Structure of cells & Neurophysiology PDF

Structure and function of cells of the nervous systemLecture 2Gorana [email protected] Lecture overviewStructure and functions of the neuron Supporting cells in CNS and the Blood-Brain-BarrierMembrane Potential and Action PotentialStructure of synapseRole of ion channelsPostsynap...

Structure and function of cells of the nervous systemLecture 2Gorana [email protected] Lecture overviewStructure and functions of the neuron Supporting cells in CNS and the Blood-Brain-BarrierMembrane Potential and Action PotentialStructure of synapseRole of ion channelsPostsynaptic potentials and their integrationPLEASE READ CARLSON CHAPTER 2 The NeuronMost neurons have the following structures: 1. soma(cell body); 2. dendrites (branches); 3. axon; 4. terminal buttons (terminals, bouton)Ty p e o f c e l l t h a t ma k e s u p t h e n e r v o u s s y s t e m a n d s u p p o r t s c o g n i t i v e function: the information processing and information transmitting element According to their function neurons can be divided into:Sensory neurons-detect changes in external and internal environment (CNS and PNS, light, sound, odours, touch...).Motor neurons-controls muscle contraction and also gland secretion (CNS and PNS).Interneurons-lie entirely within the CNS and are involved in cognition (i.e.,perceiving, learning, remembering and executive functioning such as decision making). According to their structure neurons can be divided into:Multipolarneuron–neuron with one axon and many dendrites attached to its soma.Bipolar Neuron–neuron with one axon and one dendrite attached it its soma.UnipolarNeuron –neuron with one axon attached to its soma; the axon divides, with one branch receiving sensory information and the other sending the information into the central nervous system. Early anatomistsPyramidal cellRamon y Cajal Supporting cells “glue” the nervous system togetherSupporting Cells •“Star cells”•Provide physical support to neurons•Provide nourishment•When neurons die they clean up debris and form scar tissue•Control chemical composition of fluid surrounding neuronsAstrocytes OligodendrocytesSupport axons and produce the myelinsheath -insulation, lipidsCNSPNS -Schwann cellsNodes of Ranvier–bare portionof axon Single Schwann cell wrapped aroundthe PNS axonWrapped around several adjacent axons A semipermeable barrier between the CNS and circulatory system, which helps to regulate the flow of nutrient rich fluid into the brain.Area Postrema–a region of the medullawhere the blood-brain barrier is weak. This allows toxins in the blood to stimulate this area, which initiates vomiting –poison expelled from the bodyThe Blood-Brain Barrier How can neurons produce useful behaviour?Withdrawal reflex How can neurons produce useful behaviour?The role of inhibition •Measuring Electrical Potentials of Axons–Membrane Potential –electrical charge across a cell membrane; the difference in electrical potential inside and outside the cell.–Stored up source of electrical energy–Resting Potential–membrane potential of a neuron when it is not being altered by excitatory or inhibitory postsynaptic potentials, normally about -70 mV.Communication within a neuron Studying the axonDepolarization–reduction of negative charge (toward zero) of the membrane potential when we stimulateneuronApply + charge (electrical stimulus) Action PotentialAction Potential –brief electrical impulse that provides the basis for conduction of information along an axon.Threshold of Excitation –The value of the membrane potential that must be reached to produce an action potentialHyperpolarization–increase in the membrane potential of a cell The membrane potentialBalance of two forces:•Diffusion-movement of molecules from areas of high concentration to areas of low concentration (salt in a cup)•Electrostatic pressure–when substances dissolve in water, they split into 2 parts with opposing electrical charge Na + and Cl− :IONSAttraction of oppositely charged ions (+-) and repulsion of similarly charged ions (++; --) is exerted by electrostatic pressure Control of the membrane potentialIntracellular fluidThe fluid contained within cells.Extracellular fluidBody fluids located outside cells. Sodium –Potassium Pump (Transporter)Active mechanism in the membrane that extrudes Na+out and transports K+inProtein in the membrane that pushes Na+ out of the cellsHow can Na+ be found outside of the cell, when both forces (diffusion and electrostatic pressure tend to push it inside? Ion channels: allow flow of specific ions when openProteins that open and close, thus allowing ions to pass through the cell wall 1. As depolarisation starts and the threshold of excitation is reached, sodium channels open and Na+ ions move into cell changing the membrane potential from –70 to +40 mV.2. The potassium channels open after a slight delay3. The sodium channels becomeblockedwhen the action potential reaches its peak (+40mV). No more Na+ ions can enter.4. K+ ions move out of the cell, bringing the membrane potential back towards its resting potential.5. Potassium channels close and sodium channels re-set.6. The membrane potential overshootsits resting –70mV and hyperpolarizationoccurs as a result of extra K+ ions outside the axon. As they diffuse away the resting membrane potential is restored.Action Potential Conduction of the Action PotentialAll-or-None Law –once the action potential begins, it proceeds without decrement to the terminal buttons (it either occurs, or it doesn’t occur)The speed of conduction can be calculated from the delay between stimulus and AP Rate Law –variations in the intensity of a stimulus are represented by variations in the rate at which that axon firesConduction of the Action PotentialRate of firing causes stronger muscle contractionAll-or None Law is supplemented by the rate law SaltatoryconductionConduction of action potentials by myelinatedaxonsThe action potential appears to jump from one node of Ranvierto the next.Conduction on the Action PotentialEconomy: less energy used by the Na-K pump (located only at the Nodes of RanvierSpeed: conduction much faster In a myelianetedaxonAdvantages: Saltatory is nothing to do with “salt”, its from the Latin, saltare, to leap. Communication between neurons What is a synapse?A synapseis the junction between 2 neurons –it is the primary means of communication between 2 cellsThere is a very narrow gap of about 20nm between neurons called the synaptic cleft.An action potential cannot cross the synaptic cleft, so nerve impulses are carried by chemicals called neurotransmitters. A S y n a p s ePre-synaptic neuron -neuron sending impulsePost-synaptic neuron -neuron receiving impulse NeurotransmitterNeurotransmitter is made by the pre-synaptic neuronand is stored in synaptic vesiclesat the end of the axon.The membrane of the post-synaptic neuronhas chemical-gated ion channels called neuroreceptors. These have specific binding sites for neurotransmitters. Thechemical messenger fits the binding site like a lock and key Opening of transmitter-dependent ion channels can be direct or indirectDirect opening of ion channel:ionotropicreceptor Indirect opening of ion channel: metabotropicreceptor ReuptakeExposure of the neurotransmitter to the receptors is only briefEnzyme destroys molecules of neurtransmitters Postsynaptic PotentialsExcitatory Postsynaptic Potential (EPSP) –excitatorydepolarization of the postsynaptic membrane.Inhibitory Postsynaptic Potential (IPSP) –inhibitory hyperpolarizationof the post synaptic membrane.The nature of PSP is determined by postsynaptic receptors –which ionchannels they open3 major types of ion channels: Na+, K+ and Cl- Sodium (+) EPSPPotassium (+) IPSP, Chloride (-) IPSP Postsynaptic potential is determinedby the receptor characteristics Process by which inhibitory and excitatory postsynaptic potentials summate and control the rate of firing of a neuron.Neuronal integration Neuronal integration Neuronal integrationTe m p o r a l ( i n t i m e ) s u m m a t i o n & s p a t i a l ( i n s p a c e ) s u m m a t i o n Summary –Study outline1. Describe the functions of neurons and the gliain the nervous system.2. Define membrane potential.3. Explain basic concepts: hyperpolarization/depolarization, graded potentials/action potentials, etc.4. Explain how a resting membrane potential can transform into a nerve impulse.5. Explain how selective ion gating generates the action potential.6. Explain the principles behind saltatoryconduction of an action potential7. Describe how a nerve impulse passes from neuron to neuron8. Discuss how the interplay of inhibitory and stimulatory inputs determines if a post-synaptic neuron fires.Please read Chapter 2 in Carlson Thank you Neurotransmitters & (basic) PsychopharamcologyLecture 3Gorana [email protected] Lecture overviewBasic psychopharmacology Agonists and Antagonists and their effectsNeurotransmittersStructure of synapsePLEASE READ CARLSON CHAPTER 4 (PG. 87-100)Placebo effect Drug effects The changes a drug produces in an animal’s physiological processes and behavior. In the nervous system, most drugs affect synaptic transmission.AntagonistA d r u g t h a t o p p o s e s o r i n h i b i t s t h e e ff e c t s o f a p a r t i c u l a r n e u r o t r a n s m i t t e r o n the postsynaptic cell.AgonistA d r u g t h a t f a c i l i t a t e s t h e e ff e c t s o f a p a r t i c u l a r n e u r o t r a n s m i t t e r o n t h e postsynaptic cell.PsychopharmacologyThe study of the effects of drugs on the nervous system and on behavior Main sites of action:1.Production of neurotransmitters2.Storage and release of neurotransmitters3.Effects on receptors4.Effects on reuptake Effects on ReceptorsThe most important—and most complex—site of action of drugs in the nervous system is on receptors, both presynapticand postsynaptic.Once a neurotransmitter has been released, it must stimulate the postsynaptic receptors. Some drugs bind with these receptors, just as the neurotransmitter does.Once a drug has bound with the receptor, it can serve as either an agonistor an antagonist. Indirect agonist/antagonistA d r u g t h a t a t t a c h e s t o a b i n d i n g s i t e on a receptor and facilitates the action of the receptor; does not interfere with the binding site of the principal neurotransmitter.Direct agonist/antagonistA d r u g t h a t b i n d s w i t h a n d a c t i v a t e s a receptor. This drug mimics the effects of a neurotransmitter Effects on Reuptake or Destruction of NeurotransmittersREUPTAKE: the process of termination of the postsynaptic potential The drug attach to the transporter molecules that are responsible for reuptake and inactivate them, thus blocking reuptake.In the second case the drug bind with the enzyme that normally destroys the neurotransmitter and prevents the enzymes from working. Both types of drugs prolong the presence of the neurotransmitter in the synaptic cleft (and hence in a location where they can stimulate postsynaptic receptors), they serve as agonists.Tw o p r o c e s s e s a c c o mp l i s h t h a t t a s k :1.Molecules of the neurotransmitter are taken back into the terminal button through the process of reuptake2.They are destroyed by an enzyme. Placebo EffectsWhen experimenters want to investigate the behavioral effects of drugs in humans, they must use control groups whose members receive placebos, or they cannot be sure that the behavioral effects they observe were caused by specific effects of the drug. NoceboEffectThe noceboresponse, where people can feel worse after an intervention that should have no ill effectsPlaceboAn inert substance given to an organism in lieu of a physiologically active drug; used experimentally to control for the effects of mere administration of a drughttps://www.youtube.com/watch?v=O1Q3jZw4FGs NeurotransmittersBecause neurotransmitters have two general effects on postsynaptic membranes—depolarization (EPSP) or hyperpolarization(IPSP)—one might expect that there would be two kinds of neurotransmitters: excitatory and inhibitoryIn the brain most synaptic communication is accomplished by two neurotransmitters: 1.with excitatory effects (glutamate) 2.with inhibitory effects (GABA or glycine-spinal cord)Neurons receive receive excitatory input from glutamate-secreting terminal buttons and inhibitory input from neurons that secrete either GABA or glycine They have modulatingeffects rather than information-transmitting effects.The release of neurotransmitters other than glutamate and GABA tends to activate or inhibit entire circuits of neurons that are involved in particular brain functions.What do all the other neurotransmitters do? Acetylcholine -AChThe primary neurotransmitter secreted by the efferent axons of the CNSAll muscular movement is accomplished by the release of acetylcholineAChis involved in regulating REM sleep -dreaming (doroslateralpons), perceptual learning (forebrain), and memory (hippocampus).AChreceptors: nicotinic and muscarinicAChfound at the target of parasympathetic branch of the ANS –outside of the CNS, first discovered neurotransmitter –the importance of Otto LoewiThe effects of AChare generally facilitatoryhttps://www.youtube.com/watch?v=RyfJwisRxvs CholinergicSynapsesSynapses that have acetylcholine transmitter are called cholinergic synapses.This is an electron micrograph of synapses between nerve fibres and a neuron cell body. What happens at a cholinergic synapse? Stage 1An action potential arrives at presynaptic membrane. Vo l t a g e g a t e d c a l c i u m c h a n n e l s i n t h e presynaptic membrane open, calcium ions enter the presynaptic neuron What happens at a cholinergic synapse? Stage 2Calcium ions cause synaptic vesicles to fuse with the presynaptic membrane, releasing acetylcholine into the synaptic cleft. What happens at a cholinergic synapse? Stage 3Acetylcholine diffuses cross the synaptic cleft and binds to specific neuroreceptor sites in the post synaptic membrane What happens at a cholinergic synapse? Stage 4Sodium channels open. Sodium ions diffuse into the postsynaptic membrane causing depolarisation, which may initiate an action potential. What happens at a cholinergic synapse? Stage 5Acetylcholinesterase (enzyme) breaks down acetylcholine. The products diffuse back into the presynaptic neuron where acetycholineis resynthesisedusing energy (ATP) from the mitochondria. Neuromuscular JunctionsSame stages as cholinergic synapses, but in this case the postsynaptic membrane is the muscle fibre membrane (Sarcolemma).Depolarisation of the sarcolemma leads to contraction of muscle fibre. Nicotinic receptor -an ionotropicacetylcholine receptorstimulated by nicotine Muscarinic receptor -a metabotropic acetylcholine receptor Nicotinic receptorAn ionotropicacetylcholine receptor that isstimulated by nicotine and blocked by curare (paralysis).AChreceptorsAtropine acts by preventing acetylcholine from depolarisingthe post-synaptic membrane and increases heart rateCurare acts at the junction between nerve cells and muscles causing paralysis.Muscarinic receptorA metabotropicacetylcholine receptor that isstimulated by muscarineand blocked by atropine. BotulinumtoxinAn acetylcholine antagonist; prevents release by terminal buttons.Drugs that affect AcetylcholineBlack widow spider venomA p o i s o n p r o d u c e d b y t h e b l a c k widow spider that triggers the release of acetylcholine causing convulsions-agonist The MonoaminesDopamine, norepinephrine, epinephrine, and serotonin are four neurotransmitters that belong to a family of compounds called monoamines.Because the molecular structures of these substances are similar, some drugs affect the activity of all of them to some degree. a celebrity among brainchemicals –the reward neurotransmitterDopamine……“cupcakes could be as addictive as cocaine” –they cause a surge of the reward chemical dopamine to hit the decision-making area of the brain The reward pathway and addictionNatural rewards: food, water, sex, nurturingAddiction: a state in which an organism engages in compulsive behaviour, behaviour is reinforcing (rewarding, pleasurable), loss of control for limiting intakeVTA -ventral tegementalare The reward systemSelf -administration To l e r a n c e •A s t a t e i n w h i c h o r g a n i s m n o longer responds to a drug•A h i g h e r d o s e i s r e q u i r e d t o achieve the same effectDependence•A s t a t e i n w h i c h o r g a n i s m functions normally only in the presence of a drug•Manifested as physical disturbance when the drug is withdrawnDifferent circuits in the brain: it is possible to be dependent on the morphine, without being addicted to it. Dopamine is indeed involved in addiction, but it is not only a "pleasure chemical". In fact, dopamine has lots of functions in the brain –being involved in everything from regulating movement to the control of attentionstarts in the substantianigraand terminates in the basal ganglia : plays a role in the control of movement.NigrostriatalsystemNeurological disease characterized by tremors, rigidity of the limbs, poor balance, and difficulty initiating movements; caused by degeneration of the nigrostriatalsystem; Parkinson’s disease has been treated with L-DOPA Step 1:Step 2:Dopaminergicsynapse Dopaminerigicsynapse: Step 3: CocaineCocaine binding sitesDopaminergicsynapse in nucleus accumbensThe effect of cocaine:Inhibition of dopamine reuptakeIncreased activation of the reward system Increased reward system via increased dopamineneurotransmission PET activationsMetabolic activity: glucose reduction Serotonin is involved the control:1.appetite2.sleep3.memory and learning4.temperature regulation 5.cardiovascular function 6.muscle contraction 7.endocrine regulation8.depressionSerotonin•also called 5-HT •play a role in the regulation of mood, the control of eating, sleep, dreaming, and arousal.•involved in the regulation of pain. The serotonin synapseSerotonin transporters LSDMDMAA d r u g t h a t s e r v e s a s a n o r a d r e n e r g i c a n d serotonergicagonist, also known as “ecstasy”; has excitatory and hallucinogenic effectsLSD stimulates centers of the sympathetic nervous system in the midbrain, which leads to pupillarydilation, increase in body temperature, and rise in the blood-sugar level. LSD also has a serotonin-blocking effect The psychedelic effects of LSD The effects of ecstasy on serotonintransporters:1.Prevent reuptake2.Work in reverse mode: bring more5-HT to the synapse Long term effects of serotoninAnimal studies: neurotoxicity Long term effects of ecstasyImpairments of verbal and visual memory DepressionLow serotonin levels are believed to be the cause of many cases of mild to severe depression which can lead to symptoms such as anxiety, apathy, fear, feelings of worthlessness, insomnia and fatigue.If depression arises as a result of a serotonin deficiency then pharmaceutical agents that increase the amount of serotonin in the brain should be helpful in treating depressed patients.Anti-depressant medications increase serotonin levels at the synapse by blocking the reuptake of serotonin into the presynapticcell. Epinephrine (adrenaline) isa hormone secreted by the adrenal medulla; serves as a neurotransmitter in the brain.Norepinephrine (NE) or noradrenaline is both a hormone and a neurotransmitter. As a hormone, secreted by the adrenal gland, it works alongside epinephrine / adrenaline to give the body sudden energy in times of stress, known as the "fight or flight" response.Medications that inhibit the reuptake of NE can be effective to treat depression. In addition, elevated NE are found in patients experiencing maniaNorepinephrine Amino AcidsThe most common neurotransmitters in the CNS: glutamate, gamma-aminobutyricacid (GABA), and glycine.GlutamateAn amino acid; the most important excitatory neurotransmitter in the brain.NMDA receptor -A s p e c i a l i z e d ionotropicglutamate receptorPCP –angel dustsynthetic drug –Indirect anatgonist The GABA neurotransmitter and its receptors are critical to how humans think and act GABA is part of the brain system that allows us to fine-tune our moods, thoughts, and actions with an incredible level of detailImbalances in GABA also are relevant to bipolar disorder, schizophrenia and anxiety disorder.GABA -driving a car. You need the accelerator, but at every stage you need the brakes to work. Some of our neurotransmitters apply the spark and the gas to the engine, and GABA supplies the brakes GABA provides the necessary inhibitory effect that we need in order to block out excessive brain activity that in depression may lead to excessive negative thinking.GABA as a brake systemGABA: Gamma-aminobutyric acid is an amino acid. GABAis the most important inhibitory neurotransmitter in the brain and glycine in the spinal cord. TranquilizersBenzodiazepineA c a t e g o r y o f a n x i o l y t i c d r u g s ; a n i n d i r e c t a g o n i s t f o r t h e GABAAreceptor; these drugs are used for their tranquilizing effects: Valium (diazepam), Xanax (Alprazolam) Neurotransmitter actions -SUMMARY•Acetylcholine is the transmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain, but using different types of receptors (nicotinic). •GABAis used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA. Correspondingly glycineis the inhibitory transmitter in the spinal cord. •Dopamineplays a critical role in the reward system, but dysfunction of the dopamine system is also implicated in Parkinson's disease and schizophrenia.•Serotoninregulates appetite, sleep, memory and learning, temperature, mood, muscle contraction, and function of the cardiovascular system and endocrine system. It plays a role in depression (lower concentrations of serotonin in their CSF and brain tissue).•Glutamateis used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain. Thank you