mini mod.: essential neuroscience

Question 1

Nervous systems allow for homeostatic regulation and response to the external environment
nervous system V endocrine system

Answer 1

HOMEOSTASIS: maintenance of a relatively stable internal environment

endocrine:
Wireless system
specificity of target cell binding
hormones carried in the blood to long distance
slow and long-lasting response (sec to hours)
controls long-lasted activities (growth, reproduction, metabolisms)
involuntary
influences CNS output

nervous:
Wired system
anatomical connection with target cells neurotransmitters diffuse through short distances rapid and brief response (msec to sec) coordinates fast and precise responses
voluntary / involuntary
influences endocrine output
other non-regulatory functions!!

Question 2

The human nervous systems in organised in specialised sub-divisions

Answer 2

central + peripheral nervous system:
central:
brain, brainstem, spinal cord (also splits into white and grey matter)

peripheral:
Sensory/afferent
Brings sensory info from CNS to receptors in peripheral tissues and organs

motor/efferent:
Sends motor commands from CNS to organs

Somatic nervous system
-neurons to visceral organs
(e.g. heart)
-no voluntary control
-Sympathetic
-Parasympathetic

Autonomic nervous system
- motor

Question 3

 Neurons structure(general)

Answer 3

cell body - w/ nucleus, golgi, most organelles
dendrite
axon
neurite - made up by D+A - long filamentous extension responsible for propigating action potentials
synapses - responsible for transmitting information between neurons via neurotransmitter signaling

Question 4

synapses

Answer 4

synapses are a unidirectional chemical junction between neurones

Synapses allow information to pass between neurons
Pre-synapse releases neurotransmitters
Post-synapse carries neurotransmitter sensitive ion channel receptors that can have excitatory or inhibitory effect on the target neuron.

Question 5

Specialised neurons detect external signals, communicate with other neurons and drive responses in target cells

Answer 5

eg. interneurone, granule cell(cerebellar cortex), pyramidal neurone(gogli type1), granule neuron of cerebellum, sympathetic ganglion neurone, ventral motor neurone

specialised function:
Neurons rarely act in isolations, instead forming complex, interconnected networks of neuron subtypes with highly specialised functions:
Sensory Neurons:
Detection of external and internal information:
light, vibration, temperature, pressure, stretch
Motor Neurons:
Outputting information from the central nervous system to muscles, driving behavioural response
Interneuron:
Connecting neurons to each other, amplifying and attenuating activity of a neuronal circuit by integrating additional data

Question 6

Glia cells specialised functions
(supporting the health and function of the nervous system)

Answer 6

Neurons are also supported by essential, specialised glial cells throughout development and ageing:
‘Glia’ = glue : These cells we historically (incorrectly) thought to just hold the brain together
Proportion of neurons:glia in the mammalian brain remains controversial
Estimates range from 1:1 to 1:50*

types of glia cells:
astrocyte
microglia
myelinating glia

Question 7

astrocyte

Answer 7

Star-shaped’ glia, supporting neuron function and delivery of molecules to/from the vasculature
Activate in response to injury, neuroinflammation or degeneration in the brain:
Non-reactive: Trophic support of neurons, synapse formation and maintenance, clearance of neurotransmitters
Reactive (inflamed): Damage neurons, activate microglia, some phagocytic activity

Question 8

microglia

Answer 8

Resident immune cell of the brain, surveying for pathogens and damaged material
Important roles in development and pruning of excess synapses
Become inflamed in response to pathogens (virus, bacteria etc), injury and neurodegeneration
Morphological and functional changes when activated: increased motility, phagocytosis and release of immune factors (cytokines)

Question 9

myelinating glia

Answer 9

Myelinate neuron by insulating them in multiple layers of sphingolipids, increasing axon potential speed
CNS and PNS have different glia performing the same role

Oligodendrocytes: Myelinate multiple axons
Schwann Cells: Myelinate single axons

All motor axons are myelinated, and some sensory axons

Question 10

how researchers measure function of nervous system

Answer 10

in vitro models:

cell culture model:
Stable cells lines – easy to grown, derived from tumours
Primary neuronal cultures (derived from model organisms)
Human stem cell derived cultures
(derived from skin cells of living patients!)
Advances in cell culture technique now allow researchers to grow 3D ‘mini brains’
Powerful tools for pharmacological testing, genetic screening and electrophysiology
Useful for studying disorders associated with ageing?

in vivo models:
Model organisms are a powerful way to understand how nervous system functions
Common model organisms in neuroscience research include:
Rodents (Mouse, Rat)
Zebrafish (Dario renio)
Zebra finch (Taeniopygia guttata)
Fruitfly (Drosophila melanogaster)
Nematode worms (Caenorhabditis elegans)

Ethical considerations – must have justification for use of vertebrates, strict regulation of experiments

behaviour:
Model organisms provide a powerful means of understanding how the nervous system function
Behaviour range from simple reflexes to complex learning and memory
Behavioural responses can be manipulated
Pharmacologically
Genetically
Behavioural deficits are seem in models of developmental disorders and neurodegenerative diseases

Question 11

Neurons are excitable cells, able to propagate action potentials across their membrane

Answer 11

Most cells have a small difference in membrane potential, however not all cells are excitable
Excitable cells can propagate an action potential across their membrane and include:
muscle (myocytes, cardiomyocytes)
endocrine cells
neuronal cells

Important membrane properties:
Composed of hydrophobic lipids, impermeable to water soluble molecules
Channels/pumps facilitate cross membrane transport of ions and molecules
Channels/pumps are selective, based on size, charge and solubility of substrates

Question 12

concentration and electrical gradient

Answer 12

concentration gradient:
Molecules move down concentration gradients
i.e. high concentration to low concentration

electrical gradient:
Ions move down concentration gradients
i.e. positive charge to negative charge

Question 13

measuring electrophysiological activity

Answer 13

Important, widely used technique for measuring neuron activity in cell culture and model organisms
Intracellular recording

Intracellular microelectrode: measure internal voltage
Extracellular electrodes: measures extracellular voltage

The difference in voltage recorded between intra- and extracellular electrodes gives us the membrane potential of the cell of interest

Question 14

At resting potential, a stable chemical and electrical gradient is established across the neuronal membrane

Answer 14

concentration gradient:
Molecules move down concentration gradients
i.e. high concentration to low concentration

electrical gradient:
Ions move down concentration gradients
i.e. positive charge to negative charge

Question 15

ions cross neuronal membranes-both passive+active transport

Answer 15

When unstimulated, excitable membranes are held at a resting potential
Resting potential is the point at which difference in ion concentrations are stable across a membrane
Under resting potential, neuronal membranes are:
Permeable to passive diffusion by K+, Na+ and Cl-
Ions pass through ‘leaky’ channels (not through the lipid bilayer)
Impermeable to intracellular large anions
Organic acids, sulphates, phosphates, amino acids
Too large to pass through the membrane channels

Na+, K+ and other ion concentration gradients are maintained by active transporters
Active transporters utilize energy from ATP hydrolysis, pump ions against the chemical
gradient.
Na+-K+ pump exchanges 3 intracellular Na+ ions for 2 extracellular K+ ions

Question 16

resting potential

Answer 16

Neuronal cytoplasm is high in potassium (K+), the extracellular fluid is high in sodium (Na+)
Neuronal K+ is buffered by membrane impermeable organic anions (negative charge)
Cell membranes are permeable to K+, allowing diffusion to occur
Negative intracellular electrostatic force prevents further K+ diffusion

Question 17

summary of processes-diffusion/transport, potassium role, resting potential and sodium/chloride ions

Answer 17

Combined passive diffusion and active transport reach a steady chemical and electrical gradient
Potassium reaches an equilibrium potential (EK) of -90mV - measured as the difference between inside to outside the cell.
Resting potential is primarily the result of a potassium gradient across the neuronal membrane, though other factors also contribute:
Sodium ions – positive charge with low permeability across the neuronal membrane (ENa = +55mV)
Chloride ions – negative charge, passively distributed and dependent of Na+ and K+ distribution (ECl = -60mV)

Question 18

APs allow neurons to transmit information along their membrane

Answer 18

APs are a short-lived reversals of membrane potential
APs are triggered by input stimulation of inward current, caused by activation of post-synaptic receptors on the neuronal membrane
Cascading reversal of membrane potential transmits a signal across neurite membranes to the synapse, allowing information to rapidly travel long distances
Neurotransmitter release is stimulated by APs reaching the pre-synaptic terminal

Question 19

APs 4 phases of membrane potential activity

Answer 19

Action potentials are triggered by an input of inward current, caused by an inwards flow of positive ions
Depolarisation: rapid positive change in membrane potential from -70mV to ~+30mV.
Repolarization: rapid negative change in potential
Depolarisation-repolarization ‘spike’ lasts ~1ms
Hyperpolarisation: membrane potential becomes more negative than resting potential
Afterpolarisation: membrane potential returns to resting potential state.

Question 20

threshold stimulus

Answer 20

Not all stimulation is sufficient to induce an action potential
A threshold stimulus of input must be achieve to trigger a potential on 50% of occasions
– All neurons have different threshold stimuli, ~15mV positive of resting potential
Action potential stimulation can be considered ‘all or nothing’
– Insufficient stimuli will not trigger an action potential
– Once triggered the action potential of a neuron are all of similar amplitude

Question 21

refractory period

Answer 21

Once an action potential is stimulated, a neuron in the spike period cannot be stimulated again.

Absolute refractory period: During the spike, a neuron cannot be stimulated

Relative refractory period: During hyperpolarisation and afterpolarisation, a suprathreshold stimulus (ie larger) is required to trigger an action potential

Refractory periods allow for:
Unidirectionality of action potentials
An upper limit on firing rate

Question 22

APs-unidirectional

Answer 22

Action potentials create an active zone region of local difference in membrane potential

Differences in membrane induce a local circuit.

Current spreads from the negative active zone to positively charged surrounding membrane

Refractory period blocks action potentials from traveling in the reverse direction

Question 23

APs driven by voltage dependant ion channels

Answer 23

Actions potentials are the result of ion flow across the membrane, between neuron and extracellular fluid

Ion flow occurs through specialised transmembrane voltage dependent ion channels

Voltage dependent Ion channels have two key properties
1.Ion specific - generally only one specific ion can pass through a channel
2.Voltage sensitive – channels open/close in response to changes in membrane potential

Question 24

AP initiate in the axon hillock

Answer 24

Action potentials are triggered from a specialised region of the axon, the axon hillock

The membrane at the axon hillock has the lowest threshold across the cell

Input and integrative information is encoded in the dendrites and soma, which anatomically precede the hillock region

Voltage gated sodium channels (inward) are enriched within the hillock region

Question 25

activity of voltage dependant ion channels occur during different phases of AP

Answer 25

Stimulus threshold results in most Na+ channels being open, triggering an action potential.

Depolarisation:
Voltage gated Na+ channels open rapidly: Na+ enters the cell
Voltage gated K+ channels slowly open

Repolarization:
Na+ channels close slowly
Voltage gates K+ channels continue to open: K+ leaves the cell

Hyperpolarisation:
K+ continues to enter the cell, K+ channels close slowly

Afterpolarisation:
K+ and Na+ actively transported, membrane returns to resting potential

Question 26

Myelination

Answer 26

increases speed of action potential propagation

Question 27

Neurons form electrical and chemical synapses to transmit signals to target cells

Answer 27

Function of all nervous systems depends on neurons communication to transmit information between cells
Synapses are physical sites of communication between neurons
Two forms of synapse are found in neurons:
Electrical synapse-transmission by current
Chemical synapse-transmission by chemical

Question 28

electrical synaptic junction

Answer 28

Electrical Transmission: instantaneous, bidirectional transmission of signal via ion current
Allow for electrical coupling of adjacent cells
Rapid neuronal response (ie escape reflex)
Highly synchronised neuronal firing (ie inhibitory interneurons in mammalian brain)
Gap junction connections composted of hemichannels on pre and post synaptic side of membrane, each formed by six connexin proteins
Gap junctions close in response to elevated Ca2+
Also have important roles in glia (astrocyte Ca2+ signalling, Schwann cell layers).

Question 29

chemical synaptic junction

Answer 29

Chemical transmission:
Signal transduction is not facilitated through direct cell contact
A chemical signal is transmitted across a cleft, or gap between cells.
Diffusion of a chemical signal across the cleft is slower than electrical transmission across gap junctions
Chemical transmission allows for amplification of signal to the target neuron

Question 30

Neurotransmitters

Answer 30

Synthesized in the presynaptic neuron.
Can be released into the synaptic cleft and elicit a response in target neurons when present in sufficient concentration
Can be experimental added to a target neuron and cause same response as endogenous transmitter release
A process exists to remove the chemical from the synaptic cleft

Question 31

Chemical neurotransmitters can have an excitatory or inhibitory effect on post-synaptic neurons

Answer 31

The neurotransmitters released at chemical synapses can have an excitatory or inhibitory effect on the target cell
Effect of a neurotransmitter is dependent on the type of receptor (excitatory/inhibitory)

Question 32

axodendritic synapses

Answer 32

Axodendritic synapses are most common in the brain, with pre-synapses targeting post-synaptic receptors in the dendrites
In ‘spiny’ neurons, axo-dendritic post-synapses form on specialised spine structures

Post-synaptic receptors can also be found in other compartments of the target neuron:
Axosomatic – synapsing at the cell body
Axoaxonic – Synapsing at the axon (or presynapse)

Question 33

synapse morphology/synaptic vesicles

Answer 33

Pre-synaptic terminals contain Synaptic Vesicles (~50nm), specialised vesicles loaded with neurotransmitters
Synaptic vesicles dock with the synaptic membrane, releasing their content across the synaptic cleft (~20nm)
Chemical synapses are energetically demanding, and enriched for energy producing mitochondria
Post-synaptic can be identified by a post-synaptic density, a region enriched from receptors and associated machinery
Glia processes, typically astrocytic, are often found at synaptic junction. These glia support synapse function, particularly clearance of transmitters from the cleft.

Question 34

action potential -> calcium influx -> synaptic vesicle release -> activate post synaptic receptors

Answer 34

Action potentials reaching pre-synaptic terminal trigger an influx of calcium
Neurotransmitter release is stimulated by action potentials reaching the pre-synaptic bouton and triggering a Ca2+ influx through voltage-dependent calcium channels

Elevated calcium in the presynaptic terminal triggers synaptic vesicle release
Increased calcium in the terminal activates fusing of synaptic vesicles with the presynaptic terminal

Release neurotransmitters cross the synaptic cleft and activate post-synaptic receptors
Released neurotransmitters cross the synaptic cleft, bind their type specific receptors and trigger ion influx to either stimulate or suppress an action potential in the target neuron

Question 35

toxins target SNARE proteins to block synaptic neurotransmitter release

Botox

Answer 35

Botulinum neurotoxins(Botox)are peptide toxins composed of a heavy and light chain. Derived from Clostridium botulinum
BoNTs bind synaptic terminals of acetyl-choline releasing neurons and
internalised by endocytosis
Once within the cytoplasm, light chain of BoNTs A and E bind and cleave the c-terminal of t-SNARE SNAP25 via metalloprotease activity
Disruption of SNAP25 results in failure of neurotransmitter vesicles to fuse at the synaptic terminal
Has therapeutic application beyond cosmetics, treatment of epileptic seizures and muscle spasms

Question 36

toxins target SNARE proteins to block synaptic neurotransmitter release

Tetanus toxin

Answer 36

Tetanus Toxin (tetanospasmin) are peptide toxins derived from Clostridium tetani
Tetanus toxin binds pre-synaptic membrane glycoproteins/lipids in neuromuscular junction and enters motor neuron through endocytosis
Tetanus toxin is transported to the central nervous system and released into synaptic clefts, where it is internalised aby inhibitory interneurons
Tetanus toxin access the presynaptic membrane, then binds and cleaves synaptobrevins VAMP1/2
Loss of regulatory GABA release results in overactivity of motor neuron and powerful, damaging muscle spasms

Question 37

recovered synaptic vesicles are recycled and refilled

Answer 37

Recovered synaptic vesicles are acidified by active pumping of H+ into their lumen by vesicular proton ATPases (vATPase)
The acidified lumen then exchanges H+ for neurotransmitters via specific vesicular transporters
VGLUT: Vesicular glutamate transporter
VMAT: Vesicular monoamine transporter(Serotonin, Dopamine, Adrenaline, Noradrenaline, histamine)
VAchT: Vesicular acetylcholine transporter
VGAT: Vesicular GABA transporter

Question 38

neurotransmitter synthesis

Answer 38

Neurotransmitters are produced through enzymatic metabolism of precursors
Small amino acid neurotransmitters-
Enzymatic processing occurs in the cytosol (cell body or presynaptic terminal)
Transmitters are packaged into synaptic vesicles
Large neuropeptide transmitters-
Produced as pre-peptides in the soma ER-Golgi
Packaged into dense-core vesicles
Transported to presynaptic terminal for processing and secretion

Question 39

glutamate

Answer 39

Glutamate is the most common excitatory neurotransmitter in mammalian CNS
Pyramidal neurons in the cortex
Granule cells in cerebellum
Metabolised by cytosolic Glutaminase enzyme from precursor Glutamine
Glutamate is loaded into synaptic vesicles by VGLUT transporter
After release, glutamate is cleared from the synaptic cleft be neuronal and astroglial glutamate transporters
Neurons: Glutamate return to metabolic pool or reloaded into synaptic vesicles
Astrocytes: Glutamate converted to glutamine by glutamine synthetase. Secreted from astrocytes and taken up by neuronal glutamine transporters

Question 40

GABA

Answer 40

GABA is the most common inhibitory neurotransmitter in mammalian CNS
GABA is synthesised from glutamate by Glutamic acid decarboxylase (GAD)
[Both glutamate and GABA are produced from alpha- ketoglutarate, a produce of the mitochondria Krebs cycle]
GABA is loaded into synaptic vesicles by vesicular GABA transporter (VGAT)
After release, GABA is cleared from the synaptic cleft be
neuronal and astroglial GABA transporters
Neurons: GABA return to metabolic pool or reloaded into
synaptic vesicles
Astrocytes: GABA converted to glutamine and enters the glycine processing pathway to return to neurons

Question 41

post synaptic transmission - fast and slow

Answer 41

Fast Transmission: Ligand gated ion channels induce changes in post-synaptic membrane potential in milliseconds
Slow Transmission: Metabotropic receptors coupled to secondary messengers
Slower (milliseconds-minutes) and long lasting (minutes-days) changes

Question 42

EPSPs(Excitory Post-Synaptic Potentials) and IPSPs(Inhibitory Post-Synaptic Potentials)

Answer 42

EPSPs:
Ionotrophic receptor allow influx of Na+, K+ and Ca+
Membrane depolarisation
EPSPs stimulating an action potential in post-synaptic neuron must achieve threshold stimulus
Single ESPS are not sufficient to reach threshold
Many EPSPs stimulating a post-synaptic membrane within ~10ms are required to overcome threshold and induce an action potential

IPSPs:
Ionotrophic receptor allow influx of Cl-
Reduced change of membrane reaching threshold

Question 43

categories of Ligand-gated ion channels: Cys loop family

Answer 43

Ionotrophic channels including those for Acetylcholine, GABA, Glycine and Serotonin
All Cys-loop receptors are pentamers of subunits forming a pore
Combinations of alpha, beta, gamma and delta subunits defines channel activity (physiological function, pharmacology)

Question 44

GABA receptor specialisations

Answer 44

Ionotrophic channels GABAA channels are selective for Cl- and generally associated with inhibition
Requires binding of 2 GABA molecules to open channel
Pentameric composition of subunits - combinations of alpha, beta, gamma and delta subunits determine function (11 combinations)
GABAA receptors are targeted by endogenous molecules and drugs
Benzodiazepines are agonists for GABA receptors, binding ‘BZ’ site and potentiate Cl- influx
GABAa containing Alpha 1 = Sedative, anti-convulsant
GABAa containing Alpha 2 = Anti-anxiety, muscle relaxant
Inverse agonists BZ site and inhibit channel opening, block Cl- influx
Anxiogenic – ie increase anxiety
Endozepines – endogenous peptide derived from astrocytes

Question 45

Categories of Ligand-gated ion channels: Glutamate Receptor family

Answer 45

Ionotropic channels for glutamate, non-selective for cations (K+, Na+, Ca2+)
Three categories of glutamate receptors defined by selective inhibitors, all are tetrameric
AMPA – “alpha-amino-3-hydroxy-5methyl-4-isoxazole propionic acid”
GluR1, GluR2, GluR3, GluR4
GluR2 – responsible for voltage gating, - Ca2+ selectivity
Kainate – GluR5, GluR6, GluR7
Function less well described, more limited distribution
NMDA– “N-methyl-D-aspartate”

Question 46

NMDA receptor specialisations

Answer 46

NMDA receptors are voltage gated
Mg2+ ions block the NMDA receptor channel at resting potential
The Mg2+ block is removed by membrane depolarisation
NMDA receptor activity can be potentiated by binding of co-agonists D- serine and glycine
NMDA receptor are permeable to Ca2+, allowing longer term activation of secondary messengers
Roles in long term potentiation and long term depression through modulation of AMPA receptor activity
NMDA receptors can be blocked by Zn2+ and antagonised by Pb2+
NMDA receptors are targeted by dissociative anaesthetics including ketamine, NO and opiates

Question 47

long term habituation in Aplysia can last for several weeks

Answer 47

Long-term habituation in Aplysia can last for several weeks
Depressed synaptic potentials can persist for several weeks post-habituation

Short-term habituation: Aplysia exposed to 10 stimuli = habituated response lasts several minutes
Long-term habituation: Aplysia exposed to 10x stimuli x 4 sessions = habituated response lasts several weeks

Sensitisation: learning to avoid a noxious stimulus
Facilitation: increased strength of post-synaptic potential to a stimulus if closely paired with a prior stimulus

Question 48

Short term sensitisation signalling cascade

Answer 48

Heterosynaptic processing: synapse activity altered by a modifying neuron
Modulatory inter-neurons release serotonin (5-HT) onto G-coupled 5-HT receptors on presynaptic terminals of sensory neurons

Pathway 1
Secondary messenger cyclic adenosine monophosphate produced in presynapse
Activation of cAMP dependent Protein Kinase A (PKA) [NB PKA has 2 catalytic and 2 regulatory subunits]
Phosphorylation induced closing of outwards K+ channel extend action potential, increasing presynaptic Ca2+ levels
Increased calcium promotes increased neurotransmitter release
OR
Pathway 2
Enhanced activity of Phospholipase C (PLC)
Increased production of diacylglycerol (DAG) activates Protein Kinase C (PKC)
Phosphorylation of presynaptic proteins increases mobilisation of reserve glutamate vesicles to releasable vesicle pool

Question 49

Long-term sensitization: consolidating short-term to long-term memory

Answer 49

Consolidation : Long-term sensitization requires more stable changes in synaptic function and architecture
Sustained activation of 5-HT metabotropic receptors results in altered gene expression
Activation of CREB regulated genes results in increased production of synapses, changing the morphology of neurons and strengthening its activity