Justin Lectures Flashcards
(136 cards)
1
Q
What neural changes are responsible for learned changes in behaviour? Who proposed this? How does learning occur?
A
• Learned changes in behaviour must correspond to neural changes
o Ramon y Cajal- plasticity (changes) in synaptic connections responsible for learning and memory
o 50 years later, Konorski and Hebb described models of synaptic plasticity that could support associative learning
—Neurons for other events (e.g. Conditioned stimulus) form weak (ineffective) synapses with neurons controlling that behaviour - learned pathway
Pavlov- these connections must be acquired through learning
Hebb and Konorski- these latent connections must be strengthened through learning (only if conditions are met)
• Synaptic connection between conditioned stimulus and behavioural output is strengthened when weak conditioned stimulus input arrives simultaneously with strong unconditioned input
o Neurons that fire together, wire together
o Conditioned stimulus would be able to produce the conditioned response
2
Q
What is the Hebbian synapse?
A
o Biologically significant events (Unconditioned Stimulus) have hard-wired connections controlling behaviour (genetics have encoded these connections)-innate pathways
E.g. neurons coding for food can directly excite neurons producing salivation
3
Q
What is Hebb’s law?
A
o Neurons that fire together, wire together
4
Q
Describe the anatomy of the hippocampus proper?
A
• Hippocampus proper comprised of 3 regions- CA1, CA2 and CA3 (Cornu Ammonis)
5
Q
Describe the anatomy of the hippocampal formation?
A
• Hippocampal formation includes the dentate gyrus and the hippocampus proper
6
Q
Why is the hippocampus practical for study of a single fibre?
A
• Organisation of neural circuity in the hippocampus conveniently segregates inputs and throughputs, allowing for study of one fibre and measurement from a single neuron in a more manageable way
7
Q
Describe the input to, pathway and output from thippocampus
A
o Major input to hippocampus is perforant path (coming from the entorhinal cortex)
o Perforant path reaches dentate gyrus and forms synapses with prominent granule cells
o Granule cell output collects in mossy fibres
o Mossy fibres come through to the hippocampus proper and form synapses on the CA3 pyramidal cells
o Pyramidal cells in CA3 output into the pyramidal cells in the CA1 with Schaffer collaterals
8
Q
What is long term potentiation and what is needed to induce it? Describe the hippocampus as an example.
A
• LTP is a physiological example of synaptic plasticity
o Potential as a model for neural mechanisms of learning
• Long-term potentiation (LTP)
o Step 0: First need to establish the existing level of synaptic communication- baseline
Implant stimulating electrode in perforant path
Recording electrode implanted into granule cells of dentate gyrus
Stimulate weakly the perforant path and measure the response
Result: Weak stimulation of presynaptic input causes little, no or modest activity in post-synaptic neurons
o Step 1: Delivering strong, high, frequency (e.g. 100Hz, of about 15 seconds)- need to make sure that there is sufficient excitatory strength that there is activation of post-synaptic cells
Strong, high-frequency (e.g. 100Hz) stimulation of presynaptic input causes long-lasting increase in sensitivity of post-synaptic neurons
o Step 2: Stimulate pre-synaptic cells weakly once again to measure response
Weak stimulation of the pre-synaptic input now produces action potentials in the post-synaptic cells-> same amount of input produces bigger response
• Indicating sensitivity-> synaptic communication has increased
9
Q
What is the repeated effect of high frequency stimulation on neuron synapses?
A
• High frequency stimulation increases sensitivity of post-synaptic cells to stimulus (LTP) every single time it is delivered
The potentiation effect is selective to the pathway that is being stimulated
• Weak high frequency stimulation can produce short-lived potentiation (10 minutes), but long-lasting potentiation (hours) is achieved by strong high frequency stimulation, or high frequency stimulation at theta burst frequency-> this drives further changes
10
Q
Is LTD dose-independent? Explain.
A
• LTP is dose-dependent
o Weak high frequency stimulation (HFS) can produce short-lived/transient potentiation (10 minutes), but long-lasting potentiation (hours) achieved by strong HFS
o Duration of LTP depends on the number of theta burs stimulations- dose dependent effect
11
Q
How is HFS often delivered for LTP? Why?
A
o HFS often as a continuous volley, but can be patterned as bursts at theta frequency (theta burst stimulation) e.g. short bursts of 5 pulses in 50 ms, repeated every 200 ms (5Hz)
Neurons in the hippocampus follow this theta burst pattern-hence theta burst stimulation mimics those firing patterns
Very effective way of producing long term potentiation
12
Q
What are the 3 properties of LTP that recommend it as a model of learning and memory? Describe
A
o Persistence- potentiation is enduring, sometimes lasting weeks
o Synaptic specificity- only stimulated pre-synaptic inputs show potentiation that is, no increased sensitivity to other pre-synaptic inputs
o Associativity-can get LTP at pre-synaptic inputs weakly stimulated at the same time as strong stimulation to separate (but converging) input
13
Q
Why is it difficult to demonstrate potentiation over extended amounts of time experimentally?
A
Technically very difficult to demonstrate potentiation over extended amounts of time because can’t keep tissue alive indefinitely and in good condition in vitro
Very had to ensure that electrodes are in the same place over long periods of time in vivo
14
Q
Describe the associativity that can occur when LTP is induced if there are 2 converging pathways
A
If have 2 different converging pathways, and deliver strong high frequency stimulation through one pathway (potentiate that pathway), normally potentiation would be specific to that pathway and not transfer to another pathway even if it’s converging on the same neuron
However, can get potentiation to transfer to other converging pathway as long as weak stimulation is provided at the same time as strong stimulation across the other converging pathway
Matches Hebb’s law- this property most resembles Hebb’s model for how associations are acquired by the nervous system
HAVE TO converge on same neuron
15
Q
What are the anatomical correlations between LTP and learning?
A
o Correlations between LTP and learning
LTP is very easy to induce in hippocampus-> hippocampus is essential for learning
Age-related decline in learning correlates with age-related decline in ease of induction of LTP in the hippocampus
Similar correlations between LTP and learning in mouse model of Alzheimer’s disease
• See learning deficits in the mice and decrease in ease of LTP induction in Alzheimer’s mice
16
Q
Is LTP a saturated or unsaturated response? Describe the evidence and what can happen when too much LTP is induced.
A
o Evidence that saturation of LTP in hippocampus can prevent rats from learning in a simple maze
There is a point at which LTP is saturated-> once increase LTP past a certain point, there is a point where you don’t get any more LTP
• No further strengthening of synapses at pathway possible
• If this is done efficiently enough, can see deficits in learning as too much LTP reduces potential for plasticity within the hippocampus
17
Q
What learning can pharmacological interventions that prevent LTP do?
A
Pharmacological interventions that prevent LTP (especially drugs that block NMDA receptors) also disrupt learning, such as: • Conditioned taste aversion • Conditioned fear • Conditioned eyeblink • Maze learning
18
Q
What is LTP dependent on?
A
LTP is dependent on release of excitatory neurotransmitter glutamate
• Glutamate binding to AMPA receptors
• Glutamate binding to NDMA receptors
19
Q
What happens when glutamate binds to AMPA receptors and what EPSPs are they responsible for?
A
o Glutamate from pre-synaptic terminal binds to AMPA receptors on post-synaptic neuron, causes immediate excitation (depolarisation) of post-synaptic neurons
Glutamate binding to AMPA receptor opens the sodium channel within the AMPA receptor through confirmation changes-> causes excitatory post synaptic potentials (depolarisation) if there is enough sodium entering
o Fast EPSPs
20
Q
What happens when glutamate binds to NDMA receptors and what EPSPs are they responsible for?
A
• Glutamate binding to NDMA receptors
o Glu must also bind to NMDA receptors, opening calcium channels
Glutamate binding to NMDA receptor triggers opening of calcium channels, which in turn triggers mechanisms that allow for potentiation
21
Q
How are NMDA receptors activated, what is their purpose and what is the consequence of this?
A
o NDMA receptors have 2 special properties that underlie synaptic plasticity-
Admit calcium into the neuron (increase AMPA receptor abundance)
Calcium channels on NMDA receptors are dependent on both of these in order to open:
• Ligand-gated: glutamate (ligand)
• Voltage-gated- post-synaptic neuron must be depolarised
o Kicks out magnesium block of NMDA receptor- getting rid of magnesium block is dependent on the voltage (neuron needs to be strongly depolarised to get rid of magnesium receptor)
A way of doing this is through increased activation of the AMPA receptor
Property of NMDA receptor produces specificity and associativity
• Drugs that block NMDA receptor can prevent associative learning and LTP
22
Q
Describe how LTP occurs at the cellular/receptor level
A
o Strong, high-frequency stimulation delivered:
Potentiation will happen because strong, high frequency stimulation will release a lot of glutamate-> enough glutamate for strong stimulation of AMPA receptor which lets a lot of sodium in to depolarise the neuron and triggering an action potential
At the same time, glutamate binds to NMDA receptors of the synapse and because of the AMPA activation and subsequent depolarisation, the magnesium block of the NMDA receptor is also removed, leading to activation of the NDMA receptor-> calcium channel will open
Calcium entering leads to AMPA receptor number increase
• Intracellular cascade with both AMPA and NMDA
o When calcium ions are let in, cascade of processes triggered by calcium ions let in by the NMDA receptor activation ultimately leads to potentiation by increasing the number of AMPA receptors located in the synapse
Increased number of AMPA receptors= increased sodium influx
23
Q
Describe, at a cellular level, how the associativity LTP occurs in a convergent pathway
A
o If weak stimulation is delivered to the same neuron that has strong, high-frequency stimulation, there is hence:
Concurrent activation of the AMPA receptor due to the strong stimulation means that action potentials are produced, which means that NMDA receptors on the dendrite receiving the weak stimulation have a removed magnesium block, the calcium channel can open and the AMPA receptor number can increase on the weakly stimulated dendrite-> hence, the potentiation is made possible with weak stimulation if accompanied by strong, high-frequency stimulation from another pathway
24
Q
What are the stages of converting initial learning into long-term memory and the time-frame for each stage?
A
• Stages that convert initial learning into long-term memory:
o Generating the synaptic change (creating the initial memory trace) (1 minute)
o Stabilising changes (10-15 minutes)
o Consolidating changes (2-4 hours)
o Maintaining changes (preventing forgetting) (4 hours and more)
25
Describe how a synaptic change is generated to create an initial memory trace
o Generating the synaptic change (creating the initial memory trace) (1 minute)
Initials strengthening of synapse by PKs that traffic local AMPA-Rs back to the synapse
Post-translational changes underlying LTP
• These rapid changes called post-translational because they use existing proteins in neurons (from unused pool of proteins in synapse) and do not require synthesis of new proteins (which would require translation from RNA)
o This is why potentiation can occur rapidly
• Transient (they revert back to previous state) unless other intracellular processes are activated to stabilise the changes
o May explain why recent memory traces can be disrupted by head trauma
Post-translational process involved: constitutive trafficking and recycling of receptors
26
Describe the post-translational processes involved in constitutive trafficking and recycling of AMPA receptors and how these processes change as a result of generating a memory trace
Post-translational process involved: constitutive trafficking and recycling of receptors
• Cycle of receptors through the membrane (constitutive trafficking)
o AMPA receptors laterally diffuse through the membrane
o AMPA receptors are endocytosed
o AMPA receptors in endosomes are delivered back into the synaptic membrane
• When calcium channel of NMDA receptor opens, the calcium activates the protein kinases
o Protein kinases promote trafficking AMPA back to post-synaptic density
• When protein kinases are stimulated with more calcium, trafficking process is upregulated and increase amount of AMAP receptors in synapse-> this is what produces the boost of AMPA receptors in synapse and mediates immediate potentiation
o Blocking protein kinases can block this process
27
Describe the cellular process of stabilising changes
Strengthening the bridge between pre- and post-synaptic membranes (CAMs)
Cell adhesions molecules
• Calcium-dependent cell adhesion molecules (neural cadherins) form bridge between pre-and post-synaptic membranes (maintain alignment)
• Calcium influx through NMDA-R converts weakly-adhesive monomer to strongly adhesive dimer, stabilising synapse
28
Describe how calcium influx through NMDA-R stabilises changes during memory/LTP formation
• Calcium influx through NMDA-R converts weakly-adhesive monomer to strongly adhesive dimer, stabilising synapse
o Cadherin are normally weak monomers and they create a fairly weak bond- weakly align pre-synaptic terminal and post-synaptic spine
o Calcium ions through NMDA receptor leads to conversion of the weak cadherin to a stronger dimer form
Means that pre- and post-synaptic terminal are aligned more strongly-> will improve efficacy of synapse by ensuring that pre-synaptic terminal neurotransmitter release will be released closer to the potentiated post-synaptic spine
Stabilises synaptic change
29
How are synaptic changes consolidated during LTP?
o Consolidating changes (2-4 hours)
Synthesising proteins (from local RNA and newly transcribed RNA from the nucleus) for new AMPA receptors; building up the cytoskeleton to promote spine growth
• Dendritic spine grows as LTP occurs triggered by calcium ions
Translational processes- protein synthesis
• This LTP requires translational processes (protein synthesis); drugs that block protein synthesis can prevent long-lasting synaptic potentiation after strong high frequency stimulation (but have no effect on the initial short-lived potentiation)
Transcription of mRNA from nucleus
• New mRNA must be transcribed from DNA in nucleus to supplement pre-existing mRNA in dendrites
• Calcium ions entering from voltage-dependent calcium channels triggers processes that engage mRNA transcription in the nucleus
• Largely due to calcium entering through voltage-dependent calcium channels at soma, triggered by action potentials passing from dendrites to axons
30
Describe how synaptic changes are maintained after LTP
o Maintaining changes (preventing forgetting) (4 hours and more)
Changing the type of AMPA receptor (GluA1 replaced with GluA2). Synthesis of PKs that remain active (self-activating)
• GluA1, which was generated in initial LTP steps, are replaced by GluA2 which is a more stable receptor- allows potentiation to remain for a longer period of time)
• Self-activating PKs maintain AMPA receptor cycle
31
How can learning become relatively distributed?
• In keeping with localisation of function in the brain, different types of learning appear to be localised in different parts of the brain
• The changes are of learning/memory are relatively local, but depends on what memory is being examined-
o Structures involved in particular behavioural function, if get learning within that aspect of behaviour/that domain, synaptic changes tend to occur localised within areas of the brain important for that domain of behaviour
But often behaviour involves array of areas in the brain- so learning can become relatively distributed
32
What is the role of the hippocampus on memory?
o Hippocampus and place memory
Hippocampus has a well-recognised role to play in learning and memory
Hippocampus is good for spatial memory and navigation
Hippocampus and spatial navigation
33
Describe the 8 arm-radial maze and an experiment performed using this paradigm
8 arm-radial maze
• 8 alleyways/arm from a central arena
• McDonald and White (1993)
o Food in each of the eight arms- rat eats food from each of the arms
o Errors of the rat (revisiting already visited arms) are recorded
o Rat needs to figure out how to visit the arms it’s never visited: requires memory
o Experimenters lesioned the fornix (to eliminate output from the hippocampus) and rats with a lesioned fornix had a higher error rate than rats that did not
34
Describe the morris water maze
• Morris water maze (allocentric task)-
o Large bath filled with milky water (water is cloudy so that rat can’t see through the water)
o In the pool, there is a submerged platform that rat can’t see
o Rat is released in pool and swims around until it finds the platform
o After a few trials, the rat learns where the platform is (memory of environmental cues outside the pool), so the rat will make a beeline to the platform based on memory
To do this, rat needs an allocentric map
35
Where are the place cells in the hippocampus?
Place cells in the CA1-CA3 regions and dentate gyrus of the hippocampus
36
What are hippocampal place cells?
Neurons that become active (fire) when the rat is in a specific part of the environment
• Neurons are sensitive to where the rat is
37
What kind of receptive field do place cells have?
Place cells have allocentric receptive field (organisational structure of space defined by relations among objects rather than with reference to observer (compared to receptive fields in visual cortex))
38
Do place cells depend on visual input? Explain
Place cells respond to visual input, but do not depend on it
• Place cells will continue to show spatial firing patterns in the dark, and congenitally blind rats have place cells
Olfactory and tactile (whisker) inputs also influence spatial pattern of place cells
Place cells are multisensory
39
Describe the location specificity of a single place cell
Location specificity-
• A single place cell is stable and specific within a particular environment, but can be active in more than 1 environment (there is not a 1:1 coding between a single neuron and a location)
40
Does an individual place cell code for a specific area? Explain
o Individual cells do not uniquely code for a location, pattern of activity across multiple cells does
41
Are place cells directional?
• Place cells tend to be non-directional (active in a location regardless of rat’s direction/what direction the rat is facing)
42
Are place cells sensitive to motion?
o Not affected by the speed it is moving in either
43
What is the purpose of place cells? Describe with an example
Place cells and cognitive map
• Place cells provide a mental map of space used to navigate
o When spatial cues are removed, rat and place cells remember spatial layout
o If the maze is rotated, responses of place cells predict where the rat guesses food is located
If rotate the maze, the place cell is tricked
o It is the guide allowing the animal to work out where it is/how to navigate
44
Describe, from start to finish, the process of place cells encoding an environment
Place cells establish spatial pattern within few minutes of being introduced to novel environment and can maintaining this pattern for days or even several months
• Place rats to 2 similar enclosures. Place cell patterns were initially very similar, but after many exposures over several weeks, the patterns began to diverge
o Learning to discriminate between places
• Place cells do not have innate map- only emerge after exploration of environment
Place cells allow animal to learn and differentiate/discriminate between environments
45
Where are grid cells located?
o Grid cells in the medial entorhinal cortex
46
What do grid cells input to?
Inputs to hippocampus come from entorhinal cortex, where different types of cells provide building blocks for allocentric representation
47
Describe grid patterns in the medial entorhinal cortex
Many neurons in the medial entorhinal cortex respond to a rat’s position but follow a lattice or grid
• The grid pattern of a single cell can cover a large area (whole arena) and the cell will show the same grid across different environments (so not about encoding particular places, but rather provide coordinate frames for any space)
48
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Describe grid cells in response to:
-Changes in speed
Changes in direction of rat's movement
-Different locations
-Stability
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Grid cells retain exact grid layout despite changes in speed or direction of rat’s movement
Grid cells are active in multiple locations, but as a grid (firing patches are evenly distributed- provided as a grid)
Grid cells are stable in their grid-like pattern-> will show same pattern over multiple exposures to that environment
49
How do grid cell patterns arise?
Pattern arises from intrinsic nature of network connections among cells in medial entorhinal cortex (e.g. short-range excitation between cells and long-range inhibition)
• Coordinate properties arise because of network properties of neurons in entorhinal cortex-> all the grid cells are connected to each other, and the way they are connected, there is excitatory activity between grid cells that are very close together, and more inhibitory effects on grid cells further away in the network
• That connectivity between them creates intrinsic property that allows them to show firing patterns within certain areas and depression of activity in other areas/locations
50
What is the purpose of grid cells?
Provides spatial information as a coordinate system that is the input to the hippocampal place neuron
51
Can a single grid cell be used to accurately provide location information? What can overcome this problem?
A single grid cell provides ambiguous information about location (rat could be at any one of the many locations where activation strength is repeated-> but ambiguity can be resolved by combining across multiple grid cells that have different grid spacing and phase
52
Are all grid cells the same?
• Grid cells are not all the same- do not show the same grid like pattern
o E.g. size of grid changes between grid cells
o Information about location is being fed into hippocampus and place cells within the hippocampus are taking the activity across different grid cells in order to identify specific locations within the environment
53
What types of learning/memory is the hippocampal vital for?
o Spatial processing may be a primary function of the hippocampus, but spatial (and temporal) context is fundamentally important for many types of learning and memory (e.g. episodic, working memory)
Hippocampus is vital for identifying spatial and temporal context-spatial and temporal context is incredibly important for working memory and episodic memory
54
What is the role of the cerebellum in learning and what design lets it perform this function?
• Cerebellar contributions to learning
o Cerebellum has clear role in learning motor skills
Complex and intricate structure of cerebellum allows integration of sensory inputs for precise timing and sequencing of motor programmes
70% of neurons in our brain are in the cerebellum
Cerebellum organised in very precise structure
o Contractions of the muscles needs to be controlled-> timing of movements needs to be incredibly accurate which is what the cerebellum is doing
55
What are the types of neurons in the cortex of cerebellum?
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o Cortex of cerebellum
Types of neurons
• Purkinje cells
• Climbing fibres
• Granule cells
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56
Describe the anatomy and role of the purkinje cells in the cortex of the cerebellum
• Purkinje cells
o Output from cerebellar cortex
o Has dense arborisation of the dendritic tree, but it is incredibly flat
o Purkinje cell dendrites are covered with climbing fibres- strongly influenced by inputs
57
Describe the origin and role of the climbing fibres in the cortex of the cerebellum
• Climbing fibres
o Climbing fibres from inferior olive (olivary nuclei) outside the cerebellum
Olivary nuclei- input to cerebellum
58
Describe the origin, anatomy and role of the granule cells in the cortex of the cerebellum
• Granule cells
o Located within the cerebellum but cell bodies are deeper in the cortex
o Give rise to parallel fibres that run along alpha layer of cerebellar cortex and pass through many purkinje cell layers and making contact with all of them as they pass
Purkinje cells will get input from parallel fibres
o Input into cerebellar cortex
59
What is the most extensively studied paradigm demonstrating learning in the cerebellum?
Most extensively studied paradigm demonstrating learning in cerebellum is eyeblink conditioning in the rabbit (similar findings in humans)
60
Describe eyeblink conditioning in the rabbit
• Rabbit hears a noise (CS) followed by an airpuff to the eye (US). US normally elicits eyeblink
• After 30 to 40 trials, rabbit learns to blink in response to the noise
• Very tight coupling between airpuff and eyeblink-eyeblink conditioning is a very tight response
o Timing of response depends on the cerebellum
61
What are the nuclei involved in the eyeblink conditioned response?
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• Eyeblink conditioned response
o Eyeblink conditioned response involves the same nuclei as an unconditioned response, but more:
Red nucleus in the brainstem
Pontine nuclei in the brainstem
Inferior olive in the brainstem
Cerebellum
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62
Describe the role of the pontine nuclei in the eyeblink conditioned response and how it performs that role
• Receives input from auditory nucleus in the brainstem
o Neurons in pontine nucleus respond to sounds
• Sends signals to cerebellum (coming in from granule cells)
o Electrical stimulation of pontine nuclei can serve as effective conditioned stimulus (instead of the normal conditioned stimulus) when paired with airpuff unconditioned stimulus
o Pontine nuclei part of pathway conveying conditioned stimulus input
63
Describe the role of the inferior olive in the brainstem in the eyeblink conditioned response and how it performs that role
Inferior olive in the brainstem
• Receives input from trigeminal nucleus; output to cerebellum
o Neurons respond to airpuff
• Electrical stimulation elicits eye-blink and can serve as effective US (instead of airpuff) if paired with tone
• Inferior olive part of path conveying unconditioned stimulus input
64
Describe what happens if there is a lesion to the inferior olive in the brainstem on learning
• Lesions prevents learning, but no effect on expression of previously learned conditioned response (-> induces extinction of conditioned response)
o Stop US input from reaching the cerebellum which is necessary for maintenance of conditioned response
65
Describe the role of the cerebellum in the eyeblink conditioned response and how it achieves this role
Cerebellum
• Where the plasticity of the conditioned response occurs
• Receives converging input from pontine nuclei and inferior olive, and outputs to red nucleus
• Can get conditioning with combined stimulation of pontine nuclei and olive
66
Describe what happens if there is a lesion to the cerebellum in the brainstem on learning
• Cerebellum lesion prevents learning, and blocks expression of previously learned conditioned response
67
What happens if there is damage to the pontine nuclei, cerebellum or inferior olive regarding conditioning?
o Damage to any of the structures involved in the eyeblink conditioned response eliminates eyeblink to conditioned stimulus, but not to airpuff
68
Describe how conditioned stimulus and unconditioned stimulus information converges in the cerebellum
CS and US converge in the cerebellum
• Mossy fibres from pons synapse onto granule cells (carrying conditioned stimulus info). Parallel fibres from granule cells form synapses with very many Purkinje cells: one PC receives synapses from more than 100,000 parallel fibres
• Climbing fibres from inferior olive carry unconditioned stimulus info
• Potential for many conditioned stimuli (or many different time signatures of conditioned stimulus) to be associated with unconditioned stimulus
o CS input is diverse- weak initially but diverse
o US input- concentrated and very strong
• Structure allows cerebellum to precisely time when responses are made
69
How many climbing fibres and climbing fibre synapses are there per Purkinje cell in the cerebellum?
o Strong exclusive communication between climbing fibre and Purkinje cells: each purkinje cell receives many (500+) synapses from one and only one climbing fibre
1:1 map between climbing fibre: purkinje cell
• Single climbing fibre to single purkinje cell
70
What allows voluntary movement?
o All voluntary movement due to contraction of skeletal (striate) muscles
71
Describe how contractions occur in muscle
o Contraction: myosin filament rows along actin filaments
Myosin cross-bridges stretch between myosin and actin filament: cross-bridges slide myosin and actin against each other
72
What are muscles made up of? Describe
o Muscle made up of fascicles
Within a fascicle, there are many muscle fibres (50 um)
• Muscle fibres are made of threads (myofibril threads 1-2um)
• Myofibril threads composed of filaments
o Myosin (thick filament- 15nm)
o Actin (thin filament- 6nm)
73
How many muscle fibres are there in the biceps, and how many sarcomeres are there per fibre?
o Around 250,000 muscle fibres in the biceps, and 100,000 sarcomeres per fibre
74
Describe the neuromuscular junction and what happens at a neuromuscular junction
Process-
• Motor neurons release Ach into neuromuscular junction to stimulate muscle
• Ach binds to nicotinic receptors on motor end plate of neuromuscular junction
• Binding triggers influx of calcium that causes contraction (makes cross-bridges move)
75
What determines the precision of movement? Give an example
Number of fibres innervated by each motor axon determines precision of movement- e.g. in thigh muscle each motor unit has around 1000 fibres, whereas extra-ocular muscles have around 10 fibres per motor unit
76
What is myasthenia gravis?
Myasthenia gravis: autoimmune attack on Ach receptors-> makes it harder for motor neurons to stimulate muscles because losing receptors that motor neurons use to stimulate muscles
77
What is the function of the spinal cord in motor function?
o All motor signals to muscles go via spinal cord (or medulla). Spinal cord serves as relay from brain.
But also contributes to motor-control for very fast responses or adjustments- spinal reflexes (e.g. pain withdrawal response or stretch reflex) and some ongoing orchestrated movements (e.g. breathing and walking) driven by central pattern generators in spinal cord or medulla
78
Describe the stretch reflex and what it is for
o Spinal reflex-
Stretch reflex (knee jerk)
• One synapse reflex
• For online adjustments to muscle tension (e.g. during walking)
• Afferent input from muscle spindle (detecting muscle stretch) through the dorsal horn of the spinal cord and synapses on motor neurons in the ventral hon to send efferent output to thigh muscle (to contract)
o Excitatory input
79
What anatomical parts to the brain control descending projects from the brain to the spinal cord? Describe the role of each
o Descending control- voluntary actions under control of descending projections from brain to spinal cord
Motor cortex-
• Control muscles in arms, hands and fingers
• Fine manual movements (e.g. writing, picking up an object)
• Corticospinal pathway- very significant in humans
Red nucleus
• Controls arms and legs
• Limb movements independent of trunk (e.g. reaching)
Brainstem
• Control muscles of trunk, neck and proximal limbs (upper arms/legs)
• Posture, correcting balance
• Coordinated movements- such as walking/running
80
What is the internal capsule and its role?
o Internal capsule-
Ribbon of fibres from the cortex to thalamus, basal ganglia, brainstem and spinal cord-> carries information throughout the cortex
81
What are the 3 areas of motor cortex?
* Primary motor cortex (M1)
* Supplementary motor area (SMA)
* Pre-motor area (PMA)
82
Where is the primary motor cortex, what is its topology and what is its role/what is it involved in?
• Primary motor cortex (M1)
o Strip of cortex in front of central sulcus
o Contains a topographic map of the body- muscle groups represented by discrete patches of cortex
Has more detailed map
Large area devoted to the hands, face, mouth and tongue
o Electrical stimulation evokes movements in corresponding limb or muscle group
o Involved in final execution of movement: output to spinal cord via direct corticospinal tracts, and via red nucleus
Irreversible output-too late to stop movement
83
Describe the role of the supplementary motor area (SMA)?
• Supplementary motor area (SMA)
o Involved in planning of movements:
Neurons most active shortly before performing a movement or even before an aborted movement, or during imagined rehearsal of a movement
o Active before the motor cortex is- precede motor cortex activation
84
Describe the role of the pre-motor area
• Pre-motor area (PMA)
o Involved in planning of movements:
Neurons most active shortly before performing a movement or even before an aborted movement, or during imagined rehearsal of a movement
o Active before the motor cortex is- precede motor cortex activation
85
Describe how movement is coded/planned in the motor cortex and describe the evidence
• Neurons in the PMA and SMA code for anticipated direction destination of movement
o Monkeys moved a joystick towards a light-some cells only fired when the monkey was about to move stick in a specific direction
o These direction cells maintained firing dung a delay interval (if monkey had to wait several seconds after light went off before moving stick)
• Direction cells also perform mental rotation
o Monkey had to move joystick 90o anticlockwise from light/signal
o Monkey has to rotate where the cue is in order to imagine which movement it should be making
o Activity spread through population of neurons mapping out the rotation transformation
86
What is the role of the cerebellum?
o Cerebellum plays a role in the precise execution of movements- particular movements that require precise timing for precise execution
Does fine-tuning of signals
Connections with brain are crossed
• Left hemisphere of cerebellum contributes to movement in left side of the body
o Double-crossing over
o Cerebellum important in smooth execution of corrdinated sequences of movements, including speed
Damage to cerebellum: jerky, poorly coordinated movements- can’t use proprioceptive feedback
Cerebellum very important in learned complex skills
• E.g. flying, walking, playing musical instruments, riding bycicle + eyeblink conditioning
o Cerebellum and cognition-
Contributes to performing offline processes/actions
Cognitive impairments after Cb damage (can get frontal deficits in executive function)
87
What are the inputs and outputs of the cerebellum and what are the implications of this?
o Cerebellum receives sensory input:
E.g. vestibular, somatosensory and proprioceptive but also visual and auditory and input from cortex (via pons)
Extensive connections with association cortex
• The cerebellum is extensively connected to association cortex through thalamus to association cortex
o Send output to red nucleus and (via the thalamus) to the cortex
o Therefore, not direct control over motor output (more fine-tuning of other motor centres)
88
What is included in the association cortex?
o Association cortex- posterior parietal lobe, temporal lobe, prefrontal cortex
89
What is in the basal ganglia?
```
• Group of subcortical structures-
o Caudate
o Putamen
o Globus Pallidus
o Ventricles
o Substantia nigra
o Thalamus
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90
What two extrapyramidal diseases was an early understanding of the basal ganglia based on and why?
• Early understanding of basal ganglia based on 2 extrapyramidal diseases-
o Huntington’s disease
o Parkinson’s disease
• Both diseases characterized by motor dysfunction and basal ganglia degeneration
• Suggested that basal ganglia involved in execution of movement
91
What is the function of the basal ganglia?
• Basal ganglia function
o Electrophysiology-
Neurons in basal ganglia very active just before and during movement, but always after cortex becomes active
Neural activity in basal ganglia does not code for particular movements
92
Describe the anatomical connections to and from the basal ganglia, as well as feedback loop
o Anatomically, basal ganglia have no direct projections to motor output structures
Not connected to red nucleus
Connected via the thalamus to go back to cortex
o Basal ganglia connected to motor cortex
• Connectivity of the basal ganglia-
o Basal ganglia forms closed feedback loops with cortex and thalamus
Excitatory input from the cortex (motor cortex, prefrontal cortex, association areas)-> Caudate and putamen (striatum)-> globus pallidus-> thalamus-> cortex (back to same regions of cortex that initiated the movement)
93
What are the 3 feedback loops in the basal ganglia
o Basal ganglia form 3 feedback loops with cortex and thalamus
Direct path via globus pallidus pars interna (GPi)
Indirect pathway via globus pallidus pars externa (GPe)
Indirect pathway via subthalamic nucleus (STN)
94
Describe how the basal ganglia's direct path via globus pallidus pars interna works and its effect
Direct path via globus pallidus pars interna (GPi)
• Cortex excite striatum with glutamatergic connections-> Striatum contains GABAergic neurons which inhibit the globus pallidus pars interna so that it can no longer inhibit the thalamus-> thalamus sends excitatory input to the cortex
• Increases excitatory thalamocortical feedback
• Excitatory feedback loops
• 90% of neurons in the striatum are inhibitory (contain GABA)
95
Describe how the basal ganglia's indirect pathway via globus pallidus pars externa (GPe) works and its effect
Indirect pathway via globus pallidus pars externa (GPe)
• Cortex excites the striatum-> striatum inhibits the globus pallidus pars externa which prevent inhibition of the globus pallidus pars interna-> globus pallidus pars interna inhibits thalamus which prevents thalamus from sending excitatory input to the cortex
• Reduce the excitatory thalamocortical feedback
• Diminishes feedback to the cortex
• Negative feedback loop
96
Describe how the basal ganglia's indirect pathway via subthalamic nucleus (STN) works and its effect
Indirect pathway via subthalamic nucleus (STN)
• Cortex excites the striatum-> striatum inhibits the globus pallidus pars externa which prevents GPe inhibition of the subthalamic nucleus-> subthalamic nucleus provides excitatory input to the globus pallidus pars interna -> Globus pallidus pars interna send inhibitory input to the thalamus-> thalamus can no longer send excitatory input to the cortex
• Reduce the excitatory thalamocortical feedback
• Negative feedback loop
97
What is the role of the two indirect pathways in the basal ganglia?
The two indirect pathways simultaneously reduce the excitatory thalamocortical feedback at the same time- double negative feedback loop
98
What are the models of basal ganglia function?
o Modulate motor programmes originating in cortex
Scaling of movement:
Focusing/filtering of movement-
Error correction
----NOTE: Basal ganglia also has uses in cognitive domains-> thought processes that require online monitoring
99
Describe the scaling of movement model of basal ganglia function
Scaling of movement:
• Positive feedback via direct loop of the basal ganglia helps to initiate movement by helping to build up activity in the motor cortices
• Negative feedback via indirect loop of the basal ganglia helps to stop movement by dampening down activity in the motor cortices
100
Describe the focusing/filtering of movement model of basal ganglia function and how it would work
Focusing/filtering of movement-
• Positive feedback through direct loop boosts appropriate motor programmes (from central pattern generators)
• Negative feedback through indirect loops filters out inappropriate motor programmes (competing central pattern generators)
o That is, like stereo amplifier, enhancing signal-to-noise ratio within the motor cortex
• 100% of striatal neurons respond to signals for reward and synapse on other striatal neurons (that is, do not project outside striatum)
o These striatal neurons could be helping to bias which kinds of movements are being selected and which kinds of movements are being filtered
Learning and motivational control over response selection
If it is learned that some movements lead to positive rewards, then these signals for reward within the striatum might allow for filtering process to bias in favour of the movements that lead to reward and filter out over actions at that time
101
Describe the error correction model of basal ganglia function and how it would work
Error correction
• The basal ganglia loops provide central (internal) feedback to cortical response systems:
o Provide predictive feedback, allowing faster correction than permitted by slow peripheral feedback from external structures
• Promotes accuracy of movement
• Closed internal feedback, errors are addressed much more quickly when they are much smaller so that the corrections needed are much smaller-> much more stable error correction process
102
What is the consequence of the fact that there are multiple loops originating from different cortical regions remain segregated through basal ganglia, returning to their cortical areas of origin
o Multiple loops originating from different cortical regions remain segregated through basal ganglia, returning to their cortical areas of origin->allows for diversity of function
103
What kinds of dopamine receptors do neurons that go to the globus pallidus pars interna on the direct pathway have?
o Neurons that go to the Globus Pallidus pars interna on the direct pathway have D1 dopamine receptors
104
What kinds of dopamine receptors do neurons that go to the globus pallidus pars externa on the indirect pathway have?
o Neurons that go to the Globus Pallidus pars externa on the indirect pathway have D2 dopamine receptors
105
What is the impact of the substantia nigra on the direct and indirect pathways in the basal ganglia? How does it do this effect?
input
Dopaminergic inputs form synapses form synapses on both the direct pathway and the indirect pathway
• Two different pathways have two different types of dopamine receptors-
Substantia nigra inhibits the indirect pathway (through D2 dopamine receptors) and promotes activity in the direct pathway (through D1 dopamine receptors)
o When substantia nigra is active:
Dopamine acts at D1 receptors to increase inhibition from striatum to GPi (excites direct loop and boosts thalamocortical feedback)
Dopamine acts at D2 receptors to decrease inhibition from striatum to GPe (inhibits indirect loops and allows thalamocortical feedback)
106
What is the ultimate effect of dopamine from the substantia nigra on the thalamocortical feedback loop of the basal ganglia?
o Dopamine ultimately boosts thalamocortical feedback (increasing the excitatory feedback from direct loop and reducing dampening of that from the indirect pathway)
Regulates direct and indirect pathway
107
What is Huntigton's disease?
• Genetic disease causing progressive loss of GABA neurons in striatum (especially caudate nucleus)
o Dominant autosomal disease
108
What are the symptoms of huntington's disease and when do they occur?
• Nothing happens to the sufferer for the first 30-40 years of their life
o Effects of gene are very delayed
• Twitches in face and hands, progress to tremors through body
• Tremors can resemble voluntary movements
• Movement disorder accompanied by dementia
109
What explains the motor symptoms of Huntington's disease?
• Explaining Huntington’s disease-
o Loss of GABA neurons in the striatum leads to decreased output from GPi to thalamus
Overactivity of the globus pallidus pars externa strongly inhibiting pars interna and stopping subthalamic nucleus from exciting the pars interna-> pars interna loses its inhibitory input to the thalamus-> lots of excitatory inputs from the thalamus to the cortex
o Inappropriate motor programmes are not filtered out, and so intrude into behaviour
110
What are the major symptoms of Parkinson's disease and when do these symptoms appear?
* Afflicts people over 60, incidence climbs with age
* Major symptom: great difficulty moving, particularly initiating actions (sticking), abnormal gait (shuffling) and don’t swing arms. Also resting tremor (not essential tremor- tremor while person is moving)
111
What are the neural mechanisms of Parkinson's disease?
• Degeneration of dopaminergic-containing neurons in substantia nigra that project to caudate and putamen (nigro-striatal pathway)-> pathways start to shift in direction of favouring indirect loops
o Indirect loop starts dominating over direct loop so start to lose thalamocortical feedback
o Much more difficult for cortex to start building excitatory movements-> hard to start/initiate movement
• Death of neurons in substantia nigra leads to loss of dopamine input to basal ganglia
o Indirect pathway is favoured-> globus pallidus pars externa is strongly inhibited-> no longer inhibits globus pallidus pars interna which also gets amplified through excitatory inputs from the subthalamic nucleus-> leads to strong inhibition of thalamus and loss of excitation to cortex
o Loss of dopamine input causes filter to close, blocking all motor signals (appropriate and inappropriate) from cortex
o Initiation of any movement becomes extremely difficult
112
What are the current treatments of Parkinson's disease?
```
• Treatments of Parkinson’s disease-
o Dopamine agonist drugs (e.g. L-dopa)
o Cell transplant techniques are being developed:
o Brain lesions to GPi or STN
o Deep brain stimulation in STN
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113
How effective are cell transplant techniques for Parkinson's disease treatment?
Healthy dopamine cells (either from foetal tissue or grown in vitro in tissue cultures) are put into brain
Poor results in Parkinson’s patients, but experiments in Sweden produced excellent results with young (and otherwise healthy) patients poisoned by MPTP
• Worked in MPTP because they were no longer affected by whatever killed the cells-> means they works
114
Why are brain lesions a treatment of Parkinson's?
o Brain lesions to GPi or STN
| Trying to reduce indirect feedback loop activity-> recover thalamocortical feedback
115
How does deep brain stimulation in STN treat Parkinson's?
o Deep brain stimulation in STN
Brain stimulation jamming neuron activity-> stops STN neurons from functioning (temporary lesion)
More popular than brain lesions because it is reversible
Can titrate dose to stimulate until you get right effect you need
116
What is the genetic and neuronal basis of Huntington's disease and what is the consequence of this genetic basis?
• Huntington’s disease
o Brains of HD sufferers: death of GABAergic cells in striatum
o HT gene on chromosome 4 codes for Huntingtin protein expressed in all cells but particularly high in neurons in the striatum
o HD sufferer has longer DNA sequence on HTT which creates mutant Huntingtin protein
o Breakdown of mutant protein produces short fragments that get misfolded and form aggregates that are toxic
117
What is the neuronal and protein basis of Parkinson's disease/what is the mechanism of Parkinson's disease?
• Parkinson’s disease
o Brains of PD sufferers: loss of dopaminergic substantia nigra neurons, and lewy bodies in surviving neurons
o Lewy bodies contain aggregation of protein alpha-synuclein to toxic levels
Production of misfolded alpha-synuclein protein
o Loss of function of Parkin protein that tags misfolded proteins for destruction by enzymes
Parkin protein (which tags misfolded proteins for destruction) loses its function-> misfolded proteins not destroyed-> misfolded protein accumulates
Only accounts for some cases of Parkinson’s disease
118
How many dementia cases does Alzheimer's disease account for?
o 50% of all dementia cases
119
What is the neuropathology of Alzheimer's disease?
o Neuropathology-
Widespread loss of brain tissue in cortex
Disease most commonly starts in the medial temporal lobe around the hippocampus-> early stages of the disease starts with memory deficits
120
What is the distribution of neurodegeneration in Alzheimer's disease?
o Distribution of neurodegeneration:
Hippocampus and entorhinal cortex
Association cortex (anterior temporal and posterior parietal cortex; prefrontal cortex)
Specific subcortical nuclei:
• Nucleus basalis (cholinergic)
o Pharmacological treatment mostly AChE inhibitors
Aricept- reversible AChE inhibitor
• Locus coeruleus (noradrenergic)
• Raphe nuclei (serotonergic)
o More primary cortices are relatively spared, at least in the earlier stages of the disease
121
What is the pathology of Alzheimer's disease?
o On post-mortem, brain tissue full of abnormal material, especially:
Amyloid (senile) plaques
Neurofibrillary tangles
122
What are mamyloid plaques and how do they form in the normal brain vs Alzheimer brain?
Amyloid (senile) plaques
• Amyloid plaques- collection of neural debris, particularly beta-amyloid (a protein found in cell walls)
• Process of formation-
o Beta-amyloid precursor protein (APP) chopped into 3 pieces by secretase enzymes that then get eliminated
o In normal brain, more than 90% of beta-amyloid (one of the 3 fragments of beta-amyloid precursor protein) is short (40 AAs) and less than 10% is long (42 AAs)
Brain is able to eliminate this very easily
o In Alzheimer brain, more long form (up to 40% of 42 amino acid sequence) misfolded and toxic
123
What treatments are being developed to combat beta-amyloid in Alzheimer's disease?
o Treatments being developed using antibodies to eliminate the long forms of beta-amyloid protein that contribute to Alzheimer’s disease
124
What are neurofibrillary tangles and what do they do in Alzheimer's disease?
Neurofibrillary tangles
• Neurofibrillary tangles- clumps of tau protein detached from disintegrating microtubules (cytoskeleton) inside neuron
• Neurofibrillary tangles that accumulate in the neuron and choke the neuron
125
How are amyloid plaques anatomically distributed in Alzheimer's disease? Why?
o Distribution of plaques and activity-
Progression of disease has particular profile to it
Plaques distributed across prefrontal cortex, anterior temporal lobe, retrosplenial cortex, posterior region of parietal lobe and prefrontal areas
Looked at default network (at rest)-> see pattern of activity in the brain: default mode network corresponds to where you see greater accumulation of plaques in Alzheimer’s disease
• Areas that don’t shut down when not doing anything are the ones affected by Alzheimer’s disease
o This continuous metabolic activity may be why they continue to accumulate these proteins at toxic levels
126
What is Creutzfeld-Jacob disease and what are its symptoms?
• Creutzfeld-Jacob Disease
o Progressive degenerative disease (months, sometimes more than 1 year)
o Manifesting in neurological dysfunction (mostly loss of coordination and dementia)
127
What is the frequency of Creutzfeld-Jacob disease?
o Rare: about 1 in 1,000,000 per year
128
What is the phenotype of Creutzfeld-Jacob disease?
o On postmortem, brain full of small holes- sponge
o Spongiform encephalopathy (also scrapie for sheep, BSE for cattle and others)
Brain develops holes
129
What causes Creutzfeld-Jacob disease?
o New type of infectious agent known as prions
o Can be genetic (familial) or sporadic, but also by infection
Disease can be acquired through infectious process
o Prion- infectious protein
130
What was Kuru and how was it spread?
Kuru- disease could be due to tribal practice: elders in tribe would eat brain tissue of person who had died in the tribe
• May be why disease was so common in these tribes
131
What were Iatrogenic cases of Creutzfeld-Jacob disease caused by and how was this fixed?
Iatrogenic (caused by medical practices) cases of CJD: infectious materials from neurological surgeries of people with CJD could infect other people
• Even if instruments were sterilised through high temperatures to destroy nucleic acids
• Instead, infectious material was affected by procedures that denatured or destroyed proteins
132
How was it determined that Creutzfeld-Jacob disease was not caused by living pathogens?
o Prions not affected by procedures that destroy nucleic acids
Therefore, agent did not have DNA or RNA (not like living pathogens- viruses, bacteria etc.)
133
What are the origins of prions and are they the same across all species?
o Prion origins-
Known sequence of amino acids in the prion protein (PrP)
Discovered that all animals carry genes that codes for PrPs
• Slightly different across species, and difference increases with greater evolutionary distance between species
• Basis for species barrier to disease
134
What are the two main forms of PrPs and why are they different?
o Two forms of PrPs
Normal form
• Degraded by appropriate enzymes
Aberrant form
• That is resistant to usual enzymes-> form that causes disease
o The two forms of PrPs have different genetic codes, but same amino acid sequence
Two PrPs differ in 3D structure depending on how amino acid chain is folded up
Aberrant form has misfolded structure that makes it resistant to normal enzymes-> makes them accumulate in the cell which interferes with the normal function of the cell and can lead to death of the cell
135
Why are prions infectious/how do they spread?
o Infectiousness and understanding-
Healthy mice, injected with material from brains of diseased mice, develop encephalopathy and die
But infectious PrP does not cause disease in mice that completely lack the PrP gene
Thus infectious protein must have normal PrP present in cells to cause disease
Misfolded PrP can convert normal PrP into misfolded form
• Contact of misfolded PrP to normal PrP can make normal PrP misfolded-> source of infection and spread
136
Describe the mad cow and Creuzfeldt-Jacob disease outbreak in 1970-80 Britain including impact and reasons.
o Mad cows and CJD in Britain-
Outbreak of BSE due to change in dietary supplement for cows in 1970s-80s
• Cows were given dietary supplements that included ground-up meal from other animals
Species barrier between cows and sheep not so large (Prs differ at only 7 places) but much larger between cows and humans (PrPs differ at 30 places)
In 1990s, rise in incidence of CJD in Britain-> looks like there were cases of people in Britain that acquired form of CJD that was acquired from eating infected cattle
Shown in that infectious PrPs from BSE cows can cross species barriers to infect mice, pigs and primates
• Thus maybe can cross into humans
But no BSE in Australia, and PrPs virtually absent in skeletal muscle (that is, steak is ok)
• Offal is probably how this disease got into the human food chain
