Neurobiology of learning and memory

Question 1

What is learning and memory?

Answer 1

Learning:
* Acquisition of new knowledge or information

Memory:
* Retention of learned information

Question 2

What are the 2 main types of memory?

Answer 2

Declarative: Can declare verbally
* Generic (reference library: facts, words)
* Explicit (memory with awareness; what you wore yesterday - requires conscious effort)

Nondeclarative: Cant declare verbally, retained smtg over time but cant declare it
* Implicit (memory without awareness: past experience influences current task - procedural memory)

Question 3

What brain regions are involved in the 2 types of memory?

Answer 3

Declarative
* Medial temporal lobe (hippocampus) Nondeclarative

• Procedural: cerebellum (muscular response), striatum (habits, skills) & amygdala (emotional response)

Question 4

What are the 3 types of non declarative memory?

Answer 4

Ø Procedural (learning a motor procedure in response to sensory input)
* Non-associative learning: change in behavioural response to a repeated stimulus (e.g. Habituation & Sensitisation)
* Associative learning: forming associations between events (e.g. classical conditioning & instrumental conditioning)

Question 5

What is STM?

Answer 5

• May last seconds or hours
• Easily disrupted (distraction, head trauma)
• Apparent holding capacity is approx. 7 words*
  Working M is not just holding smtg in your head but also performing an operation on it (ex subtraction)

Question 6

What is LTM?

Answer 6

• Events/facts held for days, months or years after storage
• Not easily disrupted
  Distraction doesnt make you forget a childhood M

Question 7

How do we learn to associate one thing with another?

Answer 7

Need to engage with the target, not just be exposed to it

Question 8

How does information go from STM to LTM?

Answer 8

Information in short term memory is lost if not consolidated
For a memory to be stored long-term, it does not necessarily have to be a short-term memory first: It may be stored due to an emotional response, conscious effort Spaced-practice (repeating over time) is better than massed practice

Question 9

Learning & Memory require what 4 main changes in brain function?

Answer 9

Neuroplasticity
- Neurogenesis: New neurons from precursor cells
- Neurodegeneration: Death of neurons and rearrangement of synapses
- Changes in Dendritic: Branching:
* Increases in dendritic branches
* Pruning of dendritic branches
- Long Term Adaptations to Synapses:
* Long Term Potentiation = enhancement of synapse strength
* Long Term Depression = weakening the strength of a synapse
* Strength = ability to produce EPSP to promote action potentials

Question 10

Can we grow new neurons?

Answer 10

Yes! We have stem cells
* Embryonic (pluripotential stem cells can turn into anything) - taken from fertilised eggs (blastocyst)
* Tissue specific: Neural stem cells (ie stem cells which will become neurons)
* Development of mature cell depends on exposure to growth factors

Question 11

Where are neural stem cells?

Answer 11

Ependyma cells line the ventricles
Neural stem cells lie beneath this layer
Neural stem cells are in the subependyma of the ventricular system

Question 12

What are neural stem cells?

Answer 12

• Neural stem cells manufacture constitutively proliferating (CP) progenitor cells
• CP cells migrate out of subependyma and form new neural cells when exposed to certain conditions (e.g., growth factors such as BDNF)
• Evidence has shown migration of these cells to
  – Cortex
  – Striatum
  – Olfactory Tubercles of forebrain
• Migration of these new neurons are helped by the ependymal cells.
• The development of new neurons is called Neurogenesis
  – A lot of neurogenesis also occurs in the dentate gyrus of the hippocampus

Question 13

What is the link between depression and neurogenesis?

Answer 13

• Depression associated with decreased neurogenesis in hippocampus (dentate gyrus)
• Use of antidepressants enhance neurogenesis in dentate gyrus

Question 14

What is the link between exercise and neurogenesis?

Answer 14

• Neurons change in response to our experiences
• Exercise enhances learning through neurogenesis in hippocampus
• Regular physical exercise may protect against cognitive decline and dementia as we age
• Environmental enrichment also shows benefit for learning and memory
  Not specific to exercise, exercise is one way to enrich the env

Question 15

How can we alter the neurons that we have on top of creating new ones?

Answer 15

Neuron death and rearrangement of synapses
* Normal neurodevelopment depends on the death of some neurons
* Neurons grow to meet ‘target’ neurons
* If a growing neuron does not get the growth factors (and guidance) it needs from target cells they die off
* Neuron death helps to focus the output of remaining neurons - smaller number of postsynaptic cells = selectivity of neurotransmission

Question 16

What does experience do to dendritic branching?

Answer 16

• Neurons change in response to our experiences - they physically grow more dendrites
  Animals in enriched environments have greater dendritic branching. They also have improved learning skills.
  When learn a new skill, the dendrites in that area become more dense bc they receive more info

Similar to synaptic elimination, our dendrites can be pruned back
* For dendrites use it or lose it
* Dendrites that are not used regularly will be pruned back
If A does not receive input, the A dendrite will recede

Question 17

What does experience do to cortical reorganisation?

Answer 17

Our cortex changes in order to accommodate the motor activity that we need / use
* Cognitive Behavioural Therapy can also produce reorganisation of our “neural circuits”
Neural circuits reorganise in all the situations that we learn new things

Question 18

How do experiences change our synapses?

Answer 18

• Our synapses change in response to our experiences
• Synaptic Plasticity = long term changes in how our synapses work
• Long Term Potentiation
• Long Term Depression

Question 19

How do we study learning in the aplysia?

Answer 19

Aplysia have been used extensively to study the neuroplasticity associated with sensitisation and habituation by investigating their gill withdrawal reflex
Simple invertebrates
Few and large neurons - easy to study
Their neurons are very similar from one aplysia to the next

Question 20

What is the specificity of synaptic connections?

Answer 20

The more it’s used, the stronger it gets
The sight of the rose causes an EPSP. With repeated exposure to seeing the rose the EPSP will become large enough to produce an action potential: the synapse is strengthened

Question 21

What is synaptic cooperativity?

Answer 21

Neurons that fire together, wire together
If two sensory signals are repeatedly received within 50 ms of an action potential they become linked and strengthened. This means that one signal can have the same effect as two
* High frequency stimulation is not enough to cause LTP
* EPSP in one part of the neuron requires an action potential to occur at the same time in order to produce HUGE depolarisations
* This results in back propogation (i.e., more positive to the dendrites from the axon hillock of the firing neuron)
* Synapses that co-operate to produce this action potential are wired together and can induce firing later on independently

Question 22

What is synaptic associativity?

Answer 22

Neurons that fire together, wire together
Weak inputs paired with a strong EPSP and action potential will become stronger with more pairings
If two sensory signals are repeatedly received within 50 ms of an action potential they become linked and strengthened. This means that a weak signal can end up being a lot stronger.

Question 23

What was Hebb’s theory?

Answer 23

The neural representation of objects is the pattern of all cortical cells activated by the external stimulus
Some cortical cells are simultaneously active in response to this object
If the simultaneous activity of these cells occurs for long enough (or repeatedly), there will be a change (growth) in the neurons to consolidate this
“neurons that fire together, wire together”
This means that only a certain number of cells in this assembly would need to be activated in order to represent a rose (e.g.): different combinations instead of needing many different neurons
Successful pairing only occurs if both signals occur within 50 ms of an action potential - requires huge depolarisations

Question 24

How do different neurons fire differently?

Answer 24

Neurons fire at different frequencies (Hz)
When neurons fire they release neurotransmitter into the synapse
Frequency means the number of synaptic excitations per second
Low frequency = 1-5 Hz
High frequency = 50-100 Hz
Differences in firing frequencies can greatly alter communication between synapses

Question 25

How does firing frequency affect neuroplasticity?

Answer 25

• Long Term Potentiation (LTP): Brief high frequency electrical stimulation of an excitatory pathway leads to a long-lasting enhancement in the strength of the stimulated synapses More likely to fire in the future after the high f (aug response)
• Long Term Depression (LTD): Brief low frequency electrical stimulation of an excitatory pathway leads to a long-lasting weakening of the strength of the stimulated synapses Less likely to fire in the future after low f (dim response)
• LTP and LTD rely on the function of Glutamate receptors

Question 26

How does LTP occur?

Answer 26

High frequency Stimulation (50-100 Hz)
Huge EPSP
High level of Ca entry into cell upregulates CaMKII and PKC that enhance AMPAR
CaMKII/PKC makes more AMPA R available and makes existing AMPA R more sensitive
The cell is strengthened It will depolarise a lot faster& stronger with next glutamate signal

Question 27

What is the BCM theory?

Answer 27

Bidirectional regulation of synaptic strength (up or down)
* Long Term Potentiation
* Long Term Depression
* Synapses that are active when the cell is only weakly depolarised (i.e., only small EPSP, not action potential) will become weaker.
* Long Term Depression
Weak EPSP has diff effect on cell and dims likelyhood of cell firing

Question 28

How does LTD occur?

Answer 28

Low frequency Stimulation (1-5 Hz)
Small amount of Calcium enters cell
Leads to overall small EPSP
Small levels of calcium activate phosphatases
Phosphatases deactivate AMPA R and internalise them Glutamate cannot open AMPA R so NMDA R cannot work either
The neuron will be less affected by glutamate

Question 29

What is neuroplasticity?

Answer 29

Bidirectional regulation of the AMPA Receptor
* affects how strongly or weakly inputs are received
* affects future signalling/firing of the neuron in question
Affects how much they are used or not
Animal models (Morris water maze) have shown that NMDA receptor antagonists cause animals to ‘fail to remember’. Antagonists directed at Calcium entry to cell or that block PKC/CaMKII have similar effects
NMDA receptors are needed for the acquisition or consolidation of memories

Question 30

How do we maintain memories?

Answer 30

These occur by changes in the intracellular messengers (upregulation) which then lead to physical change in the neuron
Synthesis of new proteins and neuronal circuits (dendritic branching)
Disassembly of existing circuits (dendritic pruning)

Question 31

How is neuroplasticity linked to memory?

Answer 31

• LTP - strengthens the connections that our brains require to remember
• LTD -prunes unwanted connections to correct incorrectly learnt pathways or to ‘unlearn’ a behaviour (extinction). The increase in phosphatases also helps us to forget ‘unimportant’ information - you don’t need to remember everything
• Memories
• begin as electrical signals
• temporarily remain by changes in second messenger systems
• become long-term when synaptic proteins/structures are modified

Question 32

What is temporary/working memory?

Answer 32

Working memory is the temporary storage of information so that our actions are ongoing. In addition to short term retention it also means that you can use this to ‘manipulate’ information
Working memory involves the prefrontal cortex of the frontal lobe
Working memory is best tested using a delayed response task
Subject receives a stimulus (light over one lever (out of 10)) Light goes off, delay period (longer the delay, better the working memory)

Question 33

How is the hippocampus linked to memory?

Answer 33

The hippocampus is involved in several types of memory
H.M. had his hippocampus removed (medial temporal lobe)
Intellect and language ok
Suffered amnesia (loss of memory)
Anterograde amnesia (cannot form new memories)
Retrograde amnesia (cannot remember recent memories before surgery)
Cannot learn new facts (declarative) - bad at explicit memory (aware)
Can learn new motor skills (procedural) - ok with implicit memory (unaware)
H.M.’s condition suggested that the hippocampus was more important for some memories than others.
Not just one M module in the brain, its distributed in the brain depending on the type of M

Question 34

What 2 types of memory is the hippocampus involved in?

Answer 34

Declarative (explicit) memory - many of ours are episodic (single events)
“object recognition” tests
“Delayed matching-to-sample task”
“Delayed nonmatching-to-sample task”

Spatial memory-memories of things in space
“radial arm maze”
“Morris water maze”- finding the platform submersed in milky solution

Animals with hippocampal damage have trouble with all of these tasks

Question 35

What is Alzheimer’s disease?

Answer 35

• Neurodegeneration- selective death of Acetylcholine (ACh) cells
• Slowly progressing Dementia
• Memory loss
• Change in personality
• Apraxia - loss of ability to co-ordinate movements
• Aphasia - loss of ability to articulate ideas and comprehend written/spoken word
• Agnosia - cannot interpret sensory stimuli

Question 36

What happens in a patient with Alzheimer’s disease’s brain?

Answer 36

• Patients with Alzheimer’s Disease have reduced Acetylcholine
• Acetylcholine is prevalent in brain regions involved in memory; Hippocampus, cortex
• And movement; Striatum
  Acetylcholine binds to two (cholinergic) receptor subtypes: Nicotinic & Muscarinic
  The muscarinic antagonist atropine can disrupt memory processing.
  Atropine has also been shown to inhibit the process of neurogenesis
• Acetylcholine is involved in proliferation and differentiation of neural stem cells