Neurophysiology Flashcards
What is the function of the PM?
Defines boundaries of cell and differences between extracellular and intracellular responses
What is an organelle membrane?
Defines the boundaries of organelle and differences between intra and extra components and contents of organelle
Describe the structure of the PM
Very thin film of lipid and protein molecules
Phospholipid bilayer is common structural unit, provides basic structure
Highly dynamic, fluid structure
What is the function of the dissolved proteins in the lipid bilayer?
Mediate most of the other functions of the cell
What are the functions of the PM?
Maintain structural integrity and barrier function
Define shape
Control exchange
Site of chemical reactions (oxidative phosphorylation)
Site of ligand recognition
Cell-cell recognition
Facilitate cellular locomotion
What are the main components of the PM?
Lipids: phospholipid, cholesterol, glycolipid
Proteins: transmembrane, peripheral, integral
Glycolipids
Glycoproteins
What is meant by amphipathic?
Has both polar (hydrophilic) and non-polar (hydrophobic) regions i.e. phospholipids
What determines if phospholipids will for a micelle of bilayer?
Number of tails
1 tail: form circular micelle
2 tails: lipid bilayer
Describe the movement of lipids within the bilayer
Bilayer is highly dynamic Lipids can: move, diffuse freely within bilayer readily exchange place with neighbour in monolayer rotate around long axis hydrocarbon chain flexion RARELY swap side of monolayer
What determines the fluidity of the bilayer?
Composition and temperature
What 2 lipids are usually highly expressed in bilayer?
Cholesterol and glycolipids
Describe the structure of cholesterol
Rigid molecule of 4 hydrophobic steroid rings interacts with fatty acyl chains of membrane phospholipids
What is the function of cholesterol?
Highly expressed: up to 1 for every phospholipid to v important
Enhances permeability-barrier properties of the bilayer - tightly bound to phospholipid making membrane less soluble to v small water-soluble molecules
Describe the effect of temp on cholesterol
At physiological temp. cholesterol limits fluidity of membrane
At lower temp. prevent membrane becoming less fluid by preventing hydrocarbon chains binding each other
What are lipid rafts and what are their functions?
Micro-domain of PM rich in cholesterol and sphingolipids
Help organise proteins for transport in small vesicles or enable to function together
Explain the asymmetry of the bilayer
Outer layer of RBC have choline group
Inner layer have terminal primary amino group
What is the importance of the difference in symmetry?
Cytosolic proteins bind to specific lipid head groups thus different membranes won’t bind same proteins
What are glycolipids?
Sugar-containing lipids, found only in outer layer
Thought to partition into lipid rafts, self associate into micro-aggregates by forming H bonds with each other
What is the importance of sugar group exposure?
On surface important for interactions of cell with surroundings
Describe the 3 main types of membrane protein
Transmembrane: extend across bilayer, domains exposed both intra and extracellularly
Integral: exposed only on 1 side, usually tightly associated with membrane by lipid group
Peripheral: linked via non-covalent bonds with MP, easily released
Give examples of transmembrane, peripheral proteins
Transmembrane multipass: band 3 in RBC
Single pass: glycophorin
Peripheral: spectrin 1/4 of MP mass
What are glycoproteins?
Oligosaccharide chains bound to MPs (glycoproteins) and lipids (glycolipids)
Can also occur as polysaccharides bound to protein core forming proteoglycan (lots of sugar, little protein)
Describe the carb layer on the bilayer
Carbohydrate chains of glycolipids, glycoproteins and proteoglycans surround cell in thick coat allowing for protein binding
Why is the PM selectively permeable?
Retain barrier to EC environment
Ensure essential molecules: lipid, glucose, AAs enter cells
Maintain ionic gradient
Intracellular organelles can also have selectively permeable membrane
What is simple diffusion?
Diffusion of small molecules down conc. gradient without aid of MPs
What is the importance of membrane transport proteins?
Allow passage of polar molecules into cell Each transport only transports particular class of molecule, usually certain molecular species
What are carrier and channel proteins?
Carrier: bind specific solute, undergo conformational change to transfer solute across membrane
Channel: weakly associated, form aqueous pores when open allow specific solutes to cross membrane
What is passive diffusion?
Movement of molecules down conc. gradient without using energy usually just the conc. gradient dictates
If charged solute, both MP and conc. gradient (electrochemical gradient) will influence diffusion
What is active transport?
Movement of solutes up conc. gradient requiring energy
Carrier proteins can be active or passive, active tightly coupled to source of metabolic energy (ATP hydrolysis, ion gradient) and is directional
Define uniport, symport, antiport
Uniport: passive, 1 solute in 1 direction
Symport: active, 2 solutes in same direction
Antiport: active, 2 solutes in opposite direction (uses energy of 1 going down gradient to push other up)
Describe transcellular glucose transport
Actively pumped into gut epithelium by Na+-powered glucose symport
Diffuse out via facilitated diffusion in basal-lateral membrane
Na+ gradient maintained by Na+ pump in basal-lateral membrane that keeps Na+ low
Describe Na+/K+ATPase
Antiporter: pumps 3 Na+ out cell and 2 K+ in
Binding of intracellular Na+ changes conformation to E2 (low affinity for Na+), extracellular K+ binds to pump changing conformation back to E1 and K+ expelled in intracellularly
Maintains steep differences in Na+ and K+ concentrations
What is endocytosis?
Internal membrane system that allows uptake of macromolecules
What are the 2 types of endocytosis?
Phagocytosis: ‘cell eating’, ingestion of large particles - micro organisms or dead cells via large vesicles phagosomes
Pinocytosis: ‘cell drinking’, ingestion of fluid and solutes via small pinocytic vesicles
Describe receptor mediated endocytosis
Macromolecules bind to complementary transmembrane receptor proteins
Accumulate in coated pits
Enter cell as receptor-macromolecule complexes in clathrin-coated vesicles
What is the importance of clathrin mediated endocytosis?
Allows specific uptake of minor components of ECF in large amounts without large amounts of ECF - is concentrating mechanism
What is exocytosis?
Delivery of newly synthesised proteins, carbs, lipids to cell exterior
Vesicles fuse with PM
How does exocytosis function?
Products stored in secretory vesicles from trans Golgi network release products to exterior in response to extracellular signals
What are cel junctions?
Protein complexes that occur at cell-cell/matrix contact points in tissues - particularly plentiful in epithelial
What are the 3 functional groups of junctions?
Occuluding (tight): seal epithelial in way that prevents small molecules leaking from one side to other (gate) AND diffusion barrier within PM to maintain asymmetry (fence)
Anchoring (desomosomes): mechanically attach cells to neighbours OR ECM, strong cell adhesion, extensive mechanical strength to withstand mechanical strength
Communicating (gap): medicate passage of chemical/electrical signals
What is the resting membrane potential?
Electrical gradient across the cell membrane
In nerve cells is usually -70mV
Define depolarisation and hyperpolarisation
Depolarisation: make MP less negative
Hyperpolarisation: make MP more negative
Describe the function of the sodium pump
Any Na+ leaking into cell ejected by hydrolysis of ATP, 2K+ pumped into cell
Describe the function of the K+ channel
1 open at RMP allowing easy diffusion of K+ in/out cell
Even though pumped in by Na/K pump easily diffuse out
Describe the intracellular and extracellular conc of Na, K, Cl
Na: 145 extra, 12 intra
K: 4 extra, 139 intra
Cl: 116 extra, 4 intra
How is K+ held in the cytoplasm?
Binds to protein anions (-ve) holding K+ ions in cell
What is the effect of transporting ions across membrane?
Pumping ions has created electrical
Pumping +ve ions out has created chemical
Combined form electrochemical gradient
What is the Nernst equation?
Eion = RT/Fzln(Iout/Iin)
Describe how K+ contributes to the RMP
K+ leaks out conc gradient, -ve charge build up in cell as anions cannot cross membrane (electrical gradient formed)
-ve charge attract K+ back down electrical gradient
Net movement of K+ stops (equilibrium potential)
What is equilibrium constant?
MO at which electrical gradient opposes chemical gradient
For K+ EK = -90mV
How does Na+ contribute to RMP?
Na+ leaks in down conc. gradient, +ve charge builds up (electrical gradient) as Cl- can’t cross
Cl- attracts Na+ back down electrical gradient
Na+ movement stops
ENa = +60mV
Explain why RMP is -70mV?
Cell is ~40x more permeable to K+ than Na+ so closer to EK but small amount of Na+ still leaks into cell depolarises slightly
Despite the small voltage how is the RMP strong?
Due to how thin membrane is electric field strength is very large (rate of voltage change over distance (V/d)
What are ion channels?
Pore-forming membrane proteins
Establish and control voltage gradient across membrane by allowing flow of ions
Why are ion channels anchored to the cytoskeleton and ECM?
Keeps channel density constant in different subcellular compartments
What is special about ion channels?
Have aqueous pore that crosses membrane
Describe the structure of ions channels
2-6 subunits associate to create functional channel
Pore-forming subunits contain a-helix made by ~20 hydrophobic AAs, interact with lipid bilayer
What are the key components of an ion channel?
Selectivity filter: chooses ions to pass
Gate: shut/open (voltage/ligand) pore
Voltage sensor: detect MP
Explain how ion selectivity works
Channel shape specialised to act as molecular sieve (selectivity filter)
At filter ion arrangement of AAs strip ion of waters forming weak chemical bond with charged/polar AA residues lining channel
Explain how the bacterial KcsA channel functions
-ve charges raise local K+ availability at entrance
Hydrophobic residues of pore allow water molecules to interact with K+
Pore precisely configured to contain K+ surrounded by 8 waters
4 CO O atoms in filter serve as surrogate water
Fine tuned for K+, can’t shrink to bind Na+
Describe the ion permeability and gating properties of VGIC
Permeability: Na+, K+, Ca2+
Properties
Sensitivity: strong/weak depolarisation, hyperpolarisation
Kinetics: slow/fast, inactivating or non-inactivating
Explains VGIC activation
+ve charged residues on voltage sensors rotated towards EC by depolarisation
Voltage sensors mechanically coupled to outer helix thus open cell
Describe inactivation of VGIC
Have intrinsic blocking groups that enter permeability pore and prevent reopening
What is the importance of intrinsic inactivation?
Prevents repeated stimulation which uses lots of energy and high Ca2+ levels induces apoptosis
Describe LGC
Typically ion channels in postsynaptic cleft
Some respond to external ligands: ACh, GABA, glycine, glutamate
Or internal ligands: G-proteins, cGMP, cAMP, regulated by internal metabolites: PIP2, IP3, Ca2+, arachidonic acid
Give an example of a LGIC
NAChR
Requires 2ACh to bind in order to open pore
Fluxes Na+, K+
What are signal gated channels?
Similar to ligand but the signal comes from inside the cell
Atrial M2 receptor - GiPCR is an example
ACh binds receptor, activates Gi protein, a-GTP inhibits adenylate cyclase less cAMP production, By opens K+ channels causing hyperpolarisation of cell slowing HR
Describe modified of channel gating
Exogenous ligand can block - ir/reversible
Pore blockers - voltage dependent block of NMDARs by Mg2+
Exogenous modulators can alter action of endogenous ligands - in/dec opening period
What do cells need to communicate with and why is this important?
Immediate neighbours, cells in organ, distant organ systems
Enables body to respond in coordinated manner to internal or external environment
What are the types of intercellular signalling?
Contact dependent/juxtacrine
Autocrine
Paracrine/Synaptic
Endocrine
Describe juxtacrine signalling
Both ligand and receptor are membrane bound, require contract for info transmission
e.g. immune cell activation
Describe autocrine signalling
Secreted signal acts back on same cell
Encourages cell group coordination - make same decision during development
Cancer cells stimulate own survival and proliferation
Describe paracrine signalling
Secreted signal acts locally affecting cells in immediate environment
Can’t diffuse far, containment mechanisms: rapid uptake, destruction by EC enzymes, immobilisation by ECM
Explain histamine and infection paracrine signalling
Mast cells have large secretory granules with histamine - secreted in response to infection/injury
Histamine binds H1 receptors on local arteriolar SM causing vasodilation, enhancing local blood flow, improves ability of immune cells to reach infection site
Why must histamine use paracrine signalling?
Localised effect is vasodilation and bronchoconstriction
Peptides released stimulate invasion of infection by WBCs
Excessive activation lead to anaphylactic shock (sudden drop in BP) and airways to constrict
Describe synaptic signalling
Axons terminate at synapses - specialised intercellular junctions with either more neurons or target cells in distant organs
Communicate using APs
Arrival causes presynaptic nerve terminal to secret NT
NT bind to receptors on postsynaptic membrane transmitting signal on
Name an example of neuronal signalling
ACh
Nicotinic: excitatory, activates ion channels
Muscarinic: excitatory and inhibitory slow synaptic transmission, G-protein
Describe endocrine signalling
Form of whole body signalling
Secreted hormones into bloodstream, carries signal to distant target
How are hormones transported in blood?
Bind to carrier proteins (thyroid-globulin, cortisol-globulin)
Extends half life, increase plasma conc as otherwise rapidly eliminated by liver or kidney
Compare endocrine and CNS communication
Specific: E different cells must use different hormones; C nerve cells can use same NT still specific
Conc: E low conc diluted in blood, ECF; C high local conc
Affinity: E high affinity act at low conc; C low conc, dissociate rapidly
Speed: E slow; C faster, more precise
Describe intracellular signalling pathways
Extracellular signal binds receptor (usually on membrane)
Activates intracellular signalling pathway mediated by second messengers
1/+ interacts with target protein, altering behaviour invoking response in cell
Name the 4 types of receptors
Ion channel
G-protein
Tyrosine kinases
Intracellular
Describe intracellular receptors
Bind lipophilic ligand that can diffuse across membrane
Many located in cytoplasm before translocation to nucleus
Some bound to nuclear DNA
What are neurons?
Cells specialised for signal transport and processing
Collectively allow body to adapt behaviour
Basis for intelligence, independent thought, creativity
Describe the structure of nerves
Dendrites: inputs Soma: cell body Axon hillock: decision gate, whether propagate inputs to outputs (is threshold met?) Axon: connector Axon terminal: outputs
Describe dendrites
Project from cell body, few organelles
Membrane abundant with proteins to control input via ion gates
Electrochemical conduction of signal to soma
Describe the soma
Combines signals from dendrites
Large nucleus, abundant rER (Nissl bodies)
Axon hillock has lots of VGICs, threshold must be met for these to open
Describe axons
Transport between soma and axon terminal, very long (1m)
AP velocity increases as diameter increases
Contain microtubules
Transport: electrical charge, products made in soma
Describe anterograde transport
Towards axon terminals
Fast: kinesin transports NT packaged in vesicle by Golgi
Slow: transport proteins to make microtubules
Describe retrograde transport
Terminals to soma
Dynein transports surplus PM where it is recycled and processed by lysosomes
Exocytosis of NT causes extra PM is removed and vesicles remade
What is a myelin sheath?
Electrical insulator between neuron and ECM
Describe myelin sheath in PerNS
Schwann cells line axon, discontinuous myelin
Gaps called Nodes of Ranvier, high conc Na+ channels allow conduction over 1m, spacing optimised for efficiency
1 cell per segment
Provide mechanical support and insulation
Describe myelin sheath in CNS
Oligodendrocytes line axon
Nodes of Ranvier, discontinuous sheath
1 cell can wrap around 40-60 axons
Forms concentric rings of PM
Provides 3D scaffold
Describe the protection of nerve bundles in the PerNS
Epineurium extends from Dura and Arachnoid Mater contains nerve fascicles and blood vessels
Fascicles are bundles of axons protected by perineurium
Each axon is protected by endoneurium
Describe afferent and efferent neurons
Afferent - sensory Arrive at CNS
Efferent - response Exit CNS to excite
Describe a simple reflex arc
Pain receptor receives stimulation
Neuron travels along afferent nerve (PNS) synapses in CNS
CNS outputs neuron that travels along efferent nerve, synapses at muscle/target
Describe nerve regeneration in PerNS
If endonerium intact, Schwann cells move along to find other Schwann cell, reconnect and axon regenerated
Not possible is endoneurium broken as Schwann cells unable to find next cell
Describe nerve regeneration in CNS
Regeneration actively blocked in CNS
Astrocytes block regeneration
Get clubbed end of cut axons as can’t find other end
Prevents neuronal regeneration
Stabilise complex CNS - don’t want uncontrolled growth near brain
What are astrocytes?
Star shaped glial cell
Fibrous - white, protoplasmic - grey
Structural framework for migrating neurons during development
Transport fluid, ions from EC space to blood vessels
Energy metabolism of neurons by releasing glucose
What is an AP?
Electrical impulse that travels along nerve
Is responsible for transfer of info between 1 site and another
How is the RMP maintained?
Na/K pump and K channels
Describe the process of how VGNaC allow AP propagation
Depolarisation opens Na channels in membrane, Na+ moves into cell
Na channels outnumber K channels so produces depolarisation of cell
Describe the structure of VGNaC
Very large, single protein a-subunit forms channel
4 sub-domains of a subunit form central pore
Most have small B subunit, modulates a sensitivity
How does K+ not pass through Na channel?
No proof
Thought to be due to lysine and asparagine residues at neck
Describe the Na channel inactivation
To prevent excessive Na entry has intrinsic slow-acting, intracellular inactivation gate that closes pore
Occurs independently from channel opening mechanism
Hate resets slowly, preventing rapid reopening - refractory period
What is the effect of Na channel inactivation?
MP falls back down to resting
Na inactivation is sufficient to restore RP
Why is there delayed opening of VGKC?
Opening allows MP to rapidly re-polarise
Reduces refractory period, allows more rapid repeat of AP
Causes hyperpolarisation
Define the 2 types of refractory periods
Absolute phase - Na channels inactivated
Cannot activate AP
Relative phase - after hyperpoalrisation
Need higher intensity depolarisation to trigger AP
When are Na/K pumps used for repolarisation?
After periods of extended stimulation - not normal for regular AP firing
How are AP initiated?
VGNaC at axon hillock
High conc of channels, slow inactivating, small diameter smaller currents required
How are APs propagated?
Downstream Na channels triggered by changes in MP upstream
Inactivation prevents backwards propagation
What is saltatory conductance?
‘Jumping’ of AP from one myelin sheath to next due to nodes of ranvier
What do myelin sheaths allow for?
Small axons have faster APs
How do nerves transmit messages?
Message transmitted between cells by NTs
Describe synaptic vesicles
Not free in cytoplasm
Small membrane bound vesicles containing NTs
Labelled with many intra-membrane and surface proteins
What are the advantages of using synaptic vesicles?
Allows concentration of NTs in small package: binding proteins, active accumulation against conc gradient, release all at once v rapid
Protects against proteases, esterases
Storage system allowing rapid response to AP
Explain the quantal hypothesis
NT release is not continuous - each vesicle is single unit
Greater strength of AP requires more vesicle release
What are the 3 vesicle pools and what are their functions?
Reserve pool: mobilised by strong stimulation
Recycling pool: replenishes RRP upon mild stimulation
Readily-releasable pool: readily released
What is the importance of Ca2+ in vesicle release?
Release is dependent on influx of extracellular Ca2+
AP opens Ca2+ channels, entry causes vesicle fusion, NT released, AP continues
Why is Ca stored extracellularly?
Triggers too many processes (apoptosis)
What is the most important subunit of VGCaC?
a1 - forms pore
What are SNAREs?
Large family of membrane bound proteins involved in vesicle fusion
Describe the process of vesicle fusion
- Vesicles carry the v-SNARE - synaptobrevin
- Active zone PM target expresses t-SNAREs - syntaxin-1, SNAP-25
- RRP tethered by interaction between synaptobrevin, syntaxin-1, SNAP-25
- SNARE held by complexin- prevents vesicle fusion
- Ca2+ binds synaptotagmin causing displacement of complexin allowing vesicle to fuse, NT release
Why must synaptic vesicles be recycled rapidly?
As the supply is limited
Recycled from PM by clathrin-mediated endocytosis
Describe the lifecycle of a NT
- Precursors accumulate, NT produced
- NT packed into vesicle by selective transporters
- NT released into synaptic cleft, signal transmitted
- NT reuptake through neuronal or glial systems, degradation and recycling
How does a NT signalling through postsynaptic receptor get converted into new AP?
Directly or indirectly activate ion channels
What are the 2 effect that a NT activating a ion channel can have?
- Excitatory post-synaptic potential
2. Inhibitory post-synaptic potential
What is the difference between slow and fast EPSP/IPSP?
Fast: activate ion channels (direct)
Slow: GPCR activates ion channel (indirect) - M2 heart
How are EPSP generated?
ACh binding nicotinic receptor causes Na+ influx, EPSP - membrane depolarisation
Fundamental for function of ANS
How are IPSPs generated?
Binding GABA to GABAA triggers Cl- influx - hyperpolarisation
How sedatives - benzodiazepines, barbiturates
Describe the 3 different types of summation PSPs
Single EPSP not sufficient to trigger new AP
Temporal: fire another EPSP before last has died
Spatial: fire many EPSP in same area at once
Spatial (IPSP): cancel each other out, block responses
What is the BBB?
Structural and functional barrier which impedes, regulates influx of most comoijds from blood to brain
How is the BBB formed and what is its function?
By brain microvascular endothelial cells, astrocyte end feet, pericytes
Maintains constant environment of CNS
Protection from foreign substances in blood, may damage brain
Protection from hormones, NT
Compare structural differences of cerebral and other endothelial cells
Absence of fenestrations - abundant TJs prevent anything moving past
Compare the functional differences between cerebral and other endothelial cells
Impermeable to must substances
Sparse pinocytic vesicular transport
Inc expression of transport, carrier proteins - receptor mediated endocytosis
Only TJs
Limited paracellular and transcellular transport
Describe TJs
Appear at sites of apparent fusion between outer leaflets of PM of endothelial
Continuous and anastomosing (joining together)
Components: claudin, occludin, accessory linking to cytoskeleton
Describe junctional adhesion molecules
Integral membrane proteins with single transmembrane region
Belong to immunoglobulin superfamily
Regulate paracellular permeability and leukocyte (WBC) migration
What is homotypic and heterotypic binding in JAMs?
Homo: binding between adjacent endothelial cells acts as barrier for circulating leukocyte
Hetero: binding of JAM to leukocyte JAM guides leukocyte transmigration
Describe adherens junctions
Complex between membrane cadherin and intermediary proteins (catenins)
Cadherin-catenin complex joins to actin cytoskeleton
What is the function of adherens junctions?
Form adhesive contacts between cells
Cadherins signal cell-cell, prevent excessive cell growth
Assemble via homophilic interactions between extracellular domains of Ca-dependent cadherins on surface of adjacent cells
What are pericytes?
Cells embedded in basal lamina - interposed between endothelial and astrocytes
What is the function of pericytes?
- Mechanical/structural support
- Vasodynamic capacity - O2 sensors, shift blood supply to areas of high metabolic demand
- Barrier to passage of macromolecules
- Induce endothelial tightness by regulating endothelial proliferation, differentiation and formation of TJs
- Associated endothelial more resistant to apoptosis
- Phagocytic activity - may he involved in neuro-immune function
What is the function of astrocyte end feet?
Lattice of fine lamellar closely supposed to outer endothelial surface - separate capillaries from neurons
Biochemical support for endothelial
Direct contact between endothelial and astrocyte necessary for BBB formation
Regulate BBB by secretion of soluble cytokines
Describe the different methods of transport across BBB
Diffusion: lipophilic, down conc gradient
Carrier systems: actively selected; essential AAs, glucose, neutral AAs, glycine glutamate (NTs)
Receptor mediated endocytosis: larger molecules (insulin) - overlaps with carrier systems
What are efflux transporters?
Transporters that actively remove substances from brain
Impedes most drug delivery to brain
P-glycoprotein: removes waste products, binds whole range of molecules, most drugs fail due to function
Describe the immune system present in the brain
NONE - if directly injected into brain tumours, bacteria, viruses evade immune recognition; no control mechanism to remove
Why are there no immune cells in the brain?
They could damage neurons, synapses as not used to brain environment
Likely be activated by environment
What is the most superior region immune cells can reach in BBB?
Can reach perivascular space but can’t pass astrocyte
Why are there regions with the BBB?
Regions that require hormones - circumventricular organs
Respond to factors in circulation or involved in neuroendocrine control of homeostasis
Neuroendocrine hormones pass easily, locally deliver hormone and hormones released directly into bloodstream
What happens to the BBB during illness?
Enhanced permeability - blood borne bacteria can directly cause breakdown of inter-endothelial TJs
What can cause the significant enhancement of BBB permeability?
Ageing and chronic inflammation
Compare acute inflammation with chronic inflammation
Acute invokes physiological sickness behaviour
Chronic pathological cognitive impairments
How can drugs enter the brain?
Mimic substances for existing transporters: L-DOPA (dopamine precursor, Parkinson’s), gabapentin (AA transporter, epilepsy)
Injected intracerebrally: anti-cancer (doxorubicin)
Given into CSF: epidural anaesthetics (lidocaine)
What is the function of the Cerebrospinal fluid?
- Cushions, protects from trauma
- Mechanical buoyancy, support for brain
- Nutrients and ion supply
- Remove metabolic waste
- Protect against acute changes in arterial and venous BP
- Intra-cerebral transport of neuroendocrine hormones
What is the composition of the CSF?
Similar to that of plasma but low protein, reduced glucose (used readily), inc CO2 (high respiration)
How is the CSF circulated?
Induced by pulsating blood vessels, respiration, changes of posture, aided by ependymal
Bathes the ependymal and pial surfaces of CNS, penetrates nervous tissue along blood vessels
What are some of the pathologies that can effect the CSF?
Increase pressure: physical blockage (tumours), haemorrhage, infection (meningitis)
Congenital hydrocephalus: accumulation of CSF in ventricles
Why are pressure changes of CSF serious medical problems?
Significantly impair neuronal viability - physical effects (squeeze tissue), obstruction of O2, nutrient supply
What are the 3 parts of the brain stem?
Midbrain
Pons
Medulla oblongata
Describe the anatomy of the midbrain
Cerebral peduncles: ascending sensory and descending motor pathways
Nuclei of oculomotor and trochlear nerves
Sup. colliculi - visual reflex centres; Inf. colliculi - auditory relay centres
Substantia nigra - regulate motor function
Red nucleus - control voluntary limb movement
Cerebral aqueduct - contains CSF, connects 3 and 4 ventricles
Describe the relationship between substantia nigra and Parkinson’s
Substantia nigra is part of basal ganglia - series of integrated brain nuclei that regulate fine control of motor activity
Has dopaminergic neurons that ascend to caudate putamen (striatum)
Degeneration of dopaminergic neurons leads to Parkinson’s
Describe the anatomy of the pons
Pyramidal tracts: ascending and descending pathways
Nuclei of trigeminal, abducens, facial, vestibulo-cochlear nerves
Potine nuclei - neurones connecting cerebrum and cerebellum
Vestibular nuclei: components of balance pathways from ear
Pneumotaxic and apneustic areas of respiratory centre - control breathing
Describe the anatomy of the medulla
Ascending and descending pathways
Cranial nuclei
Inf. cerebellar peduncles: fibre tracts connecting medulla and cerebellum
Pyramids: bulges on ant. aspect of medulla
2 longitudinal ridges formed by corticospinal tracts passing between brain and spinal cord
site of decussation (X-over) of as/descending pathways
What are the main centres of the medulla?
Cardiovascular - heart rhythm Respiratory - breathing rhythm (Vomiting, swallowing, sneezing, coughing, hiccuping) Inf. olivary nucleus Cuneate nucleus, gracile nucleus
What is the role of the inf. olivary nucleus?
Integrates input from cerebral cortex, midbrain red nucleus, spinal cord, sensory info from skeletal muscle
Helps regulate neural activity of cerebellum
Has role in leading new motor skills
What is the role of the cuneate and gracile nuclei?
Carries touch pressure, vibration and proprioception info
Name the nerves that originate in each region of spinal cord
Midbrain: 3, 4
Pons: 5, 6, 7
Medulla: 8, 9, 10, 11, 12
What does the trigeminal nerve carry?
Facial sensation and oral motor functions (chewing and biting)
What are the 3 branches of the trigeminal?
Ophthalmic: sensory (positing of eye)
Maxillary: sensory
Mandibular: sensomotor
Where do the 3 branches of trigeminal converge?
On trigeminal/semilunar ganglion
Single sensory root enters brain stem at level of pons, smaller adjacent motor root emerges at same level
What are the 4 nuclei of the trigeminal?
Sensory
Mesencephalic
Pontine
Spinal
Describe the sensory nucleus of CN V
Largest of cranial nuclei
Extends from midbrain to spinal cord
Has 3 parts, chief sensory nucleus in pons
What is the role of the mesencephalic nucleus?
Proprioception of face and position of facial musculature
Info from mandible projected to motor trigeminal nucleus - mediates monosynaptic jaw jerk reflex
What is unique about the synapses in the mesencephalic nuclei?
Are electrically coupled not chemically
What is the role of the pontine nucleus?
Discriminative and light touch sensation and integrates with conscious jaw proprioception
Sensory info crosses midline and passes to contralateral thalamus
Oral cavity info passed to ipsilateral thalamus
What is the role of the spinal nucleus?
Deep/crude touch, pain, temp from ipsilateral face
Pain info from facial, glossopharyngeal and vagus
What is the light reflex and its importance?
Light entering 1 eye will elicit contraction of pupil in both
Damage to brain stem connecting neurons in oculomotor nerve leads to failure of reflex
Can be used to check life sign of patient: signs of optic nerve and oculomotor nerve damage, depressant drugs, brain stem death
If a lesion is present in the brainstem what will the affect on the light reflex be? And if it is in the oculomotor nerve?
Brainstem: only 1 eye will respond
Oculomotor: neither eye responds
What is the role of the facial (VII) nerve?
Signals voluntary movement of facial muscles, carried to facial motor nucleus in pons via corticobular tract
What fibres of facial nerve project bilaterally and what do they control? Which project contralaterally?
Cortical fibres controlling forehead muscles project bilaterally meaning the control both halves
Fibres controlling other facial muscles project contralaterally
What type of neuron lesion results in total paralysis of facial expression muscles ipsilaterally to lesion?
Lower Motor Neuron Lesion
Caused by damage to motor nucleus of facial nerve or its axons
Damage to cortical neurons or their axons projecting to facial nerve motor neurons results in what?
Upper motor neuron lesion
Voluntary control of lower facial muscles lost on contralateral side but control of forehead muscles preserved due to bilateral innervation
How is an upper motor neuron lesion usually caused?
Stroke
What is the reticular activating system?
Diffuse network of nerve pathways in large parts of dorsal brainstem
What is the function of the RAS?
Sleep arousal cycle: impulses sent to cerebral cortex to maintain consciousness and control sleep
Pain perception: modulates pain
Movement control: controls coarse motor movements
Visceral activity regulation: vasomotor, cardiac, respiratory centres regulate visceral motor functions
Filters out repetitive/weak stimuli
What are the 2 ascending pathways?
Specific
Non-specific
Which ascending pathway’s 2nd order neurons lie in the medulla and transmits sensory input for touch, joint stretch?
The specific
Sensory input can be precisely located
Axons X to other side of brain, ascend thalamus
Describe the non-specific ascending pathway
Sensory input that is difficult to precisely locate: pain, temp, crude touch
2nd order neurons lie in dorsal horn of spinal cord
Axons X to other side of brain, ascend to thalamus
What are the 2 descending pathways?
Direct/Pyramidal
Indirect/Extrapyramidal
What descending pathway originates with neurons in cerebral cortex? Describe it
Direct pathway
Impulses sent through lateral corticospinal tracts and synapse in ant. horn of spinal cord
Ant. corticospinal tract descends on ipsilateral side of spinal cord, X at level it synapses
Lat. corticospinal tract X in medulla, descends to ventral horn of spinal cord
Describe the extrapyramidal motor system
All motor pathways not part of pyramidal
Are complex, multisynaptic and regulate:
axial muscles that maintain balance and posture
muscles controlling coarse movements of prox. portions of limbs
H&N, eye movements that follow objects in visual field
Describe 1st order neurons
Sensory neuron, delivers info from receptor to CNS
Cell body located in dorsal root ganglion
Axon passes to spinal cord through dorsal root of spinal nerve
Synapses with 2nd order in spinal cord or medulla
Describe 2nd order neurons
Cell body in spinal cord or medulla oblongata
Axons decussate and terminate on 3rd order
Describe 3rd order neurons
Cell body in thalamus
Axons terminate in ipsilateral cerebral cortex
How and where are as/descending fibres organised?
In distinct bundles which occupy particular regions in white matter
What tracts are located peripherally in white matter?
Long tracts
Where are short tracts found?
Near grey matter
What is a tract?
Bundle of nerve fibres (within CNS) having same origin, course, destination and function
What does the name of a tract indicate?
Origin and destination of its fibres e.g. nigrostriatal from substantia nigra to striatum
How are axons within a tract grouped?
According to body region innervated
What is the composition and divisions of grey matter?
Composition: neuron cell bodies, dendrites, axons
Divisions: post. horn, ant. horn, lateral horn
What is the composition and divisions of white matter?
Composition: myelinated axons
Divisions: ventral/ant., dorsal/post., lateral funiculi each divided into sensory or motor tracts
What is the function of the dorsal column funiculi?
Carry impulses concerned with PROPRIOCEPTION, discriminative touch pressure and vibration from ipsilateral side of body
What are the 2 tracts of the dorsal column funiculi?
Fasiculus gracillis
Fasicuclus cuneatus
What axons do the dorsal columns contain?
Axons of primary afferent neurons that have entered cord through dorsal roots of spinal nerve
Compare where the fasciculus gracillis and fasciculus cuneatus fibres are received
FG: sacral, lumbar, lower thoracic levels
FC: upper thoracic, cervical levels
Ascend w/o interruption and terminate on 2nd order neurons in nucleus gracillis and cuneatus, respectively
Where do the 2nd order neurons decussate in the dorsal funiculi and how do they ascend?
Decussate in medulla as internal arcuate fibres
Ascend brainstem as medial lemniscus
Where does the medial lemniscus terminate?
In ventral post. nucleus of thalamus on 3rd order neurons which project to somatosensory cortex
What is the result of a left spinal cord injury in the dorsal funiculi?
Loss of sense: touch, proprioception
Patient will stagger, can’t perceive position or movement of legs, vibration in left leg
Test: cotton wool touch (light), joint position, vibration
What are the 2 spinothalamic tracts and what info do they carry?
Lateral: pain, temp
Ventral: non-discriminative touch, pressure
How are the fibres in the spinothalamic tracts arranged?
Highly somatotopically: lower limb superficial, upper limb deep
Where do the thalamic neurons of both the lateral and ant. spinothalamic tracts project?
Primary sensory cortex - somatosensory cortex on opposite side of body
Describe the lateral spinothalamic tract
Senses pain and temp
1st order neuron axons terminate in dorsal horn
2nd order axons decussate within segment of their origin
Terminate in 3rd order in ventral post. nucleus of thalamus
Describe the ant. spinothalamic tract
Sense non-discriminative touch and pressure
1sr order terminate in dorsal horn
2nd order may ascend several segments before decussating
What is the effect of a left spinal cord injury in the spinothalamic tracts?
Lose sense of touch, pain, warmth/cold in right leg
Test: pinprick, hot/cold stimuli
What do the spinocerebellar tracts control?
Posture
Movement
What are the 2 spinocerebellar tracts?
Posterior
Anterior
Where do the spinocerebellar tracts carry info from?
Muscle spindles, Golgi tendon organs and tactile receptors to cerebellum
Both convey to same side of cerebellum
Describe the post. spinocerebellar tract
Present only above L3
2nd order neurons lie in Clark’s column
Axons terminate ipsilaterally in cerebellum by entering through inf. cerebellar peduncle
Describe the ant. spinocerebellar tract
2nd order cell bodies lie in base of dorsal horn of lumbosacral segments
Axons X, ascend to midbrain, X again to enter sup. cerebellar peduncle
Terminate in cerebellar cortex
What are the symptoms of spinocerebellar damage?
Cerebellar ataxia
Clumsy movements
Incoordination of limbs
Wide based, feeling gait
What is Romberg’s test?
Test for spinocerebellar ataxia
Stand upright and close eyes, if lose balance +ve result
Require vision, vestibular function and proprioception to maintain balance
Allows distinction between sensory and cerebellar ataxia
Describe the spinal cord anatomy of afferent neurons
Enter spinal cord in dorsal root
Cell bodies in dorsal root ganglion
Describe spinal cord anatomy of efferent neurons
Cell bodies in grey matter in ventral spinal cord
Axons exit in central root
Describe the formation of plexuses
Dorsal and ventral roots fuse forming spinal nerves, exit via intervertebral foramina
Spinal nerves branch and fuse in plexuses forming peripheral nerves
What are dermatomes?
Skin territory innervated by 1 dorsal root
What is the clinical importance of dermatomes?
Overlap at edges ~50%
Total loss of sensation requires anaesthetising 3 successive spinal nerves
How are dermatomes diagnostically useful?
Damage to spinal nerves changes skin sensation within dermatome allowing localisation of vertebral damage
What are the 3 types of nerve fibre?
A: alpha, beta, gamma, delta
B
C
Which type of nerve fibre is the only 1 to be unmyelinated?
C type
Describe the relationship between diameter and conduction velocity
Directly proportional: greater diameter greater velocity
Describe afferent and efferent A alpha and gamma motoneurons
Efferent
Alpha: muscle fibre
Gamma: muscle spindle - tells brain is muscle is contracted
Afferents project to 2 specialised sensory receptors in muscle and tendon
Muscle spindle: Ia afferent
Golfing tendon organ: Ib
Describe A beta nerve fibres
General sensory afferents, mechanoreceptors
Myelinated, fast
Majority of fibres are A beta
Describe A delta nerve fibres
Nociceptor or thermoceptor
Fast pain from skin, muscle, joints
Temp sensation
Describe C fibres
Nociceptor or thermoceptor
Small, unmyelinated afferents
Conduct very slowly
Slow/aching/burning pain
Describe the structure of a nerve
Individual nerve axons and Schwann cells covered by v thin connective membrane - endoneurium
Fibres grouped in fascicles, each surrounded by tough layer - perineurium
Fascicles and blood supply surrounded by tougher sheath - epineurium
What are the 2 main locations of Schwann cells?
- Ensheathing single axon with myelin
2. Surrounding groups of unmyelinated C axons (Remak bundles)
What is the function of Schwann cells?
Provide nutrient support to axons
Promote regeneration
Do NOT insulate or provide conduction velocity
Describe myelin and its production
Fatty layer around axon that inc. conduction velocity
Produced by Schwann cells in spiral around axon
Name the 6 somatic senses and 5 special senses
Somatic
- Mechanoceptors - touch, pressure, vibration, stretch
- Chemoceptors - chemicals
- Nociceptor - pain
- Thermoceptor - temp
- Proprioceptors - muscle stretch, balance
- Baroceptors - blood pressure
Special
- Vision
- Hearing
- Taste
- Smell
- Equilibrium - balance
Define sensation
Sub/conscious awareness of changes in in/external environment
What are the 3 classes of sensory receptor?
- Free nerve endings: pain, thermoceptor
- Encapsulated: pacinian corpuscles
- Separate: hair cells, photoreceptors, gustatory receptor cells
Compare the AP production of free and encapsulate nerve endings and specialised receptor cells
Free
Generator potential produced, threshold met, AP triggered
Specialised
NT release from cell, AP triggered in sensory neuron
What are the 2 main classes of skin mechanoceptors?
- Rapidly adapting
2. Slowly adapting
What are the 5 main mechanoceptors? Are they rapidly or slowly adapting?
- Hair (follicle) receptors - rapidly
- Meissner’s corpuscles - rapidly
- Pacinian corpuscles - slowly
- Merkel’s discs - slowly
- Ruffini’s corpuscles - slowly
Describe encapsulated receptors and give 3 examples
CT capsule around nerve fibre ending
Tunes fibre to respond to certain mechanical stimuli
- Meissner’s
- Pacinian
- Ruffini’s
Describe pacinian corpuscles
Layers of elastin-containing cells around nerve ending
Mechanically filter tissue stretch or slow deformation
Leaves ending specifically sensitive to high freq. vibration
Describe the receptive field of pacinian corpuscles
Periosteum: v large, detect vibration anywhere on limb
TMJ richly supplied, feel drilling across bone
How are encapsulated sensory axon nerve endings activated?
Mechanosensitive ion channels
Physical distortion of terminal membrane activates ion channels triggering generator potential which can then initiate 1+ APs in axon
Describe free nerve endings, give 2 examples of specialised types
Abundant in epithelial and underlying CT
Respond to pain, temp. slowly adapting
- Merkel discs: epidermis, slowly adapting for light touch
- Hair follicle: wrap around hair follicles, rapidly adapting
Compare rapidly and slowly adapting fibres
Rapidly: fire short burst of APs then stop
Slowly: continually fire at slowly dec. rate
Name 3 proprioceptors and their function
- Muscle spindle: changing length of muscle; embedded in perimysium between muscle fascicles
- Golgi tendon organs: tension within tendons; near muscle tendon junction
- Joint kinesthetic receptors: sensory within joint capsules
What are receptive fields?
Area of skin where stimuli can influence a sensory receptor
Vary in size from tiny (hair follicle around single hair follicle) to very large (pascinian corpuscles)
What is the importance of receptive field overlap?
Damage to single fibre does not leave any region of skin anesthetised
Compare discrimination for many and few primary neurons converging
Many: converge into single 2ndary neuron create v large receptive field; stimuli perceived as 1 in same field
Few: much smaller receptive field; stimuli activate separate pathways, perceived as distinct
Describe neighbour inhibition
Pathway closest to stimuli inhibits neighbours causing enhancement of stimuli
Describe dental nerve endings
Tooth pulp sensory receptors arise from A delta and C fibres
Detect movement and chemical changes, signal temp and pain
Delta: enables tooth localisation
C: nociceptors mediate tooth pain (slow, throbbing tooth ache)
Define motor unit
Motor neuron and fibres it innervates
Describe the motor unit control of muscle
Muscles composed of muscle fibres
Alpha motor neuron innervates multiple fibres
Groups of alpha motor neurons innervate a muscle
How is muscle contraction increased?
Rate coding and recruitment
Compare fine and coarse movement motor unit size
Fine: multiple, small motor units
Coarse: fewer, each alpha motor neuron innervating up to 1000 muscle fibres
Compare upper and lower motor neurons
Lower: cell body in ventral horn of spinal cord, project to SM
Upper: cell body in brain/brainstem, send axons down des. spinal tracts to target lower motor neurons
What are the 3 main synaptic inputs of lower motor neurons?
- Descending tracts from UMNs
- Local interneurons (cells with all processes in CNS)
- Local sensory nerve fibres via reflexes
Describe muscle spindle receptors
Specialised receptors found in all SM
Long, thin spindles running length of muscle from origin to insertion
Within there are intrafusal muscle fibres that sensory nerves wrap around non-contractile centres of
Describe the activation of muscle spindle
Central receptor portion (no contractile machinery) activated by muscle stretch which activates Ia afferents inc. rate of AP firing
Contraction reduces AP firing
What is the role of gamma motor neurons in muscle spindle?
Adjust sensitivity of Ia afferents (muscle spindle sensory receptor)
Innervate contractile parts of intrafusal fibres
Describe the relationship between contraction of intrafusal fibres and sensitivity
Contraction inc. sensitivity of Ia afferents to stretch
What is the alpha-gamma linkage?
When alpha motor neuron activated, gamma motor neuron activated
What is the role of the alpha-gamma linkage?
Keeps spindle sensitive to stretch even at different absolute muscle lengths
Describe the muscle spinal cord connection
Ia afferent project into ventral horn providing direct connection with motor neurons
All tendon reflexes are monosynaptic
What is reciprocal inhibition?
Muscles on 1 side of joint reflex to accommodate contraction of other muscle
Flexor muscles inhibited by muscle spindle from paired extensor
Describe the knee-jerk reflex
Tapping patella causes slight stretch activating quadriceps muscle spindle
Ia afferents excite quadriceps motor neurons via monosynaptic connection
Inhibit antagonistic muscles via inhib. reflex arc
What is the importance of monosynaptic motor reflexes?
Maintain body posture in face of varying loads
E.g. holding glass that is then filled with fluid
Describe Golgi tendon organs
2nd major proprioceptors in muscle, found in muscle tendon
What is the role of Golgi tendon organs in muscle?
Prevent contracting muscles from applying excessive tension on tendons
Limits how contracted a muscle can get
Describe the activation of GTO
Activated by muscle tension and resulting compression of axon fibres
Compression opens stretch-activated cation channels, trigger APs in Ib afferents
Describe the connections of the GTO
Disynaotic connection to own motor neuron pool
Interneuron is glycinergic inhibitory neuron - glycine is inhibitory AA NT
Activation inhibits alpha motor neuron activity, preventing excessive contraction and damage
What is muscle tone?
Continuous, passive minor contractions in muscle causing resistance even in passive state
Compare damage to upper and lower motor neurons on muscle damage
Upper: exaggerated reflexes, pathological inc. in tone - muscle spasticity
Lower: reduces or absents tone - flaccid paralysis
Name 3 motor system pathologies
- Spasticity: inc. tone and tendon reflexes, UML
- Clonus: series of jerky contractions of muscle following sudden stretching of muscle
- Hyperreflexia: abnormally, pathologically brisk tendon reflex seen in 1+ muscles
What is the difference between pain and nociception?
Nociception: signal that something potentially dangerous has occurred
Pain: subjective, protective response triggered in the brain following nociceptive signals
Describe nociceptive nerves
Distributed through skin, joints, muscles, viscera, blood vessels NOT brain
All free nerve endings
What are the 2 types of fibres involved in nociceptive transmission?
- Thinly myelinated A delta fibres
2. Unmyelinated C fibres
What are the 4 classes of nociceptor?
- Mechanonociceptor
- Thermonociceptor
- Chemonociceptor
- Polymodal nociceptors
Describe mechanonociceptors
A delta and C fibres
Respond to mechanical injury accompanied by tissue damage
Describe thermonociceptors
A delta and C fibres
Respond to heat/cold at range of temps
Range depends on what receptors present in neuron
Stimuli coded by firing rate - higher freq., greater damage
Describe chemonociceptors
C fibres
Activated by endogenous mediators of tissue damage, inflammation and foreign agents (bee venom, capsaicin)
Describe polymodal nociceptors
C fibres
Respond to mechanical, thermal and chemical stimuli
Describe the activation of nociceptors
Tissue injury often immediate cause of pain
Resulting in local release of chemical agents that activate or enhance sensitivity of nerve endings to other stimuli
Are nociceptors slowly or rapidly adapting?
Neither - non-adapting
Do not rapidly return to basal activity rates
How is nociceptive transmission coded?
Nerve firing rate - greater exposure, greater freq.
Why are nociceptors able to be activated by multiple chemical mediators?
As free nerve endings have variety of receptor proteins
List some of the chemical mediators that can activate nociceptors
Capsaicin, K, H, ATP, histamine, bradykinin, substance P, eicosanoids
Describe the nociceptive pathways
Run through spinothalamic tracts
1st order: synapse in dorsal horn of spinal cord
2nd order interneurones: decussate, ascend to brainstem parabrachial nucleus or thalamus
3rd order: project to cortex and limbic system
Describe the lamina of the dorsal horn
Specific lamina where 1st order neurons synapse
A delta: lamina 1 and 5
C fibres: lamina 2
What does substantia gelatinosa refer to?
Lamina 2-4 of dorsal horn of spinal cord
What are the 2 classes of 2nd order neurons found in the dorsal horn?
- Nociceptive specific (NS) neuron
2. Wide dynamic range (WDR) neuron
Describe nociceptive specific (NS) neurons
Receptive info. from A delta and C fibres
Receptive fields restricted to small areas
Somatotopically organised
Describe wide dynamic range (WDR) neurons
Info. from nociceptive and non-nociceptive afferents
Innocuous stimuli will activate, noxious activate more strongly
WDR predominately found in lamina 5,6 some in 1,2,4
Important in linking A beta mechanoreceptor input with A delta nociceptive input
What are the 3 main pathways from spine to higher centres?
- Spinothalamic
- Spinomescencephalic
- Spinoreticular
Describe the spinothalamic tract
Terminates in med. and lat. thalamus
Outputs from thalamus terminate in somatosensory cortex
Arousal, motor responses, sensory discrimination, affective responses
Describe the spinomesencephalic tract
Terminates at periaqueduct grey (PAG) and locus coeruleus
Outputs from PAG project to hypothalamus and limbic system
Unpleasantness/fear of pain
Describe the spinoreticular
Targets the nucleus reticularis gigantocellularis in medulla
Outputs project to med. thalamus
Affective responses, autonomic responses
Describe the substantia gelatinosa
V low level of myelination, high number of glial cells
Many of what 2 types of receptors are found in the substantia gelatinosa?
Mu and Kappa opioid receptors found on pre and post synaptic nerves
Explain how ascending control pain gating functions
Fast-adapting A beta fibres stimulate inhibitory interneurons and prevent excitatory transmission cell activation
A beta fibres convey non-nociceptive mechanical and thermal stimuli thus override weak pain stimuli
What are the 3 major lower brainstem areas that the PAG projects?
- Nucleus raphe Magnus
- Locus coeruleus
- Nucleus reticularis paragigantocellularis
Explain how the nucleus raphe magnus prevents nociceptive transmission
Projects 5-HT neurons to inhibit pain transmission in lamina 1,2,5
Explain how the locus coeruleus inhibits pain transmission
Projects inhibitory noradrenergic neurons to lamina 1,5
Explain how the nucleus reticularis paragigantocellularis inhibits nociceptive transmission
Projects inhibitory 5-HT neurons to spinal cord and excitatory 5-HT neurons to locus coeruleus
What are the 2 reasons we have taste?
- Appetite: sugar; need carbs
Salt; cell signalling, fluid balance
Meat; proteins, AAs - Protection: bitter/sour; avoid poisons, off food
What are tastebuds?
Neuroepithelial cells grouped into mucosal projections
Not visible by naked eye
Describe taste papillae
Groups of tastebuds seen as raised, red dots on tongue
Visible to naked eye
4 types
What are the 4 types of taste papillae?
- Foliate
- Circumvallate
- Fungiform
- Filiform - not gustatory
Describe tastebuds
Barrel-shaped epithelial cells w/ chemosensory cells (gustatory receptor cells)
3 cell components:
- Taste receptor
- Supporting cell
- Precursor/basal cell
Narrow apical end extend into taste pore on tongue
Describe the function of each component of the taste bud
- Taste receptor: sensory transduction
- Supporting: possibly transitional cell
- Basal: differentiate into new receptor cells; derived from surrounding epithelium; renew every 10days
What is the synaptic control on gustatory receptors?
Afferent nerve terminal derived from facial, glossopharyngeal, vagus (CN 7,9,10)
Describe the central pathway of taste transduction
Afferents synapse in medulla
Ascend to thalamus and project to primary gustatory cortex
What are the 5 tastes?
- Salt
- Sour
- Sweet
- Bitter
- Umami
Define tastant
Soluble ions and molecules that activate gustatory neurons
Describe the initiation of taste
Tastant diffuses into taste pore, binds receptor
Change in ion flow across taste cell PM
Different tastes change ion flow differently
Describe salt taste transduction
Na+ enters cell via Na channels Depolarises cell Ca2+ released from internal stores NT released AP triggered in sensory nerve
Describe the sour taste transduction
H+/acetic acid enter via Na channel/proton transmembrane protein
Cytoplasm acidified
Internal H+ block proton sensitive K+ channel
Influx H+/red. K+
Ca2+ released internally
NT released
AP triggered in sensory nerve
What is different about the sweet, bitter and umami taste transduction?
Tastant doesn’t interact directly with channel
Describe taste transduction of sweet, bitter and umami tastes
Binding receptor activates G-protein G-proteins activates PLC PLC generates IP3 and DAG Ca2+ released internally from smooth ER Opens TrpM5 transmembrane action channel AP triggered in sensory nerve
What are the 4 functions of olfaction?
- Environmental sampling: alert danger, presence of food/person
- Recognition
- Detect bad, aversive smells
- Linked w/ memory
What is the requirement of an odorant?
Volatile to reach and activate olfactory neuron in nose
What are olfactory receptor neurons?
Neuronal cells embedded in olfactory epithelium with: basal cells and supporting cells
Why do ORNs regenerate every month?
To regenerate sense of smell in case of damage
Where are the odorant receptors located?
On cilia of ORNs
Cilia project from dendritic knob and bathed in mucous
What are Glands of Bowman?
Olfactory serous gland under epithelium that secrete mucous that odoriferous substances dissolve in
What is the odorant binding protein?
Protein found in secretory fluid w/ high affinity for many odorant molecules
What is the function of the OBP?
Carry odorants to receptor
Remove odorants once sensed
Amplify odorant conc.
What is the odorant receptor protein?
Transmembrane protein found in cilia PM
Describe how the ORP functions
Odorant binds to ORP Activates G-protein Alpha subunit dissociates and activates adenylate cyclase AC catalyses conversion of ATP to cAMP cAMP open Na+ channels in cilia PM Na+ influx depolarises cell AP triggered at axon hillock
Describe the connections of ORNs
Cilia project into mucous layer
10-100 axons form bundles that pass through ethmoidal cribriform plate and terminate in olfactory bulb at synaptic glomeruli
What are glomeruli?
Spherical bundles of dendritic process from ~25 mitral cells
What are mitral cells?
Principal neurons in olfactory bulb
Primary apical dendrite extends a glomerulus
Axons merge to for lat. olfactory tract
What are periglomerular cells?
Cells that mediate lat. inhibition between glomeruli
What are granule cells?
Inhibitory interneurons
Describe the olfactory central pathway
Mitral cell axons run through lateral olfactory tract to forebrain:
Hypothalamus: physiological responses
Amygdala: emotional (feeding and mating)
Hippocampus: memory
Pyriform cortex: smell discrimination
Connections to frontal cortex required for conscious perception of smell
What 2 things has the cortex evolved to do?
- Learn from environment
2. Generate activity patterns in response to specific patterns of thalamic and cortical activity
Describe how cortex activity affects consciousness
Conscious when activity normal
Sleep: altered activity - not necessarily reduced
Coma: little/no activity
What are the 3 association cortices?
- Post parietal: visual, agnosia
- Inferotemporal: memory formation, amnesia
- Frontal: executive functions and attention
What role does the post. parietal lobe play in visual processing?
Separating object from background, relative location and orientation
What is agnosia?
Inability to recognise an object
What are the 2 types of agnosia?
- Apperceptive: R post. parietal lobe lesion
2. Associative: L post. parietal lobe lesion
Describe apperceptive agnosia
Inability to recognise obscured object i.e. unusual orientations, on similar background
4 main types
What are the 4 types of apperceptive agnosia?
- Piecemeal perception
- Optic apraxia
- Constructional apraxia
- Contralateral disregard
Describe piecemeal perception apperceptive agnosia
Inability to recognise 1+ objects at a time
Describe constructional apraxia
Inability to construct 3D object using other objects or when drawing, usually produce gross simplifications
Describe optic apraxia
Inaccuracies reaching for objects
Inability to judge relative position and size
Clumsiness searching for object
Describe contralateral disregard
Inability to recognise opposite side of body
Describe associative agnosia
Inability to name/assign meaning to object from memory
Objects described in terms of physical appearance
Why can associative agnosia be caused by a lesion in either post. parietal lobe?
In visual analysis pathway info 1st passes through R lobe where objection recognition occurs then passes to L side for association with memory
What is amnesia?
Deficit in memory formation/recollection
What are the 2 types of amnesia?
- Anterograde: inability to from new memories - memories not transferred to LTM
- Retrograde: inability to recall experiences prior to disorder
How are memories transferred to LTM?
Takes few mins
Requires consciousness, consolidation
How can memories be held in STM longer?
Verbal repetition, reinsert into STM via auditory stimuli and helps consolidation
Blocked by competing sensory input
How does LTM differ from STM?
LTM is hard wired, not dependent on neuronal activity
After hypothermia patient will have severe retrograde amnesia from time they were cold but normal LTM; remember name, history, how to speak
What is the hippocampus?
Subcortical structure that projects into temporal lobes in primates
Important role in consolidation
What does damage to the hippocampus cause?
Severe anterograde amnesia and some retrograde
What are the 2 frontal association cortices?
- Dorsolateral frontal
2. Orbitofrontal
What is the role of the dorsolateral frontal association cortex?
Executive function: decision making, error correction, troubleshooting
Forward planning, ability to conceptualise future scenarios, think through consequences and choose most appropriate
What can damage to dorsolateral frontal cortex cause?
Inability to retain attention
What is the orbitofrontal cortex associated with?
Limbic system
Strongly inhibits primitive emotional and motivational behaviour to accepted social norms
What are the cortices associated with the limbic cortex?
- Cingulate
- Parahippocampal
- Orbitofrontal
What is the role of the cingulate cortex?
Emotional response to pain
What is the role of the parahippocampal cortex?
Memory formation - emotional memories
What is the role of the orbitofrontal cortex?
Integrates other limbic cortical areas, regulates output
What is the amygdala and its function?
Partly cortical, partly subcortical structure embedded in med. temporal lobe at ateroventral end of hippocampus
Emotionally labels new experiences
What can damage to the motor cortex result in?
Loss of movement with variable recovery
There is plasticity so muscle control will be taken over by new area
What is the supplementary motor area?
Part of cerebral cortex that contributes to muscle control
Located med. of premotor cortex (ant. of primary motor cortex)
What do lesions in the SMA result in?
Difficulty initiating movement and apraxia (normal reflexes but complex tasks difficult)
What are the 5 brain areas involved in motor control?
- Post. parietal cortex
- Primary somatosensory cortex
- Premotor cortex
- Supplementary motor area
- Prefrontal cortex
What is the function of post. parietal cortex in movement?
Respond to visual/somatosensory stimuli, current/future movements and mixture of both
What is the function of the primary somatosensory cortex?
Integrates touch info. and movement
What is the function of the premotor cortex?
Integrates info. about body position, organises direction of movement
What is the function of the supplementary motor cortex?
Organising rapid sequence of movements
What is the role of the prefrontal cortex?
Plan movement according to predicted outcomes of actions
What is apraxia?
Inability to properly execute learned, skilled movements following brain damage
What are the 5 types of apraxia?
- Ideomotor
- Ideational
- Orofacial
- Gait
- Constructional
What is ideomotor apraxia?
Impaired performance of movements despite intact motor, sensory and language functions
Can describe action verbally but not physically
Describe ideational apraxia
Inability to perform rapid sequence of movements in complex, multistep task (tea making)
What is orofacial apraxia?
Difficulty in skilled movements of face, neck, mouth, tongue, larynx, pharynx
What is gait apraxia?
Loss of normal function of lower limbs w/o sensory or motor neuron damage
What is constructional apraxia?
R post. parietal lobe lesion
Difficulty drawing and constructing 3D objects
What 2 groups do axons from motor cortex descend to spinal cord in?
- Lateral: independent limb
2. Ventromedial: gross limb
What 3 tracts travel in the lateral group?
- Corticospinal: hand/finger movements
- Corticobulbar: face, neck, tongue, eye
- Rubrospinal: fore- and hind-limb muscles
What 4 tracts travel in ventromedial group?
- Vestibulospinal: posture
- Reticulospinal: walking, sneezing, muscle tone
- Ventral corticospinal: muscles upper leg/trunk
- Tectospinal: eye and head/trunk movement
Why are the cortical output pathways described as the ‘direct motor pathway’?
Neurons don’t synapse until reach spinal cord
What are the 2 major pathways from motor cortex?
- Corticospinal: body regions, fine movement
2. Corticobulbar: facial regions
What are the 2 corticospinal tracts?
Ant: cross over at level of synaptic contacts with spinal motor neurons
Lat: cross over to contralateral spinal cord in pyramids
What does damage to corticospinal tract cause?
Red. of dexterity (fine finger/hand movement)
Loss of muscle strength
Describe the corticobulbar tract
UMN project from cortex to medulla
Terminate on LMN within brainstem motor nuclei
What is the role of the extrapyramidal system?
Modulate motor activity w/o directly innervating motor neurons
How does the extrapyramidal system work?
Target motor neurons in spinal cord involved in locomotion, reflexes, complex movements and postural control
How is the extrapyramidal system modulated?
By various areas in CNS: basal ganglia, sensory cortical areas, cerebellum, vestibular nuclei
What are the 2 main extrapyramidal tracts?
- Reticulospinal: projects bilaterally
2. Vestibulospinal: projects ipsilaterally
Describe origin and inputs of reticulospinal tract
From reticular formation in pons and medulla
Inputs: sensory and motor cortices, cerebellar, striatum and lat. reticular nuclei
What is the role of the reticulospinal tract?
Mediate control over most movements not requiring dexterity/maintenance of balance
Important in modulating reflexes
Describe the origin of the vestibulospinal tract
Med. and lat. vestibular nuclei in brainstem
What is the function of the vestibulospinal tract?
Control balance, posture, locomotion
How does the vestibulospinal tract function?
Fluid-filled semi-circular canals in ear detect movement and orientation of head, pass info. along CNVII to vestibular nuclei in pons and medulla
Muscle spindles detect body position
Vestibular nuclei compute motor programme to send commends to extensor muscles to keep centre of gravity above feet
What is the basal ganglia?
Group of nuclei of different origin that act as cohesive unit
What are the 4 nuclei in the basal ganglia?
- Striatum: caudate and putamen
- Globes pallidus: interior (med), exterior (lat)
- Subthalamic nucleus
- Substantia nigra: pars reticular, pars compacta
How does the basal ganglia connect to the spinal cord?
SMA -> motor cortex and basal ganglia
Basal ganglia -> motor cortex via motor thalamus
Motor cortex -> spinal cord via corticospinal and corticobulbar tracts
What does the cerebellum connect to?
Vestibulospinal and reticulospinal tracts in brainstem and (via motor thalamus) motor cortex
What is the role of the cerebellum?
Coordinates movement initiated by basal ganglia and motor cortex
What are the 3 connections of the cerebellum?
- Cerebrocerebellum: limbs and trunk
- Spinocerebellum: planning of movement
- Vestibulocerebellum: eye and head, balance
What are the 3 intrinsic factors governing coronary artery diameter?
- Physical
- Metabolic
- Autonomic
Describe the physical control of coronary perfusion
Only occurs during diastole when vessels contract pushing blood down coronary arteries
Describe the metabolic control of coronary perfusion
Local, transient ischaemia causes release of vasoactive metabolites
Describe the autonomic control of coronary perfusion
Larger arteries: a1 adrencoceptors, vasoconstriction
Smaller: B2 adrencoceptors, relaxation
Describe the relationship between coronary stenosis and angina
Stenosis (narrowing of arteries) leads to O2 deprivation to cardiac muscle
Causes sensation of chest squeezing and pain (angina) but relationship between pain severity and myocardial O2 deprivation is weak
What are the 2 types of angina?
- Stable: classic form
2. Unstable: escalates
Describe stable angina
Pain minimal at rest, develops upon physical exertion or stress
Symptoms fade rapidly upon rest
Describe unstable angina
Pain at rest and on minimal physical exertion
Severe and acute onset
Crescendo pattern: each episode worse than last
Where does the difference between the 2 types of angina lie?
In their pathological process
Chronic atherosclerosis vs acute vascular blockade
What are the 3 stages of plaque formation in atherosclerosis?
- Abnormal accumulation of lipid
- Fibrous tissue in vessel wall narrows or occludes vessel lumen
- Red. blood flow through vessel
How can stable angina lead to myocardial infarction?
If left untreated will lead to unstable angina, loss of O2 supply to heart muscle causes necrotic cell death in area supplied downstream to plaque/clot
What are the 6 risk factors of angina?
- Hypertension
- Hyperlipidaemia
- Smoking
- Obesity
- Diabetes
- Male
What are the 3 contributing factors to angina?
- Stress
- Menopause
- Systemic infection: helicobacter pylori
What is the ultimate goal in treatment of angina?
Red. heart workload thus O2 consumption
What is heart workload?
stoke vol. * arterial pressure * HR
What 3 factors is workload of the heart affected by?
- Preload: venous return
- Afterload: PR
- Sympathetic stimulation
What are the 3 main classes of drugs used in pharmacological treatment of angina?
- Organic nitrate donors: glyceryl trinitrate, isosorbide dinitrate
- B2 adrenoreceptors antagonists: propranolol, atenolol
- Ca2+ channel blockers: nifedipine, nicardipine
Describe the effects of organic nitrate donors
Widespread vasodilation: red. preload by action on venules, red. afterload by peripheral arterial relaxation
Some action on coronary artery dilation
Adverse: vasodilation, hypotension; met-haemoglobinaemia (red. o2 carrying capacity); tolerance
Compare glyceryl trinitrate and isosorbide mono/dinitrate
Glyceryl: sublingual administration, 100% first-pass metabolism, t1/2 2mins
Isosorbide: slow release, t1/2 1hr
What are the administration routes for organic nitrate donors?
Sublingual: fast acting acute attack
Oral/transdermal: slow, maintenance therapy
IV: maintenance of unstable angina or threatened MI
What effects do B-adrenoceptor antagonists have?
Red. O2 consumption by red. workload
Adverse:
Hypotension, bradycardia, bronchoconstriction, hyperlipidaemia
Depression, fatigue, red. libido
Risk of MI in rapid cessation
Compare propranolol and atenolol
Propranolol: non-selective B1&2 adrenoceptor antagonist, can target B2 receptors in bronchioles thus not used in asthmatics
Atenolol: cardio-selective B1 adrenoceptor antagonist
What are the 2 types of Ca2+ channel blockers?
- Cardiac favouring: diltiazam, verapamil
2. Vessel favouring: nifedipine, nicardipine
Explain how Ca2+ channel blockers treat angina
Prevent Ca entry into muscle cell, red. contractility, electrical impulse propagation and vascular tone
How do cardiac favouring Ca2+ channel blockers work?
Diltiazam, verapamil
Dec. SAN automaticity, red. AVN conductivity causing dec. HR and myocardial contractility
How do vessel favouring Ca2+ channel blockers work?
Relax blood vessels causing dec. BP and inc. coronary artery perfusion
What are the adverse effects of Ca2+ channel blockers?
Hypotension Bradycardia AV block Gastric distress Constipation
What 2 types of drugs are used to supplement angina treatment?
- Anti-platelets/anti-thrombotics: aspirin
2. Antilipidaemia agents: statins
What are Broca’s and Wernicke’s areas?
Broca: specialised cortical ant. to premotor cortex, adjacent to motor area for mouth that controls language vocalisation (output)
Wernicke’s: L. post., sup. temporal gyrus, control language perception (input)
What are the 2 types of aphasia?
- Expressive: difficulty saying words; Broca’s area
2. Receptive: speak fluently in meaningless way; Wernicke’s area
Compare Expressive and Receptive aphasia
Halting; fluent Repetitive; no repetition Disordered grammar; grammar ok Disordered syntax; good syntax Disordered word order; meaningless Sense behind words; inappropriate words
What is the arcuate fasciculus?
Bundle of cortico-cortical association fibres that connect Broca’s and Wernicke’s areas
Damage results in conduction aphasia
Parallel bundles run via area known as Geschwind’s area
Supplements and enhances language function
What is conduction aphasia?
Impaired ability to repeat back heard/written words
Relatively preserved language comprehension
Speech characterised by word-finding difficulties
Patients recognise paraphasias and errors, attempt to correct
What is paraphasia?
Substituting of 1 word for another, often inappropriately
What are the 3 types of paraphasia?
Phonemic: papple for apple
Verbal: confusing husband/wife
Neologistic: completely new word
What is the Wernicke-Geschwind model?
Sounds are decoded into words and meaning in Wernicke’s area
Ideas or concepts of words are formed in Wernicke’s areas, then sent via arcuate fasciculus to Broca’s area where they are converted to motor commands to vocal muscles
What is Wada’s test?
Hemisphere dominance test in which anaesthesia injected into carotid artery on 1 side of face
Anaesthetises only 1 side supplied by middle carotid artery, functions lost are noted
Describe the lateralisation of language specialisation
70-95% of people have L language specialisation
Rest either have R hemisphere language specialisation or bilateral specialisation
What is the function of the non-specialised hemisphere?
R said to be emotional and creative area NOT TRUE no evidence
In recovered stroke in Broca/Wernicke area patients, show activation in equivalent R hemisphere areas
Damage to R equivalents has subtle effects on language processing, especially auditory info and context
What is the corpus callosum?
Large fibre tract connecting R and L hemispheres
Info in the L visual field initially processed in R visual cortex
Info cross brain to Wernicke’s area for verbal recognition
What is the result of a corpus callosotomy?
Patients could recognise image but not name it as info unable to cross brain to Wernicke’s area
Describe the relationship between handedness and speech dominance
Dissociative
Majority L handers have Broca and Wernicke areas on L just like R handers
What are the 2 theories for handedness?
- Psychological/Environmental: model parents, societal pressure
- Genetic: R handedness dominant trait since antiquity, L handedness apparently not fully heritable
