Memory 1

Question 1

Define memory

Answer 1

• The retention of learned information

Question 2

Define learning

Answer 2

• The acquisition of new knowledge and skills

Question 3

Defie an engram

Answer 3

• Unit of cognitive information inside the brain

Question 4

What is declarative memory?

Answer 4

• AKA explicit
• Memories of facts and experiences that are consciously recalled
  
  • Easy to form
  • Easily forgotten
• Examples
  
  • Facts
  • Events
  • Objects
  • People
  • Places

Question 5

What is non-declarative memory?

Answer 5

• AKA implicit, procedural memory
• Memory that is acquired from direct experiences and used unconsciously
  
  • Require repetition and practice to form over a long period of time
  • Less likely to be forgotten
• Examples
  
  • Skills
  • Habits
  • Behaviours

Question 6

Describe Kandel’s Aplysia model

Answer 6

• Kandel (1965) was the first to show that in long-term memory formation and in learning, individual neurons:
  
  • Change their structure
  • Increase the number of synaptic connections with other neurons
  • Strengthen the synaptic connections between each other

Question 7

Describe the experimental evidence supporting Kandel’s Apysia model

Answer 7

• Kandel 1960
  
  • Studied the gill withdrawal reflex in aplysia
    
    • Aplysia = genus of medium-sized to extremely large sea slugs
    • They undergo sensitisation when there is simultaneous application of noxious stimuli to the tail of the animal.
  • It was shown that following long term sensitisation, protein kinase A (PKA) in the nerve terminal was active
    
    • Due to a rise in cAMP in the presence of elevated calcium
  • Stimulation of PKA resulted in the synthesis of new proteins and a two-fold increase in the number of synaptic connections made by sensory neurones

Question 8

Outline and describe the two phases of long-term potentiation

Answer 8

• Early phase
  
  • Short term changes mediated by phosphorylation and translocation of receptors into the membrane
• Late phase
  
  • Consolidation of the early phase changes by long term changes in gene expression (transcriptional changes) and protein synthesis

Question 9

Explain the early phase of long-term potentiation

Answer 9

• In the early phase of LTP, the synapse is strengthened by increased expression of the AMPA receptor
  
  • NMDA receptors act as co-incidence detectors for when both membranes are depolarised

1. Glutamate release from the presynaptic neurone binds to the AMPA receptor on the CA1 pyramidal cell dendritic spine and mediate Na⁺ entry
2. When the post synaptic membrane is depolarised, and glutamate is present in the synapse, the Mg²⁺ ion in the NDMA receptor pore is removed, opening the receptor
3. Opening of the NMDA receptor facilitates Ca²⁺ entry into the cell.
4. Ca²⁺ binds to calmodulin
   
   • which activates Ca²⁺ -calmodulin dependent kinase subtype II (CAMKII) and protein kinase C
5. CAMKII has a number of actions:

• Phosphorylation of AMPA receptors
  
  • Increase time in high conduction state
• Phosphorylation of PSD95 protein complex
  
  • Increases AMAP receptor density by reducing dynamic movement in the bilayer
  • Insertion of AMPA receptors in the membrane by the fusion of vesicles studded with AMPA receptors to the end plate

1. Addition of new membrane results in the swelling of dendritic cells
   
   • Dendritic spines are small membranous protrusions from dendrites, usually at excitatory synapses, inhibitory neurones usually innervate the cell body / soma.
   • Allows compartmentalisation of the Ca²⁺ and LTP / LTD to a particular part of the axon
2. It is thought that CaMKII can remain on even after the [Ca²⁺] has fallen, due to autophosphorylation
   
   • Autophosphorylation is an example of a molecular switch
   • It can then contribute to the maintenance of phosphorylated AMPA receptors

Question 10

Explain the mechanism of late phase long-term potentiation

Answer 10

• The late phase of LTP consolidates the changes made in the early phase through transcriptional changes known as induction and maintenance

Induction

1. The high Ca²⁺ activates PKA that forms cAMP
2. cAMP activates the CREB transcription factors
3. CREB binds to sections of DNA called cAMP response elements (CREs) to regulate expression of neighbouring genes
4. There is an increase in the transcription and thus expression of AMPA and NMDA receptors
5. This leads to an increased EPSP following stimulation.

Maintenance

• Following a fall in calcium concentration, the gene expression of AMPA and NMDA receptors is maintained by kinases that remain constitutively active at potentiated synapses
  
  • These kinases can activate transcription factors
• E.g. protein kinase M zeta
  
  • mRNA for this kinase is only translated at synapses where there is strong activation and calcium influx
  • This kinase can act to maintain AMPA receptor expression even in the absence of high [Ca²⁺] intracellularly
  • Overall, this mediates an increase in synaptic strength as increased AMPAR expression leads to a greater EPSP and more effective transmission

Question 11

Describe the experiment that elucidated the discovery of long-term potentiation

Answer 11

• Bliss & Lomo, 1973 - accredited for the discovery of LTP
  
  • Method
    
    • 18 rabbits were anaesthetised with electrodes inserted bilaterally into:
      
      • Pyramidal cells of the performant pathway
      • Granule cells of the dentate gyrus
    • The performant pathway of one hippocampus was stimulated and the resultant change in granule cell activation was measured
      
      • The unstimulated hippocampus acted as a control value
  • Results
    
    • After stimulation at low frequencies and measuring the response, they showed that a brief, high frequency (>100 Hz) train of APs resulted in a long term increase in the EPSP to future single action potential
      
      • They suggested this change was due to an increase in transmission strength, which was hypothesised to be due to:
        
        • Increased NT release
        • Increased sensitivity of the post synaptic cell to the transmitter

Question 12

What are the conditions for long-term potentiation?

Answer 12

• Frequency of synaptic stimulation is high enough to cause temporal summation
  
  • Tetany
• Number of synapses stimulation must be high enough for spatial summation
• The pre-synaptic and post-synaptic neurone must be simultaneously depolarised
  
  • Hebbian

Question 13

Describe clinical evidence indicating the importance of the hippocampus and amygdala for memory

Answer 13

Patient HM

• Patient HM underwent a bitemporal lobectomy in 1953 for the treatment of severe epilepsy that did not respond to anti-convulsant medication
  
  • Removal of medial temporal lobe
• Case outline
  
  • The operation removed an 8cm length of temporal lobe, including:
    
    • Cortex
    • The amygdala
    • Anterior 2/3 of the hippocampus.
  • It was thought the seizures were originating from this area.
  • The operation was successful in alleviating the seizures, but he was found to have post-operative, retrograde amnesia.
  • This dated back to 2 years before the operation and severe anterograde amnesia
• Surgery had no effect on his non-declarative memory
  
  • HM became proficient in table tennis but had no conscious recollection that he had played and knew how to play.
  • This suggested that non-declarative memory was localised to other areas of the brain.
• Graded retrograde amnesia and anterograde amnesia
  
  • He retained declarative memories of some things before his surgery, such as the meanings of words and famous faces.
  • This implied that the medial temporal lobe is important in the consolidation of memory but does not store all memory engrams
    *

Question 14

What areas are involved in declarative memory?

Answer 14

Sensory information –> cortical association areas –> parahippocampal & rhinal cortical areas –> hippocampus via fornix –> thalamus & hypothalamus

Hippocampus also feeds back to cortical association areas

Question 15

Explain the pathophysiology, symptoms and prevention of Korsakoff’s syndrome

Answer 15

• Korsakoff’s syndrome is a rare neuropsychiatric disorder caused by chronic thiamine deficiency
• Pathophysiology
  
  • Patients with poor dietary uptake of thiamine
    
    • Prevalent amongst:
      
      • Alcoholic
      • Patients who have undergone gastric band surgery
  • Reduction in the function of enzymes in these neurones leads to impaired cellular metabolism and results in cell injury
    
    • Thiamine is converted to its active form (thiamine pyrophosphate) in neuronal and glial cells and serves as a cofactor for enzymes involved in the metabolism of:
      
      • Lipids (myelin)
      • Carbohydrates
      • Amino acid production
      • Production of glucose-derived neurotransmitters
    • Thiamine also appears to have a role in axonal conduction in cholinergic and serotonergic neurones
• Symptoms
  
  • Characterised by:
    
    • Anterograde amnesia
    • Retrograde amnesia
    • Confabulation
    • Apathy
• This occurs predominantly in the mamillary bodies
• The symptoms of this disease implicate the mammillary bodies in the formation of declarative memories.
• Prevention
  
  • The effects of Korsakoff’s syndrome are prevented by dietary supplementation with thiamine

Question 16

What type of memory do place cells mediate? Outline an experiment illustrating this

Answer 16

• Spatial memory = store of information relating to the location of objects in the immediate environment
• Spatial memories are also a form of declarative memory
  
  • They are thought to be formed in the hippocampus.
• Spatial memory formation is thought to be mediated by place cells
  
  • Neurones that fire in relation to a particular spatial location.

John O’Keefe 1971

• Evidence for place cells was presented by John O’Keefe, 1971
  
  • It supported supporting the cognitive map theory
    
    • Cognitive map theory = theory stating that the hippocampus is specialised for creating spatial maps of the environment
    • Proposed by Edward Tolman
  • Method
    
    • 8 microelectrodes were placed into brain of rat to measure recordings from the hippocampus
    • Found a group of neurons that responded solely or maximally when the rodent was situated in a particular part of the testing platform, facing in a particular direction- ‘place cells’
    • Suggested these findings implied that the hippocampus is involved in providing the rest of the brain with a spatial reference map
      
      • However, unknown if these cells found in human hippocampi or not.

Question 17

Explain an experiment which showed the localisation of spatial memory to the hippocampus and the requirement of the cortex for consolidation

Answer 17

• Remondes & Schuman (2004)
  
  • The localisation of spatial memory to the hippocampus and the requirement of the cortex for consolidation can be studied in the Morris Water Maze (MWM)
  • First experiment
    
    • Morris water maze
      
      • Pool of cloudy water with a concealed platform.
    • Rodents placed in the pool learn the location of the platform usually within 1-2 trails.
      
      • This spatial memory is lost by hippocampal lesions
    • They lesioned the pathway between the hippocampus and cortex in the brains of rats
      
      • For the first 24 hours, this did not affect their ability to learn the location of the platform in the maze.
      • After 4 weeks, the memory of its location had been lost
  • Second experiment
    
    • To explore this further, researchers lesioned another 2 group of rats after learning the maze
      
      • First group was lesioned 24 hours after learning
      • Second group was lesioned 3 weeks after learning.
    • They found the rats lesioned after 24 hours had poor performance when tested 4 weeks later, compared to those lesioned later, who performed just as well as control groups
• The results of this study memory formation is dependent on the hippocampus, but long-term memory storage requires both the hippocampus and cerebral cortex over time

Question 18

What is the evidence that the cerebellum is involved in motor adaptation

Answer 18

• Associative eyeblinks in monkeys that have had their cerebellum surgically lesioned with puffs of air
• Method
  
  • Two groups of monkeys exposed to a sound while a puff of air is applied to the cornea, causing blinking.
    
    • Monkeys in which the cerebellum has been surgically lesioned
    • Control monkeys are exposed to a sound tone
• Results
  
  • In control monkeys, repeated exposure leads to a conditioned response in which blinking can occur upon detection of the tone but before the air puff
  • Lesioned monkeys do not exhibit this adaptation, suggesting involvement of the cerebellum

Question 19

Outlien the structure and function of the amygdala

Answer 19

• The amygdala is an ovoid collection of 3 groups of nuclei in the anterior pole of the MTL
• Receives widespread input from cortical and non-cortical areas.
• Function
  
  • Formation of long term-implicit memories
    
    • E.g. recognising emotion in facial expression.
  • Stimulus response conditioning
    
    • E.g. learned fears
• Associated structures
  
  • Amygdale-fugal pathway
    
    • From the amygdala to the hypothalamus via the ventral amygdala-fugal pathway
    • This mediates the autonomic and endocrine component of emotional responses
  • Stria terminalis
    
    • From the amygdala to the hypothalamus, nucleus accumbens (involved in reward) and septal region via the stria terminalis

Question 20

How does Kluver-Bucy syndrome arise?

Answer 20

• Syndrome resulting from bilateral lesions of the amygdala / temporal lobe

Question 21

Explain the symptoms of Kluver-Bucy syndrome

Answer 21

• Syndrome resulting from bilateral lesions of the amygdala / temporal lobe
• It was stimulated by the Kluver-Bucy experiment in Rhesus monkeys following bilateral, anterior medial temporal lobectomy
  
  • Bilateral, anterior medial temporal lobectomy = removal of the amygdala
• The monkeys displayed:
  
  • ‘Psychotic blindness’
  • The monkeys had normal vision, but difficulties with visual recognition
  • Inability to recognise the emotional importance of events
    
    • Most profound deficit
• Other features of the syndrome include:
  
  • Hyperphagia
    
    • Eating inappropriate objects
  • Hypersexuality
  • Emotional unresponsiveness
  • Visual agnosia
    
    • Inability to recognise familiar objects / people
  • Retrograde and anterograde amnesia
• In the context of a memory essay this provides evidence for the role of the amygdala in learning / remembering emotional responses

Question 22

What is Hebb’s rule?

Answer 22

• Hebb’s rule = states that if an axon of presynaptic neurone is active while the postsynaptic neurone is firing, the synapse between them will be strengthened-
  
  • “neurons that fire together, wire together’

Question 23

Explain the associavity property of LTP

Answer 23

• Weak stimulation of a single pathway insufficient to induce LTP, but strong stimulation of another pathway will induce LTP at both pathways as they are firing together

Question 24

Explain the specificity property of LTP

Answer 24

• Only those pathways that are active can undergo LTP, thus it is input specific

Question 25

Explain the co-operativity principle of LTP

Answer 25

• Activity in a number of collaterals terminating on the same cell can underlie LTP even if their input is weak (due to summation)

Question 26

What are the two main types of long-term depression in CA1?

Answer 26

• NMDA activation dependent
• mGluR activation
  
  • Not discussed

Question 27

Discuss one of the first experiments that showed long-term potentiation

Answer 27

• In 1964 Kandel et Tauc and used micropipette electrodes on giant cells in the right upper quadrant of the abdominal ganglion on Aplysia depilans (a species of sea slug)
• They observed sensitization after simultaneous EPSP at the pre-synaptic and post-synaptic ends but did not find sensitization when the EPSPSs were not concurrent.

Question 28

Explain early phase long-term potentiation

Answer 28

• In the early phase of long-term potentiation, the synapse is strengthened by increased expression of the AMPA receptor and increased AMPA receptor conductance
• Glutamate release from the presynaptic neurone binds to the AMPA receptor on the CA1 pyramidal cell dendritic spine and mediates Na⁺ entry
• When the post synaptic membrane is depolarised, and glutamate is present in the synapse, the Mg²⁺ ion in the NDMA receptor pore is removed, opening the receptor and facilitating Ca²⁺ entry into the cell.
• The Ca²⁺ ions binds to calmodulin which activates Ca²⁺ -calmodulin dependent kinase subtype II (CAMKII) and protein kinase C
  
  • ​ CAMKII has a number of actions:
    
    • phosphorylation of AMPA receptors
      
      • which increases the time in high conduction state
    • phosphorylation of PSD95 protein complex
      
      • increases AMPA receptor density by reducing dynamic movement in the bilayer)
    • It is thought that CaMKII can remain on even after the [Ca²⁺] has fallen, due to autophosphorylation
      
      • allowing CAMKII to continue to contribute to the maintenance of phosphorylated AMPA receptors.

Question 29

Explain late phase long-term potentiation

Answer 29

• In induction, the high Ca²⁺ activates PKA that forms cAMP which then activates the CREB transcription factor
  
  • ​ CREB binds to sections of DNA called cAMP response elements (CREs) to regulate expression of neighbouring genes
  • This results in an increase in the transcription and thus expression of AMPA and NMDA receptors thereby leading to an increased EPSP following stimulation.
• In maintenance, the gene expression of AMPA and NMDA receptors is maintained by kinases such as protein kinase M zeta
  
  • Remain constitutively active at potentiated synapses even when there is a fall in calcium concentration.
  • This just like the induction stage will active transcription factors to increase synaptic strength

Question 30

Outline the Morris Water Maze experiment

Answer 30

• The localisation of spatial memory to the hippocampus and the requirement of the cortex for consolidation was studied by Remondes and Schuman in 2004 through the Morris Water Maze (MWM).
  
  • The Morris Water Maze comprises of a pool of cloudy water with a concealed platform in and where rodents placed in the pool learn the location of the platform usually within 1-2 trails
  • This spatial memory is lost by hippocampal lesions
  • They lesioned the pathway between the hippocampus and cortex in the brains of rats
  • For the first 24 hours, this did not affect their ability to learn the location of the platform in the maze.
  • After 4 weeks, the memory of its location had been lost.
  • To explore this further, researchers lesioned another 2 group of rats after learning the maze
    
    • They found the rats lesioned after 24 hours had poor performance when tested 4 weeks later, compared to those lesioned later, who performed just as well as control group
    • This shows how memory formation is dependent on the hippocampus, but long-term memory storage requires both the hippocampus and cerebral cortex over time.