Structure and Function of the Hippocampus Flashcards
What structure is adjacent to the hippocampus?
Entorhinal Cortex
What parts of the hippocampus receives many of the inputs from the neocortex?
Dentate Gyrus
Which one is a glutame receptor?
NMDA
Which cortical region strongly connected to the hippocampal is associated with spatial processing?
Parahippocampal Cortex
An influx of which positively-charged ion gives rise to LTP?
Calcium
Which positively-charged ion must be moved out of membrane pores for LTP to occur?
Magnesium
Where does most LTP take place in the hippocampus?
Between CA3 and CA1 cells
What do NMDA knock-out mice do in the water maze?
Find the platform by trial and error each time
What task was used to investigate relational memory in rats?
Transitive Inference Task (Beakers)
What is the difference between recollection and familiarity?
Only recollection involves mental time travel
how did the hippocampus get its name?
hippocampus means seahorse of the similar structure / shape -> structure is very important for the functions (as functions change along the hippocampus
what does long-term memory at the level of individuals neurones reflect?
structural changes at the synapse
- when we learn something we aren’t just changing the chemical makeup of the brain but we are physically changing the synapse itself allowing us to learn new long-term memories
Which anaesthetic used as a recreation drug disrupts the ability to form memories?
Ketamine is an NMDA receptor (type of glutamate receptor) supporting memory function
- Ketamine causes memory disruption
Where is the hippocampus?
medial temporal lobes / cortex (buried deep inside)
what is the hippocampus structure?
- along its lengths, the hippocampus shows distinct cell fields that are tightly folded
- the connections between these cell types are relatively well-understood
what is structure like within the hippocampus?
- Inputs via dentate gyrus
- Associations between CA1 and CA3 fields
- Outputs via subiculum
describe the layering of the hippocampus
layers are wrapped around each other and usually connected up -> helping us understand how long-term memories are supported by the hippocampus
There are four main types of cell fields within the hippocampus, what are they?
- CA3 and CA1 Neurones
- Subiculum
- Dentate Gyrus
How is information received and outputted in the hippocampus?
- Hippocampus receives input primarily via the dentate gyrus
- Dentate gyrus projects to CA3 and CA1 subfields of the hippocampus
- They send their outputs to the subiculum (output via subiculum) (major output system of the hippocampus)
What components sit next to the hippocampus? [need to find out how the hippocampus is connected to the adjacent cerebral cortex]
In order of closest to furthest:
* Entorhinal Cortex
* Perirhinal Cortex
* Parahippocampal Cortex
what is the hippocampus structured from and how is this different from the entorhinal cortex?
hippocampus has an unusual structure and is allocortex (different micro-structure from the cerebral cortex)
While Entorhinal cortex is a neocortex
what is the role of the Entorhinal cortex?
acts as a gateway between information in the rest of the cerebral cortex and hippocampus
what is the Perirhinal cortex important for?
localised site important for object recognition (/representation)
* stronger response in this cortex when using object recognition
what is the parahippocampal cortex important for?
spatial layout coding
- more activation when representing location (location representation)
how do we bind different representations of experience [theory of hippocampal function]?
we can bind representation which were active at the same time together in the hippocampus
i.e. objects via Perirhinal (dog and cup) and Place via Parahippocampal (beach)
what happens when we encounter these representations again?
it can reignite the whole memory
why is the structure in the hippocampus critical for it’s function
- Hippocampus
- Entorhinal feeding information into the hippocampus (major gateway into hippocampus from rest of the cerebral cortex) -> primarily receives it information from the parahippocampal and perihinal cortex
How does the hippocampus form associations?
- Parahippocampal (Location) and Perihinal Cortex (Object) learn about familiar objects and locations, binding together these aspects of memory by projecting information up into the hippocampus
- The hippocampus then forms associations between these different types of input via Eichenbaum et al. ‘Relational Theory’
How does the hippocampus differ in function, dependent on the region?
Posterior: greater input from parahippocampal cortex (spatial memory)
* location and spatial representation
Anterior: Greater input from amygdala and perirhinal cortex (emotional memories/processing, item familiarity/salience)
* memories for detecting novelty (new/old items)
Why is it believed the hippocampus differs?
there are differences in the anterior and posterior hippocampus functions because of the way different connections vary (and different proximities to areas which represent different information)
- thought to be explained by the balance of perihinal and parahippocampal cortex as you go from the front to the back of the brain
how can differences for the anterior and posterior hippocampus be supported?
Moser et al. (1993): spatial learning in rats impaired by posterior not anterior lesions
Strange et al. (1999): double dissociation in humans
What are some features of the hippocampus which link to memory?
- hippocampus receives diverse inputs from most of the cortex, which gets funnelled through to the entorhinal cortex and protected up to the hippocampus
what modalities does the hippocampus receive connections from?
major inputs from the amygdala (emotion), perihinal cortex (objects) and parahippocapal cortex (spatial location)
* vision, sound, smell, emotions etc
the hippocampus binds different aspects of our experience to form a hetromodal episodic memory, why?
because of memories are multisensory
the hippocampus contain many feedback loops (i.e. CA1 to CA3), what are these critical for?
learning (every time you send signals, it’s another change to bring information to the hippocampus)
* ideal for associative learning -> form chains as associative memories which link together our different experiences over time
neurones within the hippocampus have special properties which enable them to?
support memory
long-term memory at the level of individual neurones…
…reflects structural changes at the synapse
Synaptic changes underpin memory, what is Hebbian learning?
- memories are stored in connections between neurones (‘cell assemblies’)
- LTM through Hebbian learning: ‘cells that fire together, wire together’ (cells that fire together, will then strengthen their cognition) <- basis of LTM
- this all happens in the brain because of long-term potentiation (LTP)
The Biological Aspect of Memory: if you apply a weak stimulus
*action happens in the synapse
1. if you apply a weak stimulus to a pre-synaptic cell, you will produce some changes (some action potential) at the synapse, which will include the release of a little glutamate (excitatory neurotransmitter) into the synapse
2. glutamate diffuses across the synapse
3. sodium channels on the post-synaptic cells will open briefly so Na+ ions can enter
4. causes some depolarisation, but because it is weak, this depolarisation is not enough to trigger a new action potential AND there will only be a small change in membrane potential
The Biological Aspects of Memory; if you apply a stronger stimulus
- present a stronger stimulus to the presynaptic neurone (big chain of action potentials in presynaptic neurone)
- triggers the release of lots of glutamate into the synaptic gap
- glutamate leaves the presynaptic cell, diffuses across the synapse, ion channels in post-synaptic cell open for longer (and more channels open), triggering a large influx of sodium ions into the post-synaptic cell
- this triggers an action potential in the post-synaptic cell -> mechanisms which two neurones are communicating
what will a strong stimulus cause?
strengthens communication at this particular synapse - called long term potentiation (LTP)
what is long term potentiation (LTP)?
the connection between the two neurones are strengthened (potentiated in the long term)
when is the communication at the synapse, strengthen in LTP?
when you have a strong stimulus in the pre-synaptic cell
what happens if the stimulus is weak?
a weak stimulus only triggers a small depolarisation event in post-synaptic cell before the LTP has occurred
what happens if LTP has occurred and a a weak stimulus is next?
the effect will be much bigger because the post-synaptic cell is much more sensitive to the activity of the pre-synaptic neurone so you’ll get a bigger response in the post-synaptic neurone after LTP even if the stimulus is still quite weak
- might get an action potential, even if there’s a fairly low train of action potentials in the first neurone because the connection is boosted
what happens following LTP?
the post-synaptic cell will response more strongly next time the presynaptic cell fires
what does memory cause?
changes to the synapse
Bliss & Lomo (1973) discovered LTP in rabbit hippocampus. How did they find this?
showed what response they could see in the post-synaptic neurone when they gave a weak stimulus to each of the pathways
what did Bliss & Lomo (1973) find?
Two pathways: neurone 2 unconditioned & neurone 1 stimulated lots of times (to understand how it altered electrical potential)
before LTP has occurred -> only small depolarisation event happening in the post-synaptic cell for both graphs (found a subtle change in voltage in right-hand cell after left-hand pathways were stimulated)
After LTP occurred -> weak stimulus was enough to generate action potentials after long-term potentiation in neurone 1 but not neurone 2
what does EPSP stand for?
excitatory post-synaptic potential
- graph shows a change in voltage
what did they find when pathway 1 was conditioned with a high frequency stimulus?
drives a much bigger response
- increased response to stimulation of pathway 1 after synaptic link is strengthened (even if stimulation was weak -> increase in magnitude)
- this shows that LTP has occurred
what is important about LTP?
only enhances strength between one particular presynaptic and post-synaptic cell -> only when the one pathway which is stimulated a lot of re stimulated
what are hippocampal cells particularly rich in?
NMDA receptors
where does LTP happen?
across the brain
the diagram shows two hippocampal neurones, which are which and why are they important?
CA3 field at top, CA1 field at bottom
-> connection partly important for LTP in the hippocampus (because its reach in receptors which enables it to occur)
what do presynaptic terminals have?
glutamate in vesicles (which will be released when the presynaptic cell is activated)
there are two types of glutamate receptors on the pre-synaptic neurone, what are these?
AMPA and NMDA
What is AMPA?
- explains how one neurones allows the next to fire
1. when information is passed from one neurone to another glutamate diffuses across the synapse, binding to the AMPA receptors, opening the channel allowing sodium ions to enter the post-synaptic cell
what happens if there is only a small amount of glutamate in the presynaptic cleft?
(low activation)
sodium will enter but there won’t be enough sodium to trigger depolarisation and an action potential
what is NMDA?
IF a lot more sodium enters because there’s a stronger response, you’ll get a lot more sodium in the post-synaptic cell and the NMDA receptors will become activated
How do the NMDA cells become active?
- sodium can unblock the NMDA receptor (which is blocked initially by magnesium)
-> mg+ has a positive change and na+ has a positive charge so repel each other -> magnesium gets pushed out of the way if the depolarisation is large enough - AMPA is open and NMDA is open and active allowing in both sodium ions (stronger action potential) and calcium ions
what are NMDA receptors blocked by?
magnesium
what do calcium ions do?
drive a load of different synaptic changes which allow you to remember this connection in the future
changes are different over time, what are some short changes (after LTP)?
- increased amount of glutamate held in the pre-synaptic neurone ready to be released
- increase in AMPA receptors ready to receive more glutamate driving a bigger response after learning
Over this time (long-term), changes are consolidated at the synapse, what are these?
- growth in the size of the synapse (enlargement of synapse)
- formation of new dendritic spines (double spine which pick up released glutamate)
- increase in receptor density
- increase in neurotransmitter release
- division of the synapse
what are changes in the synaptic function and morphology assiociated with?
LTP maintenance
what are synaptic changes called?
synaptic consolidation
what are these changes?
structural
-> move from chemical and structural to just structural i.e. new dendritic spines forming after LTP
what is LTP the cellular and molecular unpinning of?
memory
what is LTP?
long lasting enhancement in signal transmission between 2 neurones after repeated stimulation
why is ATP mostly studied at the synapse?
because shape collate axons of CA3 and CA1 pyramidal cells
when are post-synaptic receptors activated?
after the binding of neurotransmitter glutamate
what is the AMPA receptor permeable to?
sodium ions
what is the NMDA cell permeable to?
sodium and a higher permeability to calcium
what happens in a synapse when the action potential is low?
- When a low frequency action potential is propagated down the shelfer collateral, a small amount of glutamate is released
- AMPA receptors open and allow sodium into the CA1 post-synaptic cell -> allowing a slight depolarisation event in the post-synaptic cell
- Glutamate also binds to NMDA receptors but ions will not pass through the port due to the magnesium blockage. While the small amount of neurotransmitter release signals a response, it is not enough to cause LTP
what happens in the synapse when the action potential is high frequency?
- high frequency action potential travels down terminal -> large amount of glutamate is released from pre-synaptic terminal -> high frequency action potentials
- greater depolarisation in AMPA receptor (remain open for longer, due to increased glutamate concentration, allowing a large amount of sodium to enter through the AMPA receptor)
- The influx of sodium causes a large depolarisation event in the post synaptic cells, which repels the magnesium blockade from the NMDA receptors through electrostatic repulsion -> NMDA receptor with glutamate bond allow sodium and calcium to enter through the port
- significant depolarisation and strengthening of the connection between the two neurones
why is NMDA a coincidence detector?
requires a presynaptic and post-synaptic event for channel opening -> binding of presynaptic to release glutamate and a significant post-synaptic depolarisation via activation of the AMPA receptors
how does LTP happen?
- influx of post-synaptic calcium acts as an important secondary messenger activating many secondary intracellular cascades
- increase in calcium contributes to early and late phases of LTP
what is the early phase of LTP?
- calcium binds to its respective binding proteins and causes insertion of new AMPA receptors onto the post-synaptic membrane at the active CA3, CA1 synapse
- AMPA receptors are stored in the post-synaptic CA1 internal cell stores and will only insert when there’s a large influx of calcium through the model receptor
- allowing more AMPA receptors to be available for future depolarisation effects
- the early phase changes only last a few hours, requiring a increase in calcium levels during the late phase
what is the late phase of LTP?
- Prolonged influx of calcium causes an increase in transcription factors, resulting in gene expression and new proteins to be synthesised including AMPA receptors which are inserted into the post-synaptic celll membrane
- Increase in growth factors, involved in the formation of new synapses -> basis for synaptic plasticity (these synapses are formed between the CA3-CA1 neurons allowing for a stronger connection between the two neurones)
- The late phase changes can last from 24 hours up to a life-time
How do hippocampal cells form associations?
by LTP between CA1 and CA3 hippocampal neurones
what are some features of long-term potentiation?
- LTP can be induced by a single high frequency train - memory for a single event Is possible
- LTP elicits changes that last for weeks -> ‘synaptic consolidation’ -> making memories durable
- specificity: only synapses active during the stimulation are increased; inactive pathways to the same neurone are not
How is LTP so specific?
allows us to separate overlapping memory (might be the mechanism we can separate things happening to us in the same environment)
-> memories can be differentiated
when do calcium ions increase?
when NMDA channels are open (as only permeable to this)
what is critical for LTP to happen?
long-term
what pushes the magnesium out causing NMDA receptors to open?
depolarisation through synaptic transmission in the AMPA receptors
how is LTP caused?
strong events in the presynaptic and postsynaptic neurone at the same time
-> multiple weak signals will not cause LTP
what actually is a strong signal?
a single neurone having a very fast train of action potential
What is Morris Water Maze?
Inside the Water, there’s a hidden platform
Trial 1: Rat searches for way out and discovers hidden platform
Trial 2: Rat remembers location of platform. Swims there much faster, using landmarks around the room to navigate
How important are hippocampal lesion studies in rats?
- shows roles of hippocampus in memory tasks
- shows posterior hippocampus is more important for spatial memory -> as posterior lesions would give rise to deficits in learning the location of the platform in the water maze
what do hippocampal lesions in rats not show us?
the contribution to specific processes like LTP
Morris (1986) bathed hippocampus of rats in NMDA receptor antagnoist (to block glutamate binding sites). What did they find?
rats were unable to learn location of the platform
-> inability to learn spatial location
how did they make neon transgenic rats?
gene splicing to change genetic makeup of individual cells in particular brain area
-> specific and altered the NMDA function, specifically in the hippocampus without altering every other functions in the brain
Tonegawa (1996) used gene-splicing to create strain of knockout mice that lacked NMDA receptor in CA1. What did they find?
- impaired spatial learning for knock-out rats (had no memory of where the platform was)
-> other forms of learning i.e. classical conditioning were preserved (suggesting LTP memory is about the association of learning and NOT classical conditioning)
(control rats spent most the time exploring where the platform was hidden)
how could researchers prove this is spatial and not procedural learning?
release rat on different position, motor movements are different and then shows the rat has an abstract representation of the location of the platform
what are place cells?
cells which represent spatial locations (i.e. form a cognitive map in the hippocampus)
O’Keefe & Kostrovsky (1971) recorded single neurones (microelectrode embedded in the hippocampus) in an awake behaving animal. Each colour is the action potential from a different neurone. They found cells in CA1 become active when the rat in particular places. Further explain this.
- Cells in the CA1 subfield response in a space specific way
- Each neurone has a ‘place field’ that it responses to
- each neurones have tuning so they respond to particular locations -> firing -> these are place cells
- transforming our understanding of how our brains represent things
i.e. when an animal is searching a particular place, a particular cell will fire (pink), and then when he reaches another certain point (yellow will fire)
What do O’Keefe and Nadel (1978) suggest?
Hippocampus provide an internal map that codes for spatial relations between objects in the environment
Miguire (2000) investigated Hippocampus and Spatial memory in Humans. She looked at method of analysing MRI using Voxel-based Morphometry measuring the physical amount of tissue within a brain structure. What did she find?
Experienced taxi drivers have (slightly) more voxels in the posterior hippocampus
-> responsible for spatial information
Place Cells in Epileptic Patients (Ekstrom et al. 2003). Microelectrodes arrays were implanted prior to epilepsy surgery - allows recording from single neurones in human hippocampus. Patients were asked to identify certain locations in virtual reality while researchers looked for how many cells looked at a space specific response at certain locations. What did they find?
-> 25% of hippocampal neurones were place cells
-> 5-10% were found in other specific areas
proportion of neurones that fire in response to specific locations in hippocampus, parahippocampal cortex, amygdala and frontal cortex
-> place cells represent in humans and not specifically to hippocampus (perhaps more wide spread)
how can we relate place cells to amnesia?
severe and selective deficits of episodic memory in amnesia
-> link this to difficulty in binding together the elements of experience, which is why there’s an episodic memory impairment
Spatial deficits in amnesia
- patients show deficits in tasks which don’t appear to have spatial dimensions i.e. word lists
- yet all episodic memories are coded and recalled in spatial locations -> mental time-travel involves reconstructing environment in which memory took place; spatial location is a profound cue to recall and therefore a critical aspect of episodic memory
- when a spatial environment is matching between encoding retrieval, it’s that match which provides the cue and allows the hippocampal representation to reconstruct or reinstate the rest of the memory
- often have spatial deficits (HM couldn’t learn his way to the bathroom)
- both episodic memory and spatial learning require a relational code -> potential overlap
what has similar cognitive domains?
map and episodic memory
-> relational memory system
Dusek & Eichenbaum, had a number of locations (beakers) coded with smells. One would have a treat covered in sand and the rat would have to dig it up. They argued that the hippocampus supports relational memory, how?
Rats with hippocampal lesions can remember individual associations but cannot infer relations
- rats without lesions would learn which beaker is rewarded with buried food when comparing them in pairs of associations
- while lesion rats couldn’t infer which cup would be rewarded (as done previously - when both cups have been rewarded previously) when they had never been trained on the pair and instead had to infer
-> need relational framework
Recollection vs. Familiarity
- hippocampus unique role of time travel
Yet there are different types of declarative conscious memory which are both LTM, episodic but one of them involves the hippocampus (mental time travel)
what is recollection?
involves relations between items and contexts
-> Hippocampus responds to these recollection trials -> and it is crucial for this type of mental time travel
-> reconstructing the whole environment
what is familiarity?
a form of declarative memory (feeling of familiarity is conscious)
-> But Familiarity is a form of conscious declarative memory but doesn’t involve full mental time travel -> instead perirhinal cortex which is important for object representation -> feeling of familiarity from the ease of processing the information in the perirhinal cortex but it never reaches the hippocampus or reinstates the aspect of the memory
-> related to priming in perirhinal cortex (which shows strong response to novelty)
hippocampus is crucial for episodic memories which aren’t?
overly spatial
