Neurology and Neuroscience Flashcards
What are the components of the CNS and the PNS?
The central nervous system (CNS) consists of the two cerebral hemispheres, the brainstem, the cerebellum and the spinal cord. The peripheral nervous system (PNS) consists of the nerve fibres originating from the CNS.
Outline the structure of the cerebral hemispheres
The cerebral hemispheres (also known as the telencephalon) have a distinctive convoluted surface appearance where the ridges are called gyri (singular gyrus) and the valleys are called sulci (singular sulcus).
What are the 4 functionally distinct regions/lobes comprising the cerebral hemispheres?
1) Frontal: Responsible for executive functions such as personality
2) Parietal: Contains the somatic sensory cortex responsible for processing tactile information
3) Temporal: Contains important structures such as the hippocampus (short term memory), the amygdala (behaviour) and Wernicke’s area (auditory perception & speech)
4) Occipital: Processing of visual information
What are the components of the brainstem?
The brainstem consists of the midbrain, pons and the medulla in descending order. These structures have a multitude of important functions (e.g. control of respiration & heart rate) and are the target or the source of all the cranial nerves.
Outline the location and function of the cerebellum
The cerebellum is located towards the dorsal region of the CNS and is attached to the brainstem. It has an important role in motor coordination, balance and posture.
Outline the location and function of the spinal cord
The spinal cord extends down from the medulla and acts as a conduit for neural transmission but can coordinate some reflex actions.
What is a mature neuron?
A mature neuron is a non-dividing excitable cell, with a heterogeneous morphology, whose main function is to receive and transmit information in the form of electrical signals. Although neurons come in a variety of different shapes and size, they do share a number of common features.
Outline the morphology of the 4 types of neurons
1) Unipolar: 1 axonal projection
2) Psuedo-unipolar: Single axonal projection that divides into two
3) Bipolar: 2 axonal projections from the cell body
4) Multipolar: Numerous axonal projections from cell body
> Pyramidal cells: ‘pyramid’ shaped cell body
> Purkinje cells: GABA neurons found in the cerebellum
> Golgi cells: GABA neurons found in the cerebellum
What are the functions of the soma, axon and dendrites?
1) Soma (cell body, perikaryon)
> Contains nucleus, & ribosomes
> Contains neurofilaments which are important in maintains the structure structure, as well as useful for transportation
2) Axon
> Long process (aka nerve fibre) - originates from soma at axon hillock
> Can branch off into ‘collaterals’
> Usually covered in myelin
3) Dendrites
> Highly branched cell body - NOT covered in myelin
> Receive signals from other neurons
Other than neurons, what other cells are found in the CNS?
1) Astrocytes: the most abundant cell type in the mammalian brain. They function as structural cells and are known to play an important role in cell repair, synapse formation, neuronal maturation and plasticity.
2) Oligodendrocytes & Schwann cells: oligodendrocytes are the myelin producing cells of the CNS, whilst Schwann cells perform the same function in the PNS. Each oligodendrocyte cell body sends out numerous projections that form internodes of myelin covering the axons of neurons. Whilst each oligodendrocyte is capable of myelinating a number of axons a Schwann cell only myelinates a single axonal segment.
3) Microglia & Ependyma: microglial cells are specialised cells that are similar to macrophages and they perform immune functions in the CNS. Ependymal cells are epithelial cells that line the fluid filled ventricles regulating the production and movement of cerebrospinal fluid.
What is the resting membrane potential (RMP)?
This is an ionic imbalance between the extracellular fluid and the intracellular fluid of a neuron with an unequal distribution of the major physiological ions. These concentrations are determined by the activities of a variety of membrane bound channels and transporters. The resting membrane potential due almost entirely to the movement of K+ ions out of the cell.
How are the major physiological ions distributed in RMP?
1) Sodium (Na+):
> Intracellular conc. 5-15 mM
> Extracellular conc. 140-155 mM
2) Potassium (K+):
> Intracellular conc. 140-160 mM
> Extracellular conc. 2-5 mM
3) (Ca2+):
> Intracellular conc. ~0.0001 mM
> Extracellular conc. 1-2 mM
4) Chloride (Cl-):
> Intracellular conc. 5-10 mM
> Extracellular conc. 70-140 mM
5) Organic Phosphates (-):
> Intracellular conc. 130 mM
> Extracellular conc. 3 mMWhat is the electromotive force (emf)?
The relative concentrations of the major physiological ions is one of the factors that gives the cell membrane an electromotive force (emf), a potential difference between the inside and the outside of the cell. As the cell membranes are impermeable to the major physiological ions, transportation is regulated by channels & pumps.
How is the RMP of cells calculated?
Conventionally the outside of the cell is referred to as the zero reference point and has a voltage of 0mV, the inside of the cell (in particular the area immediately adjacent to the cell membrane) has a negative membrane potential of around -50 to -90 mV in neurones. Thus neurones are said to have a resting membrane potential (RMP) of around -70 mV.
What is an action potential?
If, the membrane potential becomes more negative, the cell is hyperpolarised. If the membrane potential becomes more positive the cell is depolarised. When a cell is sufficiently depolarised an action potential is generated, where there is a brief depolarisation spike in the membrane potential (to around +10 mV) before returning back to the RMP. This action potential is transmitted along the membrane and axon by means of cable transmission and it is the ability to propagate action potentials, which makes neurons ‘excitable’.
Outline the role of voltage-gated ion channels in action potentials
At resting membrane potential (RMP), voltage-gated Na+ channels (VGSCs) and voltage-gated K+ channels (VGKCs) are closed. Membrane depolarisation leads to a change in the ionic channel configuration, allowing VGSCs to open, causing an Na+ influx and further depolarisation. VGKCs open at a slower rate than VGSCs and lead to repolarisation, due to the efflux of K+ from the cell membrane.
Outline the function of Na+-K+-ATPase (pump)
Action potentials leave a Na+ & K+ imbalance that needs to be restored. This is accomplished using Na+-K+-ATPase (pump), which restores the ion gradients. It does this in 3 steps.
1) Resting configuration: Na+ enters vestibule and upon phosphorylation, Na+ ions are transported through the protein pump.
2) Active configuration: An exchange of energy, using ATP, allows Na+ to be removed from cell and K+ enters the vestibule.
3) Pump returns to resting configuration: This allows K+ to be transported back into the cell.
What is saltatory conduction?
The action potential spreads along the axon by ‘cable transmission’. The myelin sheath on axons prevents the action potential from spreading, due to its high resistance & low capacitance. The Nodes of Ranvier are small gaps of myelin spread intermittently along axons. The action potential can ‘jump’ between nodes by saltatory conduction. However, action potentials are unable to ‘jump’ across the gap at the axon terminal.
What are synapses?
These are the small gaps that exist between two neurones are known as synapses. The synapse itself is a junction consisting of a pre-synaptic nerve terminal (e.g. the axon terminal), which is separated from the postsynaptic cell (e.g. the dendrite of another neurone) by an extracellular space known as the synaptic cleft. Since the electrical signal cannot jump over the synaptic cleft it is converted into a chemical signal to cross the synapse and then back into an electrical signal on the post-synaptic cell.
Outline the process of neurotransmission at the synapse
1) Propagation of the action potential (AP):
> AP is propagated by VGSCs opening
> Na+ influx leads membrane depolarisation and AP ‘moves along’ the neuron
> VGKC opening allows K+ efflux and repolarisation
2) Neurotransmitter (NT) release from vesicles:
> AP opens voltage-gated Ca2+ channels at presynaptic terminal, leading to Ca21 efflux
> Ca2+ binds to vesicles containing the neurotransmitter
> The vesicles bind to the presynaptic membrane and release the neurotransmitter into the synaptic cleft by exocytosis
3) Activation of postsynaptic receptors:
> NT binds to receptors on post-synaptic membrane
> Receptors modulate post-synaptic activity
4) Neurotransmitter reuptake:
> NT dissociates from receptor and can be
1) Metabolised by enzymes (e.g. cholinesterase for acetylcholine) in synaptic cleft
2) Recycled by transporter proteins
Outline communication between neurons
The communication between neurons can be either autocrine or paracrine. Both types of communication involve the use of neurotransmitters.
Outline the 3 types of synapses
1) Axodendritic synapse: connection between presynaptic terminal and the neuronal dendrite
2) Axosomatic synapse: connection between presynaptic terminal and the neuronal soma
3) Axoaxonic synapse: connection between presynaptic terminal and the neuronal axon
What is the neuromuscular junction?
This is a specialised structure incorporating axon terminal & muscle membrane allowing unidirectional paracrine chemical communication between peripheral nerve & muscle.
Outline the process of paracrine communication in the neuromuscular junction
1) Action potential propagated along axon (Na+ & K+), leads to Ca2+ entry at presynaptic terminal.
2) Ca2+ entry causes acetylcholine (ACh) release into synaptic cleft.
2) ACh binds to nicotinic ACh receptors (nAChR) on skeletal muscle and leads to a change in end-plate potential (EPP).
4) A miniature EPP indicates quantal ACh release.
What is the sarcolemma?
This is the skeletal muscle membrane, where nicotinic ACh receptors (nAChR) activation leads to depolarisation and an action potential (AP). T-tubules are continuous with the sarcolemma and are closely connected to sarcoplasmic reticulum, the action potential travels through T-tubules.
What is the sarcoplasmic reticulum?
This surrounds myofibrils, which are contractile units of muscle. The sarcoplasmic reticulum stores Ca2+, only releasing it following sarcolemma depolarisation. The Ca2+ then causes myofibril contraction and muscle contraction.
Outline some disorders of the neuromuscular junction
1) Botulism: Botulinum toxin (BTx) irreversibly disrupts stimulation-induced ACh release from presynaptic nerve terminal.
2) Myasthenia Gravis (MG): an autoimmune disorder where antibodies are directed against ACh receptor. This causes fatigable weakness, meaning that it becomes more pronounced with repetitive use.
3) Lambert-Eaton myastenic syndrome (LEMS): an autoimmune disorder where antibodies are directed against voltage-gated calcium channels (VGCC).
What is the Nernst Equation?
This equation allows the equilibrium potential (E) to be calculated:
E (mV) = (RT/zF)*ln(X2/X1), where:
R = gas constant
T = Temperature in Kelvin (assume 310K)
z = charge on ion (-1 for Cl-, +2 for Ca2+)
F = Faraday’s number - charge per mol of ion
ln or log = natural logarithm (log to base e) or convert to common log
X2 = intracellular ion concentration
X1 = extracellular ion concentration
Why is the Nernst Equation not totally reliable?
The equilibrium potential of potassium (EK) and sodium (ENa) are theoretical values. In reality biological membranes are not uniquely selective for an ion. Membranes have mixed and variable permeability to all ions (but, for neurones at rest K+»_space; Na+). A typical resting membrane potential (Em) is -70 mV and not -90 mV which is EK. Each ion’s contribution to membrane potential is proportional to how permeable the membrane is to the ion at any time.
What is the Goldman-Hodgkin-Katz (GHK) equation?
This equation describes the membrane potential (Em) more accurately; P is permeability or channel open probability (0 = 100% closed, 1 = 100% open, 0.5 = open 50% of time), Subscript on P indicates the ion, [K+], [Na+] and [Cl-] represent concentration and the subscript i or o indicates inside or outside the cell.
Define the different terms describing membrane potential
1) Depolarisation: membrane potential becomes more positive, towards 0 mV.
2) Overshoot: membrane potential becomes positive.
3) Repolarisation: membrane potential becomes more negative, towards the resting membrane.
4) Hyperpolarisation: membrane potential decreases beyond the resting membrane potential.
What are graded potentials?
External stimulus or neurotransmitters causes a change in membrane potential. The change in membrane potential is graded in response to the type (depolarisation or hyperpolarisation) or strength of stimulation. Graded potentials produce the initial change in membrane potential that determines what happens next – they initiate or prevent action potentials. Graded potentials tend to decay from the stimulus site, along the length of the axon, as the charge ‘leaks’ from the axon and the size of the potential change decreases along the axon.
How do action potentials occur?
Action potentials (AP) occur when a graded potential reaches a threshold for the activation (opening) of Na+ channels resulting in an “all-or-nothing” event. These occur in excitable cells (mainly neurons and muscle cells but also in some endocrine tissues). Action potentials play a central role in cell-to-cell communication and can be used to activate intracellular processes.
Outline the permeability of axon membranes
Their permeability depends on conformational state of ion channels. The ion channels are opened by membrane depolarisation, inactivated by sustained depolarisation and closed by membrane hyperpolarisation/repolarisation. When membrane permeability of an ion increases it crosses the membrane down its electrochemical gradient. Movement changes the membrane potential toward the equilibrium potential for that ion.
Outline the 5 phases of the action potential
Phase 1 - Resting membrane potential:
> Permeability for PK > PNa
> Membrane potential nearer equilibrium potential for K+ (-90mV) than that for Na+ (+72mV)
Phase 2 - Depolarising stimulus:
> The stimulus depolarises the membrane potential
> Moves it in the positive direction towards threshold
Phase 3 - Upstroke:
> Starts at threshold potential
> Increase in permeability of Na+ (PNa) because voltage-gated Na+ channels open quickly
> Increase in permeability of K+ (PK) because voltage-gated Na+ channels start to open slowly
> Membrane potential increases toward the Na+ equilibrium potential
Phase 4 - Repolarisation:
> PNa decreases because the voltage-gated Na+ channels close
> PK increases as more voltage-gated K+ channels open and remain open
> Membrane potential decreases toward the K+ equilibrium constant
- At the start of repolarisation is the absolute refractory period, where the Na+ channel activation gate is open and the Na+ inactivation gate is closed. In this period, no new action potential can be triggered.
- Later in repolarisation, the absolute refractory period continues, but both the activation and inactivation gates of Na+ are closed.
Phase 5 - After hyperpolarisation
> At rest voltage-gated K+ channels are still open
> K+ continues to leave the cell down the electrochemical gradient
> Membrane potential moves closer to the K+ equilibrium - some voltage-gated K+ channels then close
> Membrane potential returns to the resting potential
- There is a relative refractory period, where some Na+ channels have recovered from inactivation – allowing the voltage-gated Na+ channels to open. However, a stronger than normal stimulus required to trigger an action potential.
Outline the regenerative relationship between the permeability of sodium (PNa) and the equilibrium potential of the membrane (Em)
Once threshold potential is reached an action potential is triggered. APs are “all-or-nothing” events, so once triggered a full-sized action potential occurs due to positive feedback. Following an action potential, there is a refractory state where the membrane is unresponsive to threshold depolarisation until the voltage-gated Na+ channels recover from inactivation.
What is passive propagation?
Adjacent to the formation of an action potential, is an area of local depolarisation caused by local current flow. The adjacent region then moves from its resting membrane potential and gradually depolarises towards a threshold value. Once the threshold value is reached, voltage-gated sodium channels will open. This leads to the gradual movement of the action potential down the length of the axon. Voltage-gated ion channels are mostly located at the Nodes of Ranvier.
Which factors affect conduction velocity?
Membrane/internal resistance of the axon, the insulation of the axon and the diameter of axon alters propagation distance and velocity. The greater the diameter and insulation of an axon, the slower the potential decays. This is because larger diameter axons have lower resistance, so ions move faster – conduction velocity is proportional to the square root of the axon diameter. For instance, in small diameter, non-myelinated axons, the conduction velocity is 1 m/s, whereas it is 120 m/s in large diameter, myelinated axons.
Which disease states are associated with reduced axon diameter and myelination?
1) Reduced axon diameter: re-growth after injury)
2) Reduced myelination: multiple sclerosis and diphtheria, cold, anoxia, compression and drugs (some anaesthetics block sodium channels).
What is pharmacology?
This is the study of how chemical agents (drugs) can influence the function of living systems. It is better defined as a chemical substance that interacts with a specific target within a biological system to produce a physiologic effect.
What questions must be asked when considering how individual drugs produce their effects?
1) What is the target for the drug?
2) Where is the effect produced?
3) What is the response produced after interaction with this target?
What is the most common use of opioids in medicine?
Opioids (e.g. morphine) are commonly used as analgesics. They target a part of the brain called the peri-aqueductal grey region.
What do opioids interact with?
Opioids bind opioid receptors, which are exogenous compounds. Endorphins are endogenous compounds released by the body that can activate opioid receptors. These opioid receptors exist in many different locations in the brain and throughout the body.
What causes side effects?
They can be produced by drug action:
1) On other targets in the same tissue or other tissues
2) On the same target in other tissues
3) Dependent on the dose of the drug administered
How is the safety of drugs determined?
The “safest” drugs are those where there is a large difference between the dose required to induce the desired effect and the dose requires to induce side effects/adverse effects. For instance, pramipexole, a dopamine receptor agonist, is used to treat Parkinson’s disease. It has a similar structure to dopamine, acting as an agonist, it tries to mimic the effects of dopamine. At low doses, it has this therapeutic effect, but as the dose increases serotonegic side effects are seen, as it is structurally similar enough to serotonin to bind to its receptors. So as dose increases, selectivity tends to decrease.
What is the key component of most drugs?
The majority of drug targets are proteins. There are 4 main classes of drug targets:
1) Receptors
2) Enzymes
3) Transport proteins
4) Ion channels
What are the 4 most commonly prescribed drugs?
1) Atorvastatin (type of statin) - acts on an enzyme (i.e. HMG-CoA reductase)
2) Amlodipine - acts on an ion channel, blocking the calcium ion channel, allowing some vasodilation, reducing blood pressure in hypertension
3) Salbutamol (found in blue asthma inhalers) - binds to a Beta-2 adrenergic receptor in the lung, which bronchodilates
4) Citalopram (selective serotonin reuptake inhibitors; antidepressant ) - acts on a transport protein, by blocking the serotonin reuptake protein
What is drug selectivity?
To be an effective therapeutic agent, a drug must show a high degree of selectivity for a particular drug target (ie the lock and key hypothesis).
Why might selectivity be more important to drugs than endogenous compounds (e.g. dopamine)?
Neurotransmitters are very specifically delivered to their drug target. Endogenous compounds like dopamine, noradrenaline and serotonin are released from the end of nerves that release the neurotransmitter specifically into the synapse that can affect the relevant drug target. Typically drugs are administered orally and gets into the bloodstream,nowhere it can be distributed to the relevant tissue to produce an effect. This means that is can be distributed to any tissue in the body, so needs high specificity so as to not bind to the wrong target.
What are side effects?
A side effect is an effect produced by the drug that is secondary to the intended effect. If that side effect has negative health consequences, then it is also termed an adverse effect. The two terms are often used interchangeably, since most side effects have some sort of negative health consequence from minor (e.g. runny nose) to major (e.g. heart attack).
Outline the diversity of neurotransmitters
Enormous diversity in variety of transmitters and their receptors including Amino acids (e.g. glutamate, γ-aminobutyric acid [GABA], glycine [Gly]), Amines (e.g. noradrenaline [NA] and dopamine [DA]) and Neuropeptides (e.g. opioid peptides). Vary in abundance from nM to mM CNS tissue concentrations. May mediate rapid (µs - ms) or slower effects (secs). Neurons receive multiple transmitter influences which are integrated to produce diverse functional responses.
Outline the steps of neurotransmitter release
Activation of transmitter release is calcium dependent and requires RAPID transduction/electromechanical transduction (200ms), describing the process linking the Ca2+ ion channels opening to the exocytosis of neurotransmitters:
1) Membrane depolarisation
2) Ca2+ channels open
3) Ca2+ influx
4) Vesicle fusion
5) Vesicle exocytosis
6) Transmitter release
How do rapid release rates of neurotransmitters occur?
Synaptic vesicles are filled with neurotransmitter (T) and the influx of calcium causes the vesicles to becomes docked in the synaptic zone on the membrane. The vesicles are then primed to release the neurotransmitter and fuse fuse with the presynaptic membrane. Special proteins (vesicular proteins such as SNARE proteins) on the vesicle and presynaptic membrane enable fusion & exocytosis. Protein complex formation between vesicle, membrane and cytoplasmic proteins to enable both vesicle docking and a rapid response to Ca2+ entry leading to membrane fusion and exocytosis.
What are neurotoxins?
Vesicular proteins are targets for neurotoxins:
1) Alpha latrotoxin (from black widow spider) stimulates transmitter release to depletion
2) Zn2+-dependent endopeptidases inhibit transmitter release
3) Tetanus toxin (C tetani) causes spasms & paralysis
4) BOTULINUM TOXIN (C botulinum) causes flaccid paralysis.
What are the 2 main groups of neurotransmitter receptors?
1) Ion channel-linked receptors: these are fast response (msecs) and they mediate all fast excitatory and inhibitory transmission. Examples include:
> CNS: Glutamate, γ-aminobutyric acid (GABA)
> NMJ: Acetylcholine (ACh) at nicotinic receptors
2) G-protein-coupled receptors: these are slow response (secs/mins). Their effectors may be enzymes (adenyl cyclase, phospholipase C, cGMP-PDE) or channels (e.g. Ca2+ or K+).
> CNS and PNS: ACh at muscarinic receptors, dopamine (DA), noradrenaline (NA), serotonin (5HT) and neuropeptides (e.g. enkephalin).
