lecture 8 - hippocampus, memory and synaptic plasticity Flashcards
(25 cards)
Research using rodents
Experiments with rodents has been at the forefront of efforts to understand how memories are encoded by neurons.
Why??
* Convenient, quick to learn, small and easy to house
* For work on welfare in rats, see: Emma Robinson’s work looking at ideal housing conditions for rats
Hippocampus easy to see – its relatively large compared to the rest of their brain - easily see hippocampal cells after death
rat hippocampus
no individual part of the brain works in isolation, different components of the hippocampus all work together as a circuit
info comes into the hippocampus through the dentate gyrus (DG) then it goes to the CA3 region and
then CA1 region and back out again = simple circuit
we can put electrodes in certain parts to stimulate certain neurones and see what happens down that pathway - you can measure what’s going on within the neurons in the circuit - important for when we study what happens at the synaptic level
the human hippocampus is organised in a similsr fashion - hoping we can take what we learn from animal studies to understand humans aswell
diagram in notes
place cells in the hippocampus
John O’Keefe put electrodes in the hippocampus and identified place cells
he placed electrodes into the CA1 of the hippocampus and recorded the activity of a moving rat - he found is that individual CA1 neurones would fire only when the rat is in a particular location and that cell is firing at a really high rate in a particular location and then another cell will fire in a completely different location
different neurones are responding to different places in the environment suggesting hippocampus is involved in spatial learning and memory. its encoding info about where the rat is in relation to the broader spatial environment
images in notes
red patches = where that cell will fire
cognitive map
O’Keefe argued that this was evidence of a ‘cognitive map’
a memory for the space that we occupy eg if you close your eyes and imagine yourself at the foot of your bed you can visualise where in your room the door is
morris water maze
frequently used to assess spatial learning in rats
a circular pool filled with water and you add some pacifier to the water so it goes milky so the rats can’t see the platform in there so the rat has to rely on spatial info to find the platform
rats are good swimmers so will just swim until they find the platform - they prefer to be on land if possible so will be motivated to find the platform and get out the maze
if after a few minutes they don’t find the platform you take them out and put them on the platform so they know where it is
the rats learn the location of the platform really very quickly
initially they will swim around randomly and then over a few trials they will directly over to the platform
we measure their spatial learning by measuring the Time taken (latency) to find the platform. the first trail takes longer after each trial they get faster and faster
you can also measure learning by taking the platform out and seeing where they are spending the most amount of time - probe test
spatial memory in rodents
if we have a circular maze and split it into quadrants you look where the platform was previously and measure how much time the rat is spending in each of the four quadrants = probe test
hippocampal lesions and water maze performance
the experiment looked at the rats knowledge of the spatial environment or where the platform is with a hippocampal lesion, a cortical control lesion = basically surgery with no actual lesion and a control condition with no surgery
both the control groups are learning very rapidly where that platform is - the latency (time taken to find the platform) is reducing over time
the hippocampal lesion group are much slower finding the platform and more variation in times
tells us hippocampus is involved in spatial memory somehow
the rats with lesions are still learning but don’t have spatial ability
morris wanted to demonstrate that the impairment in the hippocampal lesion rats wasn’t due to just some gross impairment in function so he ran a bunch of trails where theres a beacon on the platform eg a pole = rats perform well
when you remove the spatial info and its just reliant on object processing, the hippocampal lesion rats are fine. its to do with object recognition they can recognise the object and remember that that’s where they need to swim, they then got rid of the beacon again so rats had to use spatial info again to find the platform
the control rats revert rapidly to using the memory of the hidden platforms location but the hippocampal lesion rats got worse so as soon as they relied on spatial info they were not doing very well
for the probe trials the control rat spend most of their time in the correct quadrant where the platform was previously, the hippocampal lesion groups are just kind of swimming around aimlessly and spend an equal amount of time in each quadrant - they just swam around in circles until they found the platform so dont have a structured search
shows hippocampus is vital for spatial memory
Donald Hebb
- Hebb (1949) proposed an essential principle regarding learning and memory:
- “When an axon of cell A is near enough to excite cell B and repeatedly takes part in its firing, some growth process or metabolic change takes place in one of both cells such that cell A’s efficiency as one of those cells firing B is increased”.
- AKA “Cells that fire together wire together”
- Hebb’s postulate for learning (AKA Hebb’s rule):
- Co-occurrence is a physiological necessity for learning and memory
If one cell becomes activated, it will automatically set off other cells that have previously fired together
hippocampal circuitry
diagram in notes
long term potentiation
the evidence that supports the idea that cells fire together is by Timothy Bliss and lomo 1973
they put the stimulating electrode was put into the perforant path so they stimulate the neurone to fire, they record what happens at the dentate gyrus
bliss stimulated the pathway every 20s or so and recording what happens in the dentate gyrus. he then accidentally made the stimulation more rapid. when he turned it down again the response in the recording in the dentate gyrus was still much higher. the neuron is responding more to the other.
he then tried to repeat this in a series of experiments - he first did the original stimulation level as a initial response baseline to see what the postsynaptic cell was actually doing and to see the extent action potentials formed. then he provided 10s of intense high frequency stimulation to induce potentiation and this makes the response much higher. he then went back to single pulses of the low intensity current and then recording activity in the dentate gyrus and the postsynaptic cell still responded really vigorously
results
graphs in notes
tetanic stimulation = high frequency stuff
in dentate gyrus
phase one = low intensity pulses - the dentate gyrus cell depolarises slightly but not enough for an action potential - first graph
phase two = tetanic stimulation
graph two - after high frequency stimulation the post-synaptic potential and depolarisation is a lot more significant
if you measure this excitatory synaptic potential a week or month later you will still get a really large response in that neurone - theres a long term change in what happens in the connectivity between those neurones as a result of learning
the post-synaptic neurone is more easily excitable after long term potentiation has occurred
in the stimulating electrode (pre-synaptic neurone)
phase one - weak stimulation
phase two - strong stimulation
phase three - weak stimulation
in the recording electrode (post-synaptic neurone)
phase one - weak response
phase two - strong response
phase three - strong response
LTP has 2 key properties
- Long-term
○ Demonstrated by Bliss and Lomo- LTP only occurs when firing of presynaptic neuron is followed by firing of postsynaptic neuron. This co-occurrence is now seen as the critical factor in LTP.
induction of synaptic LTP
perforant path neuron = pre-synaptic
dentate gyrus neurone = postsynpatic
two types of receptor in the post-synaptic neurons membrane - NMDA and AMPA
NMDA receptors are crucial for LTP to take place
AMPA has normal transmission but NMDA receptors are blocked by a Mg ion
resting potential = -70mv
1 - glutamate is released = excitatory neurotransmitter. it increases activity and bind to the AMPA receptor
2 - then you get an influx of sodium ion that depolarisation the cell
this is the normal functioning of the cell and what we want to see during long term potentiation is the cell actually reaching the threshold of -55mv in order to fire because we want both those cells to cure together. the crucial receptor for this to happen is the NMDA receptor
during normal functioning the NMDA receptor is blocked by a magnesium ion and nothing can get into the cell via NMDA receptors during normal functioning. the mg ion is there as its positively charge and the inside of the cell is negatively charged. when the cell is depolarised it becomes more positive so the mg is repelled from the NMDA receptor. glutamate also has to bind to the NMDA receptor so there can be an influx of calcium into the cell and charge = -40mv
the calcium then leads to a series of changes in the cell eg more AMPA receptors being put into the membrane of the postsynaptic cell so its more responsive so easier to depolarise the cell as more receptors
so cells that wire together do wire together
what has to happen to get calcium into the postsynaptic cell
1 - presynaptic event of releasing glutamate so glutamate binds to an NMDA receptor
2 - the postsynaptic neurone has to depolarise enough to repel the mg ion bound to the NMDA receptor
why is the NMDA receptor also known as a coincidence detector
it detects a coincidence between two events that are happening
- presynaptic cell firing releasing glutamate
- postsynaptic cell is firing getting rid of magnesium and letting calcium in
its detecting two cells are firing together and leading them to wiring together
conclusions
- The hippocampus in both humans and animals is critical for normal spatial learning and memory.
- Spatial information forms the “where” component of episodic memory (memory of what where and when things happen).
- The hippocampus shows long-term synaptic potentiation (LTP).
LTP relies upon the opening of glutamate NMDA receptors and the influx of calcium ions (Ca2+) into the post-synaptic neuron for its induction. Hebbian synaptic transmission.
communication between neurons
🧠 Neuronal Communication & Synaptic Transmission
Neurons communicate primarily through synaptic transmission, allowing neural circuits to process sensory input, plan, and generate behavior.
Neurotransmitters are released from the presynaptic neuron’s terminal buttons, cross the synaptic gap, and bind to receptors on the postsynaptic neuron.
This binding causes postsynaptic potentials—brief depolarizations or hyperpolarizations that influence the likelihood of action potentials in the receiving neuron.
🔐 Receptors & Ligands
Neurotransmitters bind to specific receptor binding sites, like a key fits a lock.
A substance that binds to a receptor is called a ligand.
Ligands can be natural (e.g., neurotransmitters), plant-derived, animal toxins, or synthetic.
Ligands do not enter neurons through the binding site but can open ion channels to allow ion flow, affecting neuronal activity
structure of synapses
🔄 Structure of a Synapse
A synapse is the gap between the terminal button of one neuron and the dendrite, soma, or axon of another.
Many synapses are on dendritic spines—tiny protrusions on dendrites of large neurons.
Presynaptic membrane (at the terminal button) and postsynaptic membrane (on receiving neuron) face each other across the synaptic cleft, which contains extracellular fluid for neurotransmitter diffusion.
🧬 Key Synaptic Components
Mitochondria in the terminal button supply energy.
Synaptic vesicles are membrane-bound bubbles filled with neurotransmitters.
A terminal button can hold hundreds of thousands to nearly a million vesicles.
Most vesicles cluster near the presynaptic membrane, where neurotransmitter release occurs.
Microtubules transport materials between the soma and the terminal button
release of neurotransmitters
When action potentials are conducted down an axon (and down all
of its branches), something happens inside all of the terminal buttons:
A number of small synaptic vesicles located just inside the presynap-
tic membrane fuse with the membrane and then break open, spilling
their contents into the synaptic cleft. Once the vesicles release neu-
rotransmitter into the synaptic cleft, the molecules of neurotransmitter
move away from the area of high concentration (inside the vesicle) to
disperse across the synapse due to the force of diffusion.
activation of receptors
⚡️ How Neurotransmitters Affect the Postsynaptic Membrane
Neurotransmitters diffuse across the synaptic cleft and bind to postsynaptic receptors on the membrane.
This opens neurotransmitter-dependent ion channels (aka ligand-gated channels), allowing ions to enter/exit the cell → causes depolarization or hyperpolarization.
Neurotransmitters do not enter the cell—only ions pass through the channels.
🔓 Two Mechanisms for Opening Ion Channels
1. Direct (Ionotropic Receptors)
Fast-acting.
The receptor is also the ion channel.
Neurotransmitter binds → ion channel opens immediately.
2. Indirect (Metabotropic Receptors)
Slower, longer-lasting effects.
Neurotransmitter binds to metabotropic receptor → activates G protein.
G protein activates an enzyme, producing a second messenger.
Second messenger:
Opens nearby ion channels
Can enter nucleus or other parts of the cell
Triggers biochemical changes or gene expression
postsynaptic potentials
postsynaptic potentials can be either depolarizing (excitatory) or
hyperpolarizing (inhibitory). What determines the nature of the postsynaptic potential at a
particular synapse is not the neurotransmitter itself. Instead, it is determined by the charac-
teristics of the postsynaptic receptors—more specifically, by the particular type of ion channel
they open.
four major types of neurotransmitter-dependent ion channels in the postsynaptic membrane
sodium
potassium
chloride
calcium
ion channels can be directly activated (ionotropic) or activated indirectly by metabotropic receptors coupled to G proteins
neurotransmitter-dependent sodium channels
most important source of excitatory postsynaptic potentials
sodium-potassium transporters keep sodium outside the cell, waiting for the force of diffusion and electrostatic pressure to push it in
when sodium channels are opened the result is depolarisation - an excitatory postsynaptic potential (EPSP)
sodium-potassium transporters maintain a small surplus of potassium ions inside the cell. if potassium channels open, some of these cation will follow this gradient and leave the cell. the K is positively charged so will hyper polarise the membrane producing an inhibitory postsinpoatic potential (IPSP)
chloride channels
dient and leave the cell. Because K* is positively charged, its efflux will hyperpolarize the membrane, producing an inhibitory postsynaptic potential (IPSP)
At many synapses, inhibitory neurotransmitters open the chloride channels, instead of (or in addition to) potassium channels. The effect of opening chloride channels depends on the membrane potential of the neuron. If the membrane is at the resting potential, nothing happens, because (as we saw earlier) the forces of diffusion and electrostatic pressure balance perfectly for the chloride ion. However, if the membrane has already been depolarized by the activity of excitatory synapses located nearby, then opening chloride channels will allow Cl to enter the cell. The influx of Cl ions will bring the membrane potential back to its normal resting condition. Opening chloride channels and depolarizing the membrane helps neutralize EPSPs (see Figure 2.28c).
The fourth type of neurotransmitter-dependent ion channel is the calcium channel.
Calcium ions (Ca**), being positively charged and being located in highest concentration outside the cell, act like sodium ions. This means that opening of calcium channels depolarizes the membrane, producing EPSPs. But calcium does even more. For example, calcium ions in the terminal button trigger the migration of synaptic vesicles and the release of the neurotransmitter. In the dendrites of the postsynaptic cell, calcium binds with and activates special enzymes. These enzymes have a variety of effects, including the production of biochemical and structural changes in the postsynaptic neuron
termination of postsynaptic potentials - reuptake
REUPTAKE The postsynaptic potentials produced by most neurotransmitters are terminated by reuptake. This process is an extremely rapid removal of a neurotransmitter from the synaptic cleft by the terminal button. After the neurotransmitter is released into the synapse, the presyn-aptic membrane uses special transporter molecules to return molecules of the neurotransmitter from the synaptic cleft directly into the cytoplasm of the presynaptic cell. These transporters require energy to actively remove neurotransmitters from the synapse, similar to the way a vacuum cleaner uses electricity to run a motor to remove dirt from a floor. (
