ K+ Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV What if we increase extreacellular Cl- so that Depolarization ECl- is exactely -70 mV Resting potential Cl- = -70 mV What happens if the Na+ open? K+ = -98 mV The Neuron : A fast reaction device The Nernst Equation Na+ Cl- Ca2+ K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in Na+ Cl- Ca2+ K+ Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV What if we increase extreacellular Cl- so that ECl- is exactely -70 mV Resting potential Cl- = -70 mV What happens if the Na+ open? K+ = -98 mV The Neuron : A fast reaction device The Nernst Equation Na+ Cl- Ca2+ K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in Na+ Cl- Ca2+ K+ Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV What if we increase extreacellular Cl- so that Depolarization ECl- is exactely -70 mV Resting potential Cl- = -70 mV What happens if the Na+ open? K+ = -98 mV The Neuron : A fast reaction device The Nernst Equation Na+ Cl- Ca2+ K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in Na+ Cl- Ca2+ K+ Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV What if we increase extreacellular Cl- so that Depolarization ECl- is exactely -70 mV Cl- = -70 mV Resting potential What happens if I open the Na+ and then the Cl- channels? K+ = -98 mV Na+ Cl- channels channels openned openned  The Neuron : A fast reaction device The Nernst Equation Na+ Cl- Ca2+ K+ EK+ = RT zF ln ( [K+ ] ) [K+ out] in Na+ Cl- Ca2+ K+ Only the ratio between K+out and K+in Ca2+ = 130 mV is important for the Nernst potential Na+ = 67 mV 0 mV What if we increase extreacellular Cl- so that Depolarization ECl- is exactely -70 mV Cl- = -70 mV Resting potential What happens if I open the Na+ and then the Cl- channels? K+ = -98 mV The chloride (Cl-) will fight against the depolarization and bring back the membrane potential to its Nernst potential. It will prevent the depolarization (excitation) but don’t do anything in Shunting inhibition resting situation  The Neuron : A fast reaction device The Goldman-Hodgkin-Katz (GHK) equation (at room temperature) The main difference between this and the Nernst equation is the presence of additional ions and the addition of theP variable, which is the permeability of the membrane for the ion considered (membrane permeability constant). If that permeability constant was zero for everything other than potassium, then all those other ions would mathematically disappear from the equation and it would revert to looking like a normal Nernst equation. The Neuron : A fast reaction device Note: The membrane potential can be defined at proximity of the membrane. For a neurons a difference of potential at the membrane does not implies a difference of the total numberr of charge inside versus outiside the cell  The Neuron : A fast reaction device The Goldman-Hodgkin-Katz (GHK) equation (at room temperature) The main difference between this and the Nernst equation is the presence of additional ions and the addition of theP variable, which is the permeability of the membrane for the ion considered (membrane permeability constant). If that permeability constant was zero for everything other than potassium, then all those other ions would mathematically disappear from the equation and it would revert to looking like a normal Nernst equation. The Neuron : A fast reaction device Relationship between the movments of ions and potential K+ Ohms law K+ U=RxI - voltage resistance current + VM = -62mV The Neuron : A fast reaction device Relationship between the movments of ions and potential K+ Ohms law K+ V=RxI - voltage resistance current + VM = -62mV The Neuron : A fast reaction device Conductance = gk Relationship between the movments of ions and potential K+ Ohms law K+ V=RxI - voltage resistance current + VM = -62mV V I = = Vxg conductance R The number of channels openned The Neuron : A fast reaction device Conductance = gk Relationship between the movments of ions and potential K+ Ohms law K+ V=RxI - voltage resistance current + VM = -62mV V I = = Vxg conductance R The number of channels openned The Neuron : A fast reaction device Conductance = gk Relationship between the movments of ions and potential K+ K+ Ik = (VM – Ek) x gk - + VM = -62mV Current Membrane Nernst Conductance of K+ potential potential for K+ For K+ Flow of K+ ions The Neuron : A fast reaction device Conductance = gk Relationship between the movments of ions and potential K+ K+ Voltage = difference of potential Ik = (VM – Ek) x gk - + VM = -62mV Current Membrane Nernst Conductance of K+ potential potential for K+ For K+ Flow of K+ ions  The Neuron : A fast reaction device RC circuit equivalent Relationship between the movments of ions and potential extracellular Ik 1/gk Cm Voltage = difference of potential VM ++ + -- - Ek Ik = (VM – Ek) x gk intracellular Current Membrane Nernst Conductance of K+ potential potential for K+ For K+ Flow of K+ ions The Neuron : A fast reaction device Na+ Na+ K+ Cl- K+ Cl- Ik = (VM – Ek) x gk ICl = (VM – ECl) x gCl RC circuit equivalent INa = (VM – ENa) x gNa  Summary The Neuron : A fast reaction device Key concepts to understand the resting potential of a neuron A neuron has an electrical charge between inside and outside because of a difference in concentrations of charged ions This electrical charge is called the membrane potential VM A balance of electrical and chemical (conentration) forces determines the resting porential of a neuron The Nernst Equation allows us to compute the equilibrium potential of each type of ion Ohm’s law allows us to determine the flow of ions in/out of the cell  The Neuron Stimulus 1. Fast reaction 2. Various Soma and Action adaptable Flow of potentia information l reaction The Neuron : A fast reaction device VM = -62mV What if I inject a current Iext K+ - K+ + Iext Vm -> ??? extracellular Iext I Ir 1/gk dVm Im = Ir + Ic = gk Vm + Cm ++ + Cm -- - x = Iext x Ek IC dt intracellular The Neuron : A fast reaction device VM = -62mV What if I inject a current Iext K+ - K+ + Iext Vm -> ??? extracellular Iext I Differential equation Ir 1/gk dVm Im = Ir + Ic = gk Vm + Cm ++ + Cm -- - x = Iext x Ek IC dt 1 ( -t ) intracellular Vm = Iext x gk X 1 – exp ( ) rk Cm x The Neuron : A fast reaction device VM = -62mV What if I inject a current Iext Exponential with a time K+ - K+ exponential constant of response 𝝉 = rk.Cm + depolarization For a neuron 𝝉 ~100msec Iext Vm -> extracellular Iext I Differential equation Ir 1/gk dVm Im = Ir + Ic = gk Vm + Cm ++ + Cm -- - x = Iext x Ek IC dt 1 ( -t ) intracellular Vm = Iext x gk X 1 – exp ( ) rk Cm x The Neuron : A fast reaction device VM = -62mV What if I inject a current Iext Exponential with a time K+ - K+ exponential constant of response 𝝉 = rk.Cm + depolarization For a neuron 𝝉 ~100msec Iext Vm -> exponential hyperpolarization extracellular Iext I Differential equation Ir 1/gk dVm Im = Ir + Ic = gk Vm + Cm ++ + Cm -- - x = Iext x Ek IC dt 1 ( -t ) intracellular Vm = Iext x gk X 1 – exp ( ) rk Cm x The Neuron : A fast reaction device Increases in K+ conductance can result in hyperpo- larization, depolarization, or no change in membrane potential. (A) Opening K+ channels increases the conductance of the membrane to K , denoted gK. If the membrane potential is positive to the equilibrium potential (also known as the reversal potential) for K , then increasing gK will cause some K ions to leave the cell, and the cell will become hyperpolarized. If the membrane potential is negative to EK when gK is increased, then K+ ions will enter the cell, therefore making the inside more positive (more depolarized). If the membrane potential is exactly EK when gK is increased, then there will be no net movement of K+ ions. (B) Opening K+ channels when the membrane potential is at EK does not change the membrane potential; however, it reduces the ability of other ionic currents to move the membrane potential away from EK. For example, a comparison of the ability of the injection of two pulses of current, one depolarizing and one hyperpolarizing, to change the membrane potential before and after opening K channels reveals that increases in gK decrease the responses of the cell noticeably. The Neuron : A fast reaction device Cable equation The Neuron : A fast reaction device Cable equation  Summary The Neuron : A fast reaction device Key concepts to understand the active properties of the membrane Neurons respond to injected currents by changing its membrane voltage, with either exponential depolarization or hyperpolarization in time The density of ion channels determines how quickly neurones can respond to change Electrical potentials spread in spave to neighboring parts of a neurons according to the cable equation The diameter of the cell/cable determines how far membrane potential spread  Fast = electrical The Neuron response (much faster than Stimulus diffusion of molecules) 1. Fast reaction Reaction = Ions channels can be activated by Soma variation of potential Action 2. Various Flow of potentia l and information adaptable reaction The Action potential Na+K+ATPase also contributes to the return to the baseline The Action potential Some channels are sensitive to potential / voltage The are open when a certain threshold is crossed Sodium voltage-gated channel (Na+ V-gated channels) Potassium voltage-gated channel (K+ V-gated channels) Reaction = Ions channels can be activated by variation of potential -> voltage-gated channel The Action potential The Action potential The Action potential : Hodgkin-Huxley Model VM = -62mV What if I inject a current Iext Exponential with a time K+ - K+ exponential constant of response 𝝉 = rk.Cm + depolarization For a neuron 𝝉 ~100msec Iext Vm -> exponential hyperpolarization extracellular Iext I Differential equation Ir 1/gk dVm Im = Ir + Ic = gk Vm + Cm ++ + Cm -- - x = Iext x Ek IC dt 1 ( -t ) intracellular Vm = Iext x gk X 1 – exp ( ) rk Cm x  The Action potential : Hodgkin-Huxley Model Na+ Na+ K+ K+ Voltage-gated Na+ Channel : g Na+ = f(Vm) Voltage-gated K+ Channel : gK++ = f(Vm)  The Action potential : Hodgkin-Huxley Model Na+ Na+ K+ K+ Voltage-gated Na+ Channel : g Na+ = f(Vm) Voltage-gated K+ Channel : gK++ = f(Vm)  The Action potential : Hodgkin-Huxley Model Na+ Na+ K+ K+ Voltage-gated Na+ Channel : g Na+ = f(Vm) Voltage-gated K+ Channel : gK++ = f(Vm)  The Action potential : Hodgkin-Huxley Model Na+ Na+ K+ K+ Voltage-gated Na+ Channel : g Na+ = f(Vm) Voltage-gated K+ Channel : gK++ = f(Vm) https://en.wikipedia.org/wiki/Hodgkin–Huxley_model  The Action potential : Hodgkin-Huxley Model Voltage-dependent K+ channel is a receptor formed by 4 sub-units that actuelly explained the exponent 4 Na+ Na+ K+ K+ Voltage-gated Na+ Channel : g Na+ = f(Vm) Voltage-gated K+ Channel : gK++ = f(Vm) https://en.wikipedia.org/wiki/Hodgkin–Huxley_model  The Action Potential Key concepts to understand the action potential Action potential is caused by transient changes in conductances gk and gNa Conductances gk and gNa can be activated by depolarization The activation is followed by a refractory period that explain the propagation of the action potential in the axon Relatively few ions actually cross the membrane therefore ion concentration do not change during an action potential Thus the equilibrium potential EK,ENa, also do not change during an action potential Ion concentrations are maintained by Na+K+ATPase and astrocytes The Action Potential propagation in the axon The Action Potential propagation in the axon  The Action Potential propagation in the axon The action potential is indeed an all-or-none process, meaning that once it is triggered, it either occurs fully or not at all. This characteristic ensures that the action potential is a reliable signal for neural communication. Importantly, as the action potential propagates along the axon, its size (or amplitude) remains constant. Here’s an explanation of why this happens: 1. All-or-None Principle When a neuron reaches its threshold for depolarization, voltage-gated sodium (Na++) channels open, causing a rapid influx of Na++ ions into the neuron. This influx generates the action potential. The action potential either fully occurs if the threshold is reached, or it does not happen at all if the stimulus is below the threshold. Once triggered, the action potential always reaches the same peak amplitude regardless of the strength of the stimulus that initiated it (as long as the stimulus reaches the threshold). This is the basis of the all - or-none law.  The Action Potential propagation in the axon The action potential is indeed an all-or-none process, meaning that once it is triggered, it either occurs fully or not at all. This characteristic ensures that the action potential is a reliable signal for neural communication. Importantly, as the action potential propagates along the axon, its size (or amplitude) remains constant. Here’s an explanation of why this happens: 2. Constant Amplitude During Propagation As the action potential propagates along the axon, the voltage change generated at one point of the axon is enough to depolarize the next segment of the membrane to the threshold, triggering a new action potential in that adjacent segment. The voltage-gated ion channels ensure that each segment of the axon experiences the same depolarization and repolarization events. Therefore, the amplitude of the action potential remains constant as it moves along the axon, regardless of the axon’s length or distance from the initiation site.  The Action Potential propagation in the axon The action potential is indeed an all-or-none process, meaning that once it is triggered, it either occurs fully or not at all. This characteristic ensures that the action potential is a reliable signal for neural communication. Importantly, as the action potential propagates along the axon, its size (or amplitude) remains constant. Here’s an explanation of why this happens: 3. Regeneration of the Action Potential As the action potential moves along the axon, it is regenerated at each successive segment of the axonal membrane by the opening of Na++ channels. This ensures that the signal does not diminish over distance, unlike graded potentials, which decrease in size as they travel. The constant regeneration of the action potential means that it does not "fade" as it travels, allowing neurons to transmit signals over long distances (e.g., from the spinal cord to the foot) without a loss in signal strength. The Action Potential propagation in the axon In summary: The all-or-none nature of the action potential ensures that the neuron fires a full signal when stimulated. The constant amplitude of the action potential as it propagates ensures that the signal remains strong and reliable, regardless of the distance it travels along the axon. 4. Myelinated Axons (Saltatory Conduction) In myelinated axons, the action potential is regenerated at the nodes of Ranvier, where ion channels are concentrated. Even in this case, where the action potential appears to "jump" between nodes, the amplitude of the action potential remains constant at each node as it is regenerated along the axon. 5. Unmyelinated Axons (Continuous Conduction) In unmyelinated axons, the action potential is regenerated continuously along every point of the axon membrane. Here, too, the amplitude remains constant, as each section of the axon undergoes depolarization and repolarization with the same ionic mechanisms. Why Is This Important? The constancy of the action potential’s size is crucial for reliable neural signaling. Regardless of how far the signal needs to travel, it reaches its destination with the same strength as when it was initiated. This allows the brain to effectively communicate with distant parts of the body, such as muscles or sensory receptors, without losing the strength of the signal.  The Action Potential propagation in the axon Propagation of Action Potentials: With and Without Myelin The propagation of action potentials along axons is a fundamental process that allows neurons to communicate over long distances. The efficiency and speed of action potential conduction are greatly influenced by the presence or absence of myelin, a fatty insulating layer produced by specialized glial cells (Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system). Myelin dramatically changes the way action potentials travel down an axon, and understanding these differences is essential for understanding neural function.  The Action Potential propagation in the axon Biological Implications of Myelination 1.Faster Information Processing: Myelinated neurons, due to their faster conduction velocity, enable more rapid communication between different parts of the nervous system. This is particularly important in pathways that control reflexes, motor coordination, and high-level cognitive functions. 2.Long-Distance Signaling: Myelination is especially important for neurons with long axons, such as those in the peripheral nervous system and corticospinal tracts, where fast and efficient signal transmission is crucial for proper motor and sensory function. 3.Energy Efficiency: Myelinated neurons conserve energy by minimizing the number of areas where ion exchange is needed, reducing the energy demands on the Na++-K++ pumps. Potential Pitfalls Without Myelin 1.Demyelinating Diseases: In conditions like multiple sclerosis (MS), the immune system attacks myelin sheaths, leading to slower and less reliable signal transmission. This results in symptoms such as muscle weakness, vision problems, and impaired coordination due to the impaired ability of neurons to communicate rapidly and efficiently. 2.Neuronal Communication Deficits: Without myelin, the brain and spinal cord would face major challenges in transmitting information quickly and efficiently. This would result in slower reaction times and impaired cognitive processing, particularly in complex, long-distance signaling pathways. Conclusion The presence of myelin allows for saltatory conduction, a much faster, more energy-efficient, and reliable form of action potential propagation compared to the continuous conduction seen in unmyelinated axons. The difference between these two mechanisms is crucial for the nervous system’s ability to transmit signals rapidly over long distances and with minimal energy expenditure, allowing for efficient communication and coordination across different regions of the body. The axonal lesion in central and peripheral nervous system The axonal lesion in central and peripheral nervous system  Fast = electrical The Neuron response (much faster than Stimulus diffusion of molecules) 1. Fast reaction Reaction = Ions channels can be activated by Soma variation of potential 2. Various Action Flow of potentia l information and adaptable reaction  Fast = electrical Neurotransmission response (much faster than Stimulus diffusion of molecules) 1. Fast reaction Reaction = Ions channels can be activated by Soma variation of potential 2. Various Action Flow of potentia l information and adaptable reaction Neurotransmission Neurotransmission  Neurotransmission Schematic representation of the life cycle of a classical neurotransmitter. After accumulation of a precursor amino acid into the neuron (1), the amino acid precursor is metabolized sequentially (2) to yield the mature transmitter. The transmitter is then accumulated into vesicles by the vesicular transporter (3), where it is poised for release and protected from degradation. Once released, the transmitter can interact with postsynaptic receptors (4) or autoreceptors (5) that regulate transmitter release, synthesis, or firing rate. Transmitter actions are terminated by means of a high-affinity membrane transporter (6) that usually is associated with the neuron that released the transmitter. Alternatively, transmitter actions may be terminated by diffusion from the active sites (7) or accumulation into glia through a membrane transporter (8). When the transmitter is taken up by the neuron, it is subject to metabolic inactivation (9). Neurotransmission : Receptors Neurotransmission : Receptors Neurotransmission : Receptors  Neurotransmission Ca2+ = 130 mV Na+ = 67 mV 0 mV Depolarization Resting potential -70 mV Cl- = -90 mV Hyperpolarization K+ = -98 mV  Neurotransmission Ca2+ = 130 mV Na+ = 67 mV 0 mV Depolarization Resting potential -70 mV Cl- = -90 mV Hyperpolarization K+ = -98 mV Neurotransmission Neurotransmission Neurotransmission  Neurotransmission Glutamate Excitation Ionotropic AMPA/Kainate : Na+ NMDA : Ca2+ Glutamate (Excitation) Metabotropic Complex (mGluR 1-5 ) GABA (Inhibition) GABA Inhibition Ionotropic GABA-A (fast) Metabotropic GABA-B (slow)  Neurotransmission Acethylcholine Ionotropic Nicotine Ca2+ (alpha, beta…) Metabotropic Complex (M1-…-M5 ) Role: Memory, attention Localisation: Basal Forebrain,Brainstem (PPT, LDT) Acethylcholine Some neurons in the Striatum (motor) Dopamine Noradrenaline Dopamine Metabotropic D1-like D1/D5 +AMPc (action) Serotonin D2-like D2/D3/D4 -AMPc (block) Localisation: Substantia Nigra : Motor Ventral tegmental area (VTA): Reward, Prediction, Addiction D1 pathway (direct): Facilitates movement by increasing thalamic excitatory output to the motor cortex. D2 pathway (indirect): Inhibits movement by reducing thalamic excitatory output to the motor cortex. Noradrenaline Metabotropic Complex (alpha, beta…) Role: awareness, arousal, attention Localisation: Locus coeruleus (brainstem) Serotonin Ionotropic 5HT3 excitateur Metabotropic 5HT 1,2,4,5,6,7 Complex Role: Complex! mood, …. Localisation: (complex) Raphe nucleus and mainy other nucleus Neurotransmission Dopamine Metabotropic D1-like D1/D5 +AMPc (action) D2-like D2/D3/D4 -AMPc (block) Localisation: Substantia Nigra : Motor Ventral tegmental area (VTA): Reward, Prediction, Addiction D1 pathway (direct): Facilitates movement by increasing thalamic excitatory output to the motor cortex. D2 pathway (indirect): Inhibits movement by reducing thalamic excitatory output to the motor cortex. Neurotransmission Dopamine D1 pathway (direct): Facilitates movement by increasing thalamic excitatory output to the motor cortex. D2 pathway (indirect): Inhibits movement by reducing thalamic excitatory output to the motor cortex. D2 D1 SNr / GPi Neurotransmission : Noradrenaline Noradrenaline / Norepinephrine Characteristics of a norepinephrine (NE)- containing catecholamine neuron. Tyrosine (Tyr) is accumulated by the neuron and then is metabolized sequentially by tyrosine hydroxylase (TH) and l-aromatic amino acid decarboxylase (l-AADC) to dopamine (DA). The DA is then taken up through the vesicular monoamine transporter into vesicles. In DA neurons, this is the final step. However, in this NE-containing cell, DA is metabolized to NE by dopamine-- hydroxylase (DBH), which is found in the vesicle. Once NE is released, it can interact with postsynaptic noradrenergic recep- tors or presynaptic noradrenergic autoreceptors. The accumulation of NE by the high-affinity membrane NE transporter (NET) termi- nates the actions of NE. Once taken back up by the neuron, NE can be metabolized to inactive compounds (DHPG) by degradative enzymes such as monoamine oxidase (MAO) or taken back up by the vesicle. Neurotransmission GABA Schematic depiction of the life cycle of a GABAergic neuron. -Ketoglutarate formed in the Krebs cycle is transaminated to glutamate (Glu) by GABA transaminase (GABA-T). The transmitter GABA is formed from the Glu by glutamic acid decarboxylase (GAD). GABA that is released is taken by high- affinity GABA transporters (GAT) present on neurons and glia. Neurotransmission : Neuropeptides Neuropeptides Schematic illustration of the synthesis, release, and termination of action of the peptide transmitter neurotensin (NT). The illustrative panels of the bottom show processing of NT from the prohormone (left) and enzymatic inactivation of NT (right). Neurotransmission : Neuropeptides A single neuron can release a classical neurotransmitter and a neuropeptide The pattern of action potential leading to the release of classical neurotransmitter is different from the one taht will release both the neurotransmitteur and the neuropepitde (the stimulation msut be stronger to release both the neurotransmitter and the neuropeptide LDCV : large core vesicules SV : synaptic vesicule Neurotransmission : Neuropeptides A single neuron can release a classical neurotransmitter and a neuropeptide The pattern of action potential leading to the release of classical neurotransmitter is different from the one taht will release both the neurotransmitteur and the neuropepitde (the stimulation msut be stronger to release both the neurotransmitter and the neuropeptide LDCV : large core vesicules SV : synaptic vesicule Neurotransmission : Neuropeptides  Neurotransmission : Acethylcholine Acetylcholine (ACh) plays a crucial role as a neurotransmitter in both the central and peripheral nervous systems. It has widespread effects on cognitive functions, neuromodulation, and motor control. Anatomical Projections of Acetylcholine: 1.Basal Forebrain: The basal forebrain cholinergic system, consisting of the nucleus basalis of Meynert, medial septal nucleus, and diagonal band of Broca, is one of the main sources of cholinergic projections in the brain. This system sends widespread cholinergic fibers to the cerebral cortex and hippocampus, which are important for learning and memory.  Neurotransmission : Acethylcholine Acetylcholine (ACh) plays a crucial role as a neurotransmitter in both the central and peripheral nervous systems. It has widespread effects on cognitive functions, neuromodulation, and motor control. Anatomical Projections of Acetylcholine: 2. Brainstem (Pedunculopontine and Laterodorsal Tegmental Nuclei): These cholinergic nuclei in the brainstem project to various parts of the brain, including the thalamus, hypothalamus, cerebellum, and basal ganglia. These projections are involved in regulating arousal, sleep-wake cycles, and motor control.  Neurotransmission : Acethylcholine Acetylcholine (ACh) plays a crucial role as a neurotransmitter in both the central and peripheral nervous systems. It has widespread effects on cognitive functions, neuromodulation, and motor control. Anatomical Projections of Acetylcholine: 3. Striatum: ACh is also released by local interneurons in the striatum (a key part of the basal ganglia), where it plays a modulatory role in motor control and is involved in action selection and habit formation.  Neurotransmission : Acethylcholine Behavior of Ach at the synapse: Behavior: ACh is released from presynaptic neurons into the synaptic cleft, binds to postsynaptic receptors, and transmits signals before being degraded. Synthesis: ACh is synthesized from choline and acetyl-CoA by choline acetyltransferase in the presynaptic neuron. Inactivation: ACh is rapidly broken down by acetylcholinesterase into choline and acetate, with choline recycled for further synthesis. Neurotransmission : Acethylcholine Atropine (antagonist / blocker)  Neurotransmission Glutamate Excitation Ionotropic AMPA/Kainate : Na+ NMDA : Ca2+ Glutamate (Excitation) Metabotropic Complex (mGluR 1-5 ) GABA (Inhibition) GABA Inhibition Ionotropic GABA-A (fast) Metabotropic GABA-B (slow)  Neurotransmission Acethylcholine Ionotropic Nicotine Ca2+ (alpha, beta…) Metabotropic Complex (M1-…-M5 ) Role: Memory, attention Localisation: Basal Forebrain,Brainstem (PPT, LDT) Acethylcholine Some neurons in the Striatum (motor) Dopamine Noradrenaline Dopamine Metabotropic D1-like D1/D5 +AMPc (action) Serotonin D2-like D2/D3/D4 -AMPc (block) Localisation: Substantia Nigra : Motor Ventral tegmental area (VTA): Reward, Prediction, Addiction D1 pathway (direct): Facilitates movement by increasing thalamic excitatory output to the motor cortex. D2 pathway (indirect): Inhibits movement by reducing thalamic excitatory output to the motor cortex. Noradrenaline Metabotropic Complex (alpha, beta…) Role: awareness, arousal, attention Localisation: Locus coeruleus (brainstem) Serotonin Ionotropic 5HT3 excitateur Metabotropic 5HT 1,2,4,5,6,7 Complex Role: Complex! mood, …. Localisation: (complex) Raphe nucleus and mainy other nucleus Synaptic integration Synaptic integration : intrinsic properties Simulation of the effects of the addition of various ionic currents to the pattern of activity generated by neurons in the mam- malian CNS. (A) The repetitive impulse response of the classical Hodgkin–Huxley model (voltage recordings above, current traces below). With only INa and IK, the neuron generates a train of five action potentials in response to depolarization. Addition of IC (B) enhances action potential repolarization. Addition of IA (C) delays the onset of action potential generation. Addition of IM (D) decreases the ability of the cell to generate a train of action potentials. Addition of IAHP (E) slows the firing rate and generates a slow after- hyperpolarization. Finally, addition of the transient Ca2+ current IT results in two states of action potential firing: (F) burst firing at 85 mV and (G) tonic firing at 60 mV. From Huguenard and McCormick (1994). Synaptic integration : intrinsic properties Voltage-dependent T-type calcium channel (Cav) LTS : Low threshold calcium spikes) IT current Must be activated by previous hyperolarization Rebound of excitation after hyperpolarization Voltage-dependent calcium channels (Cav) of the T-type family (Cav3.1, Cav3.2, and Cav3.3) are activated by low threshold membrane depolarization Synaptic integration : intrinsic properties Voltage-dependent T-type calcium channel (Cav) LTS : Low threshold calcium spikes) IT current Must be activated by previous hyperolarization Rebound of excitation after hyperpolarization Voltage-dependent calcium channels (Cav) of the T-type family (Cav3.1, Cav3.2, and Cav3.3) are activated by low threshold membrane depolarization Synaptic integration : intrinsic properties Two different patterns of activity generated in the same neuron, depending on membrane potential. (A) The thalamic neuron spontaneously generates rhythmic bursts of action potentials due to the interaction of the Ca2+ current IT and the inward “pacemaker” current Ih. Depolarization of the neuron changes the firing mode from rhythmic burst firing to tonic action potential generation in which spikes are generated one at a time. Removal of this depolarization reinstates rhythmic burst firing. This transition from rhythmic burst firing to tonic activity is similar to that which occurs in the transition from sleep to waking. (B) Expansion of detail of rhythmic burst firing. (C) Expansion of detail of tonic firing. From McCormick and Pape (1990). Synaptic integration : intrinsic properties Two different patterns of activity generated in the same neuron, depending on membrane potential. (A) The thalamic neuron spontaneously generates rhythmic bursts of action potentials due to the interaction of the Ca2+ current IT and the inward “pacemaker” current Ih. Depolarization of the neuron changes the firing mode from rhythmic burst firing to tonic action potential generation in which spikes are generated one at a time. Removal of this depolarization reinstates rhythmic burst firing. This transition from rhythmic burst firing to tonic activity is similar to that which occurs in the transition from sleep to waking. (B) Expansion of detail of rhythmic burst firing. (C) Expansion of detail of tonic firing. From McCormick and Pape (1990). Synaptic integration Synaptic integration Synaptic integration Synaptic integration Synaptic integration Synaptic integration Synaptic integration Synaptic integration Synaptic integration Active membrane mechanism and synaptic integration (a) Passive integration. Dendritic synaptic input generates fast local excitatory postsynaptic potentials (EPSPs) that are filtered and attenuated as they spread to the soma, where they summate to initiate an action potential (AP, red) in the axon initial segment. This AP then propagates down the axon. Synaptic integration Active membrane mechanism and synaptic integration (b) Active integration. Dendritic synaptic input initiates a local dendritic spike, which spreads to the soma facilitating AP generation. (c) Backpropagation. In some cells