Nervous System Flashcards
Why is the generation of electrical signals such a central part of our ability to act/carry out task in the world?
Our ability to conduct ourselves in the world is highly dependent on our ability to move which relies on musclar contraction - hence, given that the signals that co-ordinates movement are electrical in nature (neuronal communication), these electrical signals play a central role in our existence
Therefore, we can see that disruption of this system can lead to negative health outcomes.
What is amyotrophic lateral sclerosis (ALS)?
ALS is a motor neuron disease
- Progressive degeneration of upper and lower motor neurons
Upper motor neurons – descend down from cortex into spine
Lower motor neurons – spine to periphery -control activation of skeletal muscles - Signals required for movement of the muscles and their contorl are disrupted
- Inability to initiate and control voluntary movements
- Eventually leads to inability to speak, eat, move and eventually breathe
- ALS does not affect brain function (cognition, sensory perception etc)
- There is no known cure for ALS - mortality is 100%
Outline the disease progression for ALS.
Risk factor - head impact
Early symptoms - Slight weakness and tingling in the hands and limbs (early symptoms)
As the disease progresses (weeks to months):
- twitching & cramping of the muscles
- loss of motor control hands & legs
- tripping & increased incidence of falling
- persistent fatigue
- slurred speech
Late stage symptoms (>1 year):
- Difficulty breathing
- Difficulty swallowing
- Paralysis
Average life expectancy after diagnosis 2-5 years.
What do we know so far about ALS disease mechanism?
Disease mechanisms
- Exact cause of the disease is unknown
- Genetic mutations & environmental factors have equal importance
- 20 genes have been associated with ALS (SOD1, C9orf72..)
- Genetic dysfunction leads to protein aggregation in upper and lower motor neurons - proteinopathy
- Neuronal dysfunction & cell death drive main ALS symptoms
What is multiple sclerosis? What are the associated symptoms?
MS is a demyelinating disease that affects the conduction of electrical signals in the CNS - autoimmune disease
Commonly develops & is diagnosed in patients in their 20s or 30s
Causes a wide range of symptoms (blurred vision, uncontrolled voluntary movement, loss of sensation & balance)
Average life expectancy is only slightly reduced and symptoms can be managed - less severe than ALS
Outline the disease progression for multiple sclerosis?
The different stages include…
- Clinically isolated syndrome (CIS) - first episode that causes inflammation & damage to nerves (myelin)
- Relapsing-remitting MS (RRMS) - follows a predictable pattern where symptoms worsen and then improve (relapse and remission - oscillation)
- Secondary-progressive MS (SPMS) - RRMS can develop into a more aggressive and progressive form of the disease if left untreated - more advanced/severe form - cumulative negative impacts on neurons
On a cellular level what does the pathophysiology of MS look like?
Main characteristics
1. Formation of lesions in the CNS (called plaques)
2. Inflammation due to autoimmune response
3. Destruction of myelin
Combined effects: disrupted signalling between neurons in the CNS, leading to blurred vision, uncontrolled voluntary movement, loss of sensation & balance etc
Describe the socioeconomic burden caused by ALS?
- Estimated 250,000 cases worldwide
- Affects people of all races & ethnic backgrounds
- Military veterans 1.5-2 times more likely to develop ALS - reasons unknown, could reflect exposure to lead, pesticides & toxins
Annual costs:
€78K per patient / year
€250K per patient lifetime
High costs due to the requirement of 24-hour care in the latter stages of the disease
What are the current treatment strategies of ALS?
Incurable neurodegenerative disease
Life expectancy after diagnosis 2-5 years
Main treatment strategy is symptom management:
- physical, occupational, speech & respiratory therapies
- exercise in moderation
- hot sauna/steam rooms to relax muscles – some patients report constant contraction
FDA approved drug - ‘riluzole/rilutek’
1st drug to prolong survival
by 2-3 months
Why are there no/limited number of treatments for ALS?
Limited understanding of pathophysiology - making it difficult to create treatments
Limited understanding of the genetic origins and environmental factors –> hence, resulting in a reduced capacity to design drugs & target therapies
Hence, we need to develop a deeper understanding of disease mechanisms so that entry points for therapeutic interventions can be created.
Desrcibe the socioeconomic burden of MS?
Estimated 2.5 million cases worldwide
~130,000 in the UK alone
Affects people of all races & ethnic backgrounds
Identical twins share the same genetic makeup, but the risk for an identical twin is only 1 in 4 - highlights the importance of environmental factors
Annual costs:
£10-40K per patient / year depending on severity
£0.4M - £1.6M per patient lifetime - overall larger cost as the patients are able to live for longer
Differing levels of home care depending on severity
What are the current treatment strategies for MS?
No cure, symptom management - reduce number of relapses and accumulative damage
- Focus on managing relapses (avoiding nerve damage due to inflammation) via…
a) corticosteroids reduce inflammation
b) plasmapheresis (plasma exchange)
Disease modifying treatments (DMTs)
variety of approved drugs available
- Betaseron, Avonex, Copaxone…. all drugs reduce relapses & inflammation
Aslo consider rehabilitation - exercise programme to address physical challenges associated with MS
Psychosocial support - chronic, debilitating disease can affect mental health, support groups provide support structure
Why are there a limited number of treatments available for MS?
- Disease modifying treatments are available and slow disease progression, but efficacy varies (significant side effects)
- Limited understanding of the genetic origins and environmental factors - makes it hard to develop effective therapeutics
- Require a deeper understanding of disease mechanisms to provide entry points for therapeutic interventions
What was the neuron doctrine prosposed by Santiago-Ramon y Cajal?
Law of Dynamic Polarisation - preferred direction for cell-to-cell communication - neurons send information in a unidirectional manner (from dendrites to axons) –> holds true
What are the different compartments of a neuron?
Note - Cell body or soma
What are the three categories of specialised glial cells present in the nervous system?
Astrocytes:
- Most numerous cells in the brain
- Fill spaces between neurons
- Regulate the chemical content of the extracellular space
Schwann cells:
- oligodendroglial cells - CNS
- Schwann cells - PNS
- provide myelination of axons
Microglia
- brain’s resident immune cell
What are the two main divisions in of the nervous system?
Central Nervous System (C.N.S)
- brain and spinal cord
Peripheral Nervous System (P.N.S)
- long axons radiate from C.N.S to innervate the rest of the body
- sensory (afferent) axons take information from the periphery to the C.N.S
- motor (efferent) axons convey information from the C.N.S to muscles
What are the dorsal and ventral roots? What types neurons do they have?
Refers to the two main neuronal bundles that exit/enter the spinal cord into the periphery
- Dorsal roots contain afferent axons - send information to the spinal cord
- Ventral roots contain efferent axons - neurons that innervate muscles
- Spinal nerves contain a mix of afferent and efferent axons
What are some activities/actions controlled by the brain and spinal cord?
The brain: cognition, motivation, emotion, learning & memory, volitional movement
Spinal cord: reflexive actions which are automatic, short-latency responses to stimuli, which does not require the brain.
What are the three general functions that electrical excitable are used for?
Excitable cells are electrically charged and use electrical currents to:
- Sense stimuli (e.g. chemicals, pressure, pain, touch)
- Transmit information to each other often over long distances
- Do something (e.g. contract a muscle fibre, release messenger molecules like hormones or neurotransmitters)
What is the basis of electrical excitability of cells?
Since all living systems exist in a water environment
Electrical currents in biology are driven by the movement of ions in solution –> used to generate current
The main ions of interest are: Na+, K+, Cl- & Ca2+
Given that the phospholipid membrane is impermeable to ions, what are the two ways of transport across?
There are only two ways that ions can move across the cell membrane:
- Through ion pumps - active pumping
- Through ion channels - allow free passage of ions down concentration gradient
In a neuron at resting potential, what is the charge across the membrane and what does the ion distribution look like?
Resting potential is roughly -67mV –> means that the inside is more negatively charged relative to the outside
Ions located extracellularly - High Na+ & High Cl-
Ions located intracellularly - High K+ + presence of negatively charged proteins inside the cell
What is one of the main pumps responsible for re-establishing the resting potential ion concentrations?
Sodium-potassium ATPase (Na+/K+ pump)
Na+/K+ pump transfers 3 Na+ ions from inside the cell to outside & simultaneously takes 2 K+ ions from outside and transfers into cell - ATP dependent
What are ion channels?
Ion channels are proteins which make pores or gates that allow ions to move across the lipid membrane
Ion channels can be:
- Selective - for particular ions (e.g. Na+, K+) - - Switched to be open or closed
What is the two-pore domain potassium channel and what role does it play in neurons?
Two-pore domain potassium channels…
are open at rest when the cell is not excited and help set the resting membrane potential - important role - allows for the flow of K+ ions to the extracellular space (driven by conc. and electrical gradient)
They are regulated by pH, oxygen tension and stretch
What does the nerst equation helps us calculate?
Allows us to calculate the membrane potential by looking at the ion concentrations on either side of a membrane
What are the two proteins that play an important role in establishing the membrane potential?
Excitable cells act like batteries, with a charge (‘resting potential’) of about -65 mV
This is brought about by the activity of the sodium-potassium pump and open K+ channels (leak) in the membrane (more important)
How do the neurons create bioelectricity/signals using the ion gradients?
Excitable cells use bioelectricity to
generate brief electrical pulses called action potentials - refers to a rapid change in membrane potential
Action potentials – basic functional unit of the nervous system - packets/units of information used by the nervous system
These units/packets can come in multiples – encode another level of information – firing rate
Hence, their timing and frequency is used to encode NS information
Why are action potentials important?
Long range communication (C.N.S. & P.N.S.)
- fast efficient signalling e.g. across long axons
- frequency and pattern of action potentials encode information
Used for Bidirectional communication
- Motor commands to muscles
- Feedback sensory information (e.g. proprioception, muscle tone, pain)
When action potential communication becomes disrupted:
- Multiple sclerosis
- Charcot-Marie-Tooth disease
- Alzheimer’s disease
- Locked-in syndrome
- ALS
What are the different parts of the action potential?
All-or-nothing event
- Resting potential no stimulus - maintained by Na+/K+ ATPase pump and K+ leak channel (1)
- Membrane depolarisation – triggered by multiple factors - causes a switch in membrane potential
- If threshold is reached – tigger an action potential - all or nothing
- If succesful, we get full depolarisation - opening of local voltage gated sodium channels (Rising phase 2)
- Falling phase (3) - Repolarisation (return to resting potential) – following depolarisation as Na channels close and K+ channels open leading to K+ efflux
- Undershoot (4) - lower potential than resting potential (neuron is desensitized) –> after which we get a return to resting potential
What has the patch-clamp recording technique allowed us to do?
Allow for measurements of ionic currents through channels
What are the properties of Na voltage gated channels?
Na voltage gated channels
- Channels are closed at rest (-70 mV)
- Depolarisation to -40 mV induces a conformational change in the protein opening a pore
- Pore acts as selectivity filter to allow passage of Na+ ions - driving depolarisation
- 12x more permeable to Na+ than K+ ions
- Channel opening is very fast, producing a rapid depolarisation (rising phase)
- Channels stay open for ~1 ms before inactivating (physical pore block) - inactivation gate blocks pore, which is different from the closed state, known as the inactivated state
- Re-opening can occur when the membrane potential returns to rest (-65 mV)
What are the properties of K voltage gated channels?
K+ voltage gated channels
- Similar to Na+ channels, K+ channels require depolarisation to open
- Unlike Na+ channels, K+ channels are slow to open (~1 ms after depolarisation)
- Pore acts as a selectivity filter to allow passage of K+ ions
- Delay in opening and reset membrane potential = delayed rectifier
- Channels close when the membrane potential returns to rest (-65 mV)
Outline the contributions of the different channels at the different stages of the action potential.
- Two pore potassium channels at rest – sets MP
- Activation of Na channels – depolarization
- Activation of K+ channels – repolarization
- Resting potential re-set - two pore K+ channels
What are the two types of refractory period following an action potential?
Refractory period - the time in which an excitable cell is unable to generate a subsequent action potential
Refractory period – two types
- Absolute refractory period - when all the Na+ channels are open – you can’t introduce another stimulus as they have all been recruited – one action potential at a given time
- Relative refractory period - repolarization phase – hyperpolarization makes the neuron less sensitive stimuli – harder to produce a action potential – greater change in membrane potential required to reach threshold
What is the axon hillock?
Axon hillock – point between soma and axon – high concentration of Na+ channels – region where action potentials are generated
Explain how action potentials move across an axon in a unidirectional manner.
As Na+ channels open, Na+ diffuses along the neuron in turn depolarizing regions that lay ahead (opening Na+ voltage gated channels) resulting in a propagation of the action potential – known as a wave of depolarization
Upstream Na+ channels that were activated become inactivated after ~1ms & K+ channels also open, in turn blocks the bidirectional propagation of action potentials
What factors influence the velocity that action potentials can travel?
Axon conduction velocity in unmeylinated axons - 1-10 m/s
Factors influencing velocity
1. Resistance of the plasma membrane
2. Diameter of membrane – big axon = faster conduction
3. Sodium channel density
How is myelin organised in neurons? How is it created? How does it speed up the rate of communicaiton?
Oligodendrocytes/Schwann cells – produce myelin sheath
Myelin sheath is organised following a discontinuous nature
Gaps are known as nodes of Ranvier
High density of Na+ channels found at the nodes - this allows for rapid saltatory conduction between nodes of Ranvier - node-to-node propagation of action potentials (described as a domino effect)
What is the difference in velocity of conduction between myelinated and non-myelinated axons?
Myelinated axons conduct action potentials much faster than unmeylinated axons
Unmyelinated axons - 1 - 10 m/s
Myelinated axons - 60 - 120 m/s
What are the four types of axons/neuron categories, list them in order of speed and what they are used for.
How are sensory input detected in the skin?
Mechanoreceptors - stretch, bend or pressure sensitive unmyelinated fibres
Mechanosensitive ion channels- gating depends on stretch of surrounding membrane - intiating membrane potential
If stimulus triggers an action potential, it will propagate via the neuron(s) via the dorsal root to the spinal cord
What is a dermatome? What do they do?
Dermatome - an area of skin that contains primary afferents that transduce information from the periphery to the spinal cord
Dermatomes - tile the surface area of the body, linking specific areas of skin with specific spinal nerves - think of it as a neuronal map of the skin
How many cervical, thoracic, lumbar and sacral nerves are there?
8 cervical, 12 thoracic, 5 lumbar & 5 sacral nerves….relaying sensory information from the skin to the brain, via the spinal cord.
What are receptive fields and how do we map them out?
Receptive fields - looks at which areas the neurons receive information from
How do we map them? - Introduce a stimulus and observe whether this triggers activity in a specific neuron
What aspect of the action potential(s) encodes the stimulus strength & onset/offset?
Stimulus strength - is encoded by the action potential firing frequency
Stimulus onset / offset (timing) - is encoded by the timing of the 1st / last AP
How do two different neurons communciate with eachother?
Excitable cells communicate via chemical neurotransmission
Specialised structures called synapses are where neurons contact each other
What are the different criteria (5) needed to classify a chemical as a neurotransmitter?
- There are precursor molecules and/or synthesis enzymes located in the presynaptic terminal
- The chemical is present in the presynaptic terminal
- It is available in sufficient quantity in the presynaptic neuron to affect the postsynaptic neuron
- There are postsynaptic receptors that bind the transmitter
- A biochemical mechanisms for inactivation is present
What are the different classes of neurotransmitter?
Classes of neurotransmitters:
- Amino acids - glutamate, aspartate, serine,
Ɣ aminobutyric acid (GABA), glycine - Monoamines - dopamine (DA), noradernaline
(NA), adrenaline, histamine, serotonin (5-HT) - Others - acetylcholine (ACh), adenosine, nitric oxide
- Peptides - over 50 neuroactive peptides, sometimes released with other neurotransmitters
What does the life cycle of a neurotransmitter look like?
Do the volume of activity - there has to be a quick replenishment of neurotransmitters –> hence, we often see recycling of molecules - cyclical
Outline the cascade the intiates neurotransmitter release?
Sequence of events leading to neurotransmitter release:
- Action potential invades the presynaptic terminal
- Membrane depolarisation occurs
- Voltage-gated calcium channels open
- Increase in calcium promotes vesicle fusion – caclium binds to SNARE proteins allows for vesicular fusion
- Vesicles release neurotransmitters into the synaptic cleft - exocytosis
Outline the endocytosis and exocytosis cycle of vesicles that takes place in the pre-synaptic terminals?
- Docking - vesicle binds to membrane, before AP invades terminal - primed
- Ca2+ sensing - Ca2+ entry triggers fusion of the vesicle - SNARE complex driving fusion
- Endocytosis - new vesicle membrane “pinched” off - formation of new vesicles
- Loading - new vesicle is filled with neurotransmitter
Cycle completes and can start again
What are the two types of receptors found at the post-synaptic terminal?
Ionotropic receptors = fast response (µs - ms), ion channels open when neurotransmitter binds - tend to be ion channels that allow for direct membrane depolarisation
Metabotropic receptors = slow response (ms
- s), activation of a second messenger - GPCRs
What are some common targets of metabotropic receptors?
- Phospholipase C - cleaves PIP3 into IP3 and DAG –> secondary messengers
- Adenylate Cyclase - converts ATP into cAMP
Can synapses be both excitatory and inhibitory?
Synapses are either excitatory or inhibitory - this is determined by neurotransmitter they release
What is an EPSP and lPSP (excitatory and inhibitory)?
Post-synaptic potentials (PSPs) are called excitatory (or EPSPs) if they increase the likelihood of a postsynaptic action potential occurring, and inhibitory (or IPSPs) if they decrease this likelihood.
EPSP - increase movement of Na+ into the post-synaptic neuron - increasing the liklihood that it fires - depolarisation
IPSP - increase movement of Cl- into the post-synaptic neuron - increasing the liklihood that it will not fire - hyperpolarisation
How do neurons integrate multiple different synaptic inputs?
Neurons don’t just receive input from one other neuron
They integrate inputs from tens to thousands of presynaptic neurons –> Example: Cerebellar Purkinje cell receives ~100,000 excitatory synaptic inputs
Different types of summation
1. Spatial summation - summation of EPSPs generated at different synapses - integrated effect
2. Temporal summation - summation of EPSPs generated at the same synapse - before EPSP decays we have the arrival of another EPSP – leads to summation – domino effect
Likewise, we have the arrival of IPSPs –> suppresses the excitation, reducing the membrane depolarisation and preventing the generation of an action potential
What are agonists and antagonists?
Agonist - mimics the effect of the endogenous neurotransmitter
Antagonist - blocks the effect of the endogenous neurotransmitter
Examples shown in image
- Ach - endogenous neurotransmitter –> activates nicotinic and musarinic receptors
- Nicotine - activates nicotinic receptors
- Muscarine - activates muscarinic receptors
- Curare - inhibits nicotinic receptors - poison for arrow tips, blocks muscle contraction, paralysis
- Atropine - inhibits muscarinic receptors -opthalmic use, dilates the pupils - cleopatra used it for vanity
What effects do ethanol, barbiturates and neurosteroids have?
Act on the GABAergic system
Ethanol - affects the level of inhibition, affects CNS (cognition) and PNS (motor function)
Barbiturates - mild sedation to full anaesthesia (commonly misused drug)
Neurosteroids - endogenous modulators, levels changed during menstrual cycle
What do we call the neurons that innervate and control skeletal muscles?
Skeletal - somatic motor cells
What does the sympathetic nervous system consist of and what does it do?
Chain of sympathetic ganglion (body of neuronal bodies)
Preganglionic neurons release acetylcholine
Postganglionic neurons release noradrenaline
Sympathetic neurons located next to targets Participates in ‘fight-or-flight’ response
By binding to different postsynaptic adrenoreceptors:
1. Relaxes airways in the lungs
2. Inhibits digestion
3. Accelerates heart rate
4. Constrict blood vessels
Adrenaline - used to treat patients in cardiac arrest (increases peripheral resistance & accelerates heart rate)
What does the parasympathetic nervous consist of and what does it do?
Releases acetylcholine
Compliments sympathetic nervous system, acts as a brake to the sympathetic system
Controls actions that do not require an immediate reaction:
1. digestion
2. metabolic functions (liver, GI tract)
3. regulates kidneys, liver etc
4. Vasodilation of blood vessels
By binding to different postsynaptic acetylcholine receptors, results in:
1. constriction of airways
2. stimulates digestion
3. slows heart rate
ACh acts on two types of receptors, the muscarinic and nicotinic cholinergic receptors.
- Preganglionic neuron releases ACh at the ganglion, which acts on nicotinic receptors
- Postganglionic neuron then releases ACh to stimulate the muscarinic receptors of the target organ
Parasympathetic neurons travel large distances
How are somatic motor neurons organised?
Somatic motor system: under voluntary control and generates behaviour
Divided into upper and lower motor neurons
What are lower motor neurons?
Lower motor neurons - located in spinal cord and conntect to muscle fibres
- Directly command muscle contraction
- Skeletal muscle movements, initiate by ‘lower’ motor neurons
- Activated by local spinal cord circuits
- Each motor neuron innervates a single muscle
How are lower motor neurons organised?
Lower motor neurons are distributed
within the ventral horn in a predictable way –> Spatial organization/map of the body in the spinal cord - muscles located more distally are located laterally in the spinal cord (visa-versa)
Spatial map of body musculature
Neurons innervating flexors are dorsal to those innervating extensor muscles
What is an alpha motor unit?
The alpha motor neuron and all the muscle fibres it innervates is classed as the motor unit
What is a motor neuron pool?
Muscle contraction - results from the individual and combined action of motor units
Motor neuron pool - collection of alpha motor neurons that innervate a single muscle (e.g. biceps) - drive contraction of a single muscle
This arrangement maintains normal muscle activity when damage to a single motor neuron occurs - redundancy in the system
Why are multiple synaptic terminals at a neuromuscular junciton required?
Spread contractile load - ensures that the entire muscles produces force in an even manner
What is the main neurotransmitter at the neuromuscular junction?
Muscle contraction - initiated by Ach release and binding to postsynaptic ACh receptors
1 presynaptic action potential is sufficient to trigger 1 postsynaptic action potential in a muscle fibre
Ach activity
1. Ach – binds to receptor
2. AChE breaks down Ach into choline and acetic acid
3. Choline recycled and pumped back into neuron – symport with Na+
4. Choline + Acetyl CoA used to resynthesize Ach
Outline the structure of a muscle fibre.
What is the molecular basis of muscular contraction?
Muscle contraction - thin (actin) filaments slide along the thick (mysoin filaments)
Contraction coupling -
1. Ca2+ binds to troponin, exposing myosin binding sites on actin
2. Myosin binds actin, myosin head pivots, sliding actin down
4. Myosin disengages at the expense of ATP hydrolysis
5. Cycle repeats
Summary of muscle contraction.
- AP in the alpha motor neuron
- Exocytosis of ACh
- Postsynaptic depolarisation
- Ca2+ release from sarcoplasmic reticulum
- Sliding actin/myosin filaments
- Muscle contraction
Relaxation occurs when Ca2+ or ATP levels reduce
What does increased motor unit recuirtment result in?
Number of motor neuron recruitment will change the level/force of contraction – higher Hz more motor unit activity
80 Hz action potentials = full contraction
What is a reflex?
An involuntary, nearly instantaneous movement in response to a stimulus (does not require the brain)
Important role in responding to noxious stimuli
E.g. Platellar or Knee-jerk reflex
What is a myotatic or stretch reflex?
Myotatic or stretch reflex: reciprocal innervation of flexors and extensors
One contracts the other is inhibited
Using the Patellar or knee-jerk reflex, describe the stretch reflex mechanism.
Basically interneuron is present which sends an inhibitory signal to the flexor (hamstring), whereas the extensor (quad) receives an excitatory stimulus.
Explain what happens in he crossed-extensor reflex.
Reflex pathway
1. Painful stimulus
2. Activation of sensory (afferent) axons
3. Activates excitatory interneurons
4. Motor neurons (efferent) induce contraction
But on its own this reflex would make you unstable –> Muscles don’t work separately - coordinated activity to ensure stability
Crossed extensor reflex – accounts for loss of balance induced by initial reflex in response to noxious stimulus – compensation to ensure body remains stable/balanced
Consists of a system of interneurons
What is the vestibulo-ocular reflex?
The vestibulo-ocular reflex (VOR) is a reflex acting to stabilize gaze during head movement, with eye movement due to activation of the vestibular system.
How does it fundamentally work?
Contraction of opposite muscle relative to direction of head rotation – allows to fix gaze on a specific target
Heads rotates to the right - the left extraocular muscles contract whereas the right one’s are inhibited
