Lecture 3- Cellular and molecular mechanisms mediating learning and memory Flashcards
What are the two types of nondeclarative (implicit) learning?
- Nonassociative learning 2. Associative learning
What are the two types of nonassociative learning?
- Habituation: reduction in responding to a repeatedly delivered stimulus 2. Sensitisation: an enhancement or augmentation of a response produced by the presentation of a strong stimulus
What is associative learning?
-e.g. Classical (Pavlovian) conditioning paradigm: temporal correlation ensures that the conditioned stimulus (bell) provides information about the unconditioned stimulus (food), critical for learning -learning about the relations between events in the organism’s environment
Which memory is damaged in dementia and Alzheimer’s?
-declarative
What was the early study of learning done on?
-the sea slug Aplysia –simple nervous system -easier to study -behavioural response= provide stimulus to the siphen-gill reflex -persistent synaptic enhancement with long-term sensitization of a withdrawal reflex in Aplysia -tactile stimulus stimulates withdrawal -pre conditioned slug= huge change in the siphon withdrawal -the siphon retracted for longer as paired with the painful stimulus -hgher post synaptic potential after sensitization
What did Donald Hebb discover?
-when an axon of cell A excites cell B and repeatedly and persistently takes part in firing it, some growth process or metabolic change takes place as one of the cells firing B is increased -neurons fire together= wire together
What did Tim Bliss and Terje Lomo discover?
-a brief high frequency train of action potentials within specific inter-neuronal pathways leads to an increase in synaptic strength = Long-Term Potentiation (LTP)
Where is the hippocampus?
-buried in the medial temporal lobe
What is the circuit in the hippocampus connected to the LTP?
- input via the dentate gyrus and output
- well defined circuit going from dentate gyrus to CA3 to CA1
- these are the areas where synaptic plasticity has been most studied
What happens to synaptic strength after repeated stimulus is applied?
-after repeated stilmuli the EPSP response is stronger and lasts much longer
What are the two types of glutamate receptors?
- Ionotropic glutamate receptor: AMDA and NMDA receptors, capsulate channels, ions can move through 2. Metabotropic glutamate receptor: form a subclass of G-coupled protein receptors, don’t have a channel -transmit information postsynaptically via G-proteins and downstream signalling
What is the early phase of LTP? (induction)
–tetanus induces increased firing= more glutamate released
- this induces changes post-synaptically
- one change is initially: the NMDA receptor is no longer blocked by the magnesium ion and then Ca influx occurs
- so increase in Ca in the postsynaptic terminal (Ca important transmitter of signals in neurons, and non-neurons- it can bind to other proteins such as calmodulin and this can in turn activate particular kinases
- calcium signal leads to changes in kinase C, tyrosine kinase (fyn) and Ca2+/ calmodulin kinase
- that in turn leads to changes in the other form of the ionotropic receptors
- the AMPA receptors, they are transducing the fast currents whenever the synapse is activated, in response to the change more AMPA receptors are inserted into the membrane
- postsynaptic response is greater now! -induction the first stage of LTP
What is the yin and yang of synaptic plasticity?
-synaptic plasticity can be bi-directional, as well as strengthening synapsis, we can have weakening of the synaptic atrength= LTD is the depression of the postsynaptic response -Homosynaptic= that it is studied at a single synapse -the strong stimulus at the synapse can lead to stronger postsynaptic response, increase in strength= LTP LTD- association due to weak stimulus, the key is the postsynaptic neuron
What is an NMDA receptor made up of?
- proteins
- PSD95=regulator of synaptic plasticity
How was the PSD95 knockout mice made?
- start with the DNA sequences, then target a sequence, targeting vectors= cassettes from bacteria= allow you to label the cells that took up the cassettes
- cut out chunk of the gene -it stops the protein being made
- no PSD95 protein in the knockout mouse
- so the only difference is the lack of PSD95
How did the PSD-95 knockout mouse perform in the Morris water maze?
- the platform is dropped, the control remembers
- the knockout does not remember
- cannot lay out new spatial memories
What was synaptic plasticity like in the PSD-95
- knockout there is excessive LTP , much bigger than the wild type
- range of frequencies in the wild type, when low= get LTD, when high get LTP
- knockout=curve is completely thrown out, even with low frequency there is LTP not LTD
How does the change in synaptic plasticity in PSD-95 knockout affect learning?
- null mutation in the PSD-95 mouse
- the network has to have selective strengthening (red) and weakening (blue)
- in the knockout almost all strengthen, there isn’t any balance and the ability to encode is lower
- the green thing= the frequencies that are important for people and mice for learning
- over 100 genes involved in schizophrenia, number are connected to NMDA receptor, and the signaling in LTP
What does micro-development mean?
- brain is an organ that changes throughout your life -encoding memories structurally alters your brain -Purkinje neuron in the cerebellum= 200 000 synapses made onto a single neuron -10 000 onto the hippocampal
What is the late phase LTP like?
- have to create new synapses for a long term memory
- signal through calcium
- via adenylyl cyclase then
- via cyclic AMP into the nucleus of the postsynaptic neuron
- via cyclic AMP responsive elemnt CREB-1 (transcription factor) binding proetin so it binds to the sequence of DNA the cyclic AMP responsive element that codes for a range of genes -one of them is BDNF(so can get more brain derived neurofactor) and through the effector proteins they can induce the formation of new synapses
- now more synapses so increased response
- long term storage of memories
What is the ratunculus?
- the somatosensory cortex is mapped in the barrel cortex in mice
- feeling their way around in the dark
- whiskers used as a way of exploring
- 4-12 Hz/ sec in the dark the wshiskers when being used
- the sensory information is transduced by the brain stem via the thalamus to the primary somatosensory cortex into individual barrels
- in layer 4 neurons from receive infor from thalamus
- each barrel represents a single whisker
- mapping of whiskers onto the cortex = can study LTP in vivo
How does multiphoton imaging of GFP-expresing neurons in barrel cortex of mice work?
-derive genes from jellyfish and put into mice= so it glows and can image it much more easily -the neurons glow -can anesthesise the mice and can image it with a multiphoton microscope through the skull -can image down to individual synapses -then let themice go and anesthesize again and can zoom in again -day after day -on day 5 appearance of a new synapse= appearing and disappearing in the brain
What did multiphoton imaging of GFP-expresing neurons in barrel cortex of mice reveal?
-formation of new synapses from day to day
How does environmental enrichment influence synaptic growth?
- enhances it
- more synapses formed
