Hippocampal memory & plasticity Flashcards
What is learning?
The process by which new information is acquired by the nervous system, which gives rise to changes in behaviour.
What are the three components of memory?
Encoding, storage and retrieval of learned information.
Memories can be categorized based upon time, name these and also think of an example of each category.
- Immediate memory → memory of something that occurred very recently, such as a recalling a telephone number. Only this kind of memory may be forgotten after its immediate use.
- Working memory → retaining a memory for a brief period of time while performing mental operations on that information. Example: calculating the total bill of your groceries as you are shopping
- Long-term memory → keeping a memory for an extended period, such as learning to ride a bike and from that point on always knowing how to ride a bike.
What is anterograde and retrograde amnesia?
- Anterograde → inability to form new memories.
- Retrograde → inability to recall prior events and memories.
Memory can be separated into declarative and non-declarative memory. What is declarative and non-declarative memory?
- Declarative → storage and retrieval of information that is available to our consciousness and can largely be expressed by language (daily episodes, words and their meaning, history).
- Non-declarative → often called procedural memory that is often not available to consciousness and covers many memory processes which are non-verbalized (like playing the piano → mostly motor skills).
In animals it’s very hard to study declarative memory. So we have to rely on our intuition towards how we think animals think.
What can be tested in animals as for declarative memory?
Tests can be:
- Spatial (where)
- Episodic-like recollection (what/where/when)
The hippocampus plays an important role in declarative memories.
This has been concluded based on several conditions where the hippocampus was affected. What was seen/found (in humans and in rodents)?
- In clinical case studies it was seen that patients with memory problems had lesions/hippocampal damage. This was also seen in other fMRI and MRI studies and also in hippocampal diseases.
- In rodents this was further established, where they found that hippocampal lesions impaired memory.
Henry Molaison had epilepsy and experimented on himself by removing both its temporal lobes to treat his epilepsy. But the outcome of the surgery was a bit different than he’d expected. What was seen and what was very interesting about this?
What happened to this guy?
He had severe anterograde amnesia (and thus could not make new long-term memories). Interestingly, his procedural memory was not damaged.
Another patient (K.C.) had damage to his hippocampus and parahippocampus. What was seen in this patient?
He had severe anterograde- and retrograde episodic memory impairment.
However, his procedural learning and memory were intact and even his retrograde ‘semantic’ memory (recalling general knowledge) was also still intact.
So what has been concluded based on the patients that had hippocampal damage?
That hippocampal damage is selective for declarative memories, but it leaves procedural memories intact.
What is seen in regard to navigation and hippocampal activation? And what is seen in London taxi drivers?
In general, the hippocampus is activated when navigating (recalling memories of navigation). It is also seen that the accuracy of navigation correlates with hippocampal activity.
London taxi drivers need to pass a navigational memory test called ‘The Knowledge’, to test how good they are at memorizing pre-set routes in the city. An extraordinary finding is that the posterior part of the hippocampus is enlarged in these taxi drivers. So there’s also a correlation beween the size of the posterior part of the hippocampus and the time spent as a taxi driver.
What happens in Alzheimer’s disease?
Here, neurofibrilary tangles and amyloid-beta plaques build up in the brain. This starts out in the hippocampus and then spreads out. Thus in Alzheimer’s disease, the most damage is in the hippocampus, as is why patients of Alzheimer’s disease have often trouble with memory.
So in animals, it’s very hard to study declarative memory. So we have to rely on our intuition towards how we think animals think. The spatial (where) and episodic-like recollection (what/where/when) are two things that can be tested. How is spatial learning and memory tested in rodents?
By the Morris Water Maze test → rodents must learn to find the submerged platform to get out of the water and stop swimming. Here, the animal uses external cues in the room to learn and later remember where the platform is.
What can be seen in the Morris Water Maze test in rodents with hippocampal lesions?
That their memory is severely affected. In the picture, this is also depicted, where the control rat takes a very short route to find the submerged platform (after 10 trials), whereas the rat with hippocampal lesions takes a much longer route to find the submerged platform.
What was found when studying rodents?
That there were spatially-modulated neurons in the hippocampus that would fire at specific locations → these neurons are called place cells.
There are also grid cells, head direction cells, border cells and nest cells.
What is the function of these cells?
- Grid cells → only fire in specific patterns.
- Head direction cells → only fire when the head is in a certain direction.
- Border cells → only fire when you’re facing a border/wall.
- Nest cells → only fire when you enter your own home.
The place cells are located at a different brain region compared to the grid cells, border cells and head direction cells. Where are these cells located?
- Place cells → hippocampus
- Grid cells, border cells and head direction cells → entorhinal cortex
What can be concluded based on the fact that patient H.M. (who removed his medial temporal lobes) had anterograde, but not retrograde amnesia?
He could recall earlier memories even though he couldn’t make new ones. This would imply that long- and short-term memories are stored at different places in the brain.
So studies were done where they looked for where long-term memories are stored. For this, they used three different types of mazes (ranging from easy/simple to hard/complex) and used rats with different (cortical) brain lesions.
What did they see when they compared the complexity of the maze with the brain lesions?
The most complex maze becomes harder when the amount of cortical damage is larger. Thus, long-term memory is distributed throughout the cortex.
The distribution of long-term memory in the cortex was further researched in humans.
Here, they asked people to look at an object (e.g. a chair), removing the object from the screen and next asking the people to recall the object that had just been shown to them. What was seen, was that the perception of the chair (by looking at the picture), activated the same cortical brain region as when recalling the object from memory.
This goes a little bit against the fact that long-term memory storage is a distributed process in the cortex.
Why does this experiment still support the graded decrease in brain function that was also seen in rodents in the complex maze?
Because you don’t have to rely on one specific set of cues, you can actually integrate many different cues. So if you damage a piece of the cortex, you still have other cortical memory to rely on.
What do all mammalian orders have in common in regard to the hippocampus?
The Cornu Ammonis (CA) region that is divided into three parts (CA1-CA3).
What are two main regions in the hippocampus?
The dentate gyrus and the Cornu Ammonis (CA) region.
Why is the perforant pathway in the hippocampus referred to as a trisynaptic circuit?
Because it has three important excitatory synaptic connections:
- The synaps between the input from the perforant path from the entorhinal cortex and the granule cells of the hippocampus.
- The synaps between the mossy fibers of the granule cells and the CA3 pyramidal cells.
- The synaps between the Schaffer collaterals of the CA3 pyramidal cells and the CA1 pyramidal cells.
Why are the dendritic spines of CA3 ‘special’?
Because they’re very complex and thorny spines.
Describe the structure of the CA1 region.
- Stratum oriens → dendrites
- Stratum pyramidale → layer of cell bodies of CA1 neurons → because these are all pyramidal cells, it’s termed as pyramidale.
- Stratum radiatum → input from Schaffer collaterals (axons of CA3 pyramidal cells)
- Stratum lacunosum-moleculare → tips of CA1 dendrites.
Note: you don’t have to memorize this by heart.
Are the spines of CA1 dendrites also ‘special’?
No, these spines are normal again.
What other inhibitory neurons exist in the hippocampus?
Interneurons. Such an interneuron is depicted in the picture, where the interneuron is red that is connected to CA1 cells (green).
Note: there’s a huge amount of variability in anatomy and projection patterns of interneurons.
What is Hebb’s postulate?
A theory that claims that an increase in synaptic efficacy arises from a presynaptic cell’s repeated and persistent stimulation of a postsynaptic cell.
Or in other words: When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.
Do short- and long-term potentiation/depression occur in the same timescale?
No, there are different timescales of synaptic plasticity.
What was seen in a neuron that got stimulated with a normal stimulus (every 10 or 20 seconds)? And what was seen when the intensity of the stimulus was increased?
- First, a baseline of neuronal activity was established.
- When the stimulus intensity increased, the response of the neuron also increased → long-term potentiation.
One of the conditions for long-term potentiation is specificity. What is meant by this?
When you strongly stimulate one of the axons, while weakly stimulating the other axon, the synapse of the axon that is weakly stimulated will not strengthen (so no long-term potentiation). This, while the axon that is strongly stimulated, results in the strengthening of the synapse.
This is important for memory formation → memories need to be specific, so you don’t want to strengthen a pathway that is not important for a specific memory.
How long can this long-term potentiation last?
It can last for a year, as can be seen in the picture.
One of the conditions for long-term potentiation is associativity. What is meant by this?
Long-term potentiation caused by strong stimulation of the axon, does initiate LTP in nearby weakly active synapses when the weak stimulus is coincident with activation of the postsynapse. Therefore, weak stimulation in combination with coincident postsynaptic activity, will result in strengthening of the synapse.
How is short-term potentiation initiated in hippocampal synapses?
- When the presynaps is depolarized and glutamate-filled vesicles are released into the synaptic cleft, glutamate can bind to AMPA and NMDA receptors.
- Na+ then flows into the postsynaptic cell through AMPA, which causes postsynaptic depolarization. This releases the Mg+ block on the NMDA receptor and calcium and sodium can flow into the postsynaptic cell via the NMDA receptor.
- Calcium can then initiate short-term potentiation via activation of calmodulin kinase 2 and PKC.
- Activation of these kinases leads to the insertion of extra AMPA receptors on the postsynaptic membrane.
How does NMDA receptor activation explain associativity?
When glutamate is presynaptically released into the synaptic cleft, it is able to bind to NMDA and AMPA receptors. This activates the AMPA receptor, but not the NMDA receptor since the NMDA receptor still has a Mg+ block. This Mg+ block can only be released if the postsynaptic membrane is depolarized by incoming sodium via the AMPA receptor. So you need some form of (weak) stimulation by glutamate to depolarize the postsynaptic membrane, so that you also can activate NMDA receptor.
How is long-term potentiation initiated in hippocampal synapses?
- When the presynaps is depolarized and glutamate-filled vesicles are released into the synaptic cleft, glutamate can bind to AMPA and NMDA receptors.
- Na+ then flows into the postsynaptic cell through AMPA. And when the Mg+ block is released on the NMDA receptor, calcium and sodium can flow into the postsynaptic cell via the NMDA receptor.
- Calcium can then initiate long-term potentiation via activation of calmodulin kinase 2 and PKC.
- Calmodulin kinase 2 (CaMKII) phosphorylates CREB and CREB can then translocate to the nucleus to activate gene transcription.
What happens when you add inhibitors of proteins synthesis and try to induce long-term potentiation?
Long-term potentiation cannot occur, since CREB activation normally would lead to the transcription and translation of proteins needed for long-term potentiation (like more synaptic connections by synapse growth and novel postsynaptic spines).
What happens when the stimulus that is given to this axon is low frequency (instead of high frequency stimulation as was discussed before) and after 15 minutes you give a second (normal) action potential?
Long-term depression occurs.
How/why does long-term depression occur when you give a low frequency stimulus?
The main player is still calcium. But sinds you give low frequency stimulation, the concentration of calcium is much lower. Instead of kinases being activated, now phosphatases are activated. These proteins dephosphorylate proteins, which results in:
- It makes AMPA receptors more mobile, which makes them have the tendency to leave the postsynaptic density and become endocytosed. This decreases the concentration of AMPA receptors on the spine.
