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Taking a Trip Down Memory Lane

Memory Formation

Embarrassing flashbacks, knowing the lyrics to the entirety of ABBA Gold and constantly repeating that one conversation to check you didn't say anything stupid; just some of the really useful things your memory is capable of storing for years and years. Although sometimes we wish we could forget certain moments (karaoke at the Christmas party… who would ever want to relive that?), memory is one of the strongest tools we humans hold. We have used our extensive memory to our evolutionary advantage; we can separate our friends from our enemies, tell a poisonous berry from a tasty one and run very fast when we come face to face with a hungry tiger. Disorders which affect our memory can be debilitating for the individual with memory loss and devastating for all those around them. Trying to understand what a memory physically is may help us reverse some forms of amnesia and potentially help our cognitive performance day to day. Deep in the brain lies the hippocampus; a specific region crucial for memory formation as neurons from this region connect to other neurons around the brain to create unique circuits. The strength of the connections between neurons within these circuits is enhanced when a memory is made but can weaken over time if a memory is not deemed ‘important’. So let’s get learning about how we learn!

Do You Remember the 21st night of September: The Hippocampus and Memory Formation

What makes a memory? Well, one vital ingredient is the hippocampus. The hippocampus is seahorse-shaped region located in the temporal lobe of the brain and is one of the only brain regions where new neurons can be made. The hippocampus can be further split into 3 sub-regions (named CA1 – CA3) based on the different layers of neurons. The hippocampus is neighboured by the entorhinal cortex (EC), the subiculum and the dentate gyrus (DG). The EC contains neurons which deliver messages to the CA1/CA3 hippocampal regions, the subiculum and the DG. These signals trigger an almost unidirectional pattern of firing from the DG up to the subiculum, which proceeds to send the outgoing signal back to the EC. This can then go on to pass the signal to other cortical regions; connecting the many different aspects (like sight, sound and emotion) which make a memory.

Without the hippocampus, new memories cannot be made. One of the most fundamental case studies solidifying this information came from the removal of the hippocampus from a patient, “HM”, with severe temporal lobe epilepsy. HM contracted debilitating seizures after being hit by a car and doctors decided to remove the over-active brain region triggering the seizures; containing the hippocampal formation. Following the procedure, patient HM had no more seizures but could not make any new memories. In fact, it was reported he could only retain new information for about 30 seconds. However, memories made from about year before the operation remained intact, highlighting the hippocampus’ role in creating new long-term memories.

If the hippocampus plays such an important role in human memory, why could patient HM remember snippets of information for 30 seconds and early events in his life? Remembering information for 30 seconds or less is the time frame which defines your ‘short-term memory’. Short term memory is distinct from long-term memory as short-term memory uses pre-defined neuronal circuits in the frontal lobe to temporarily hold information. If this memory is deemed ‘important’, the hippocampus and its surrounding structures will kick into action in order to convert it into a long-term memory. Importance is defined by specific emotions you associate with the information (trauma, fear, excitement) and other senses. Physically, a memory is a unique pathway of connections between neurons. In your brain you have over 80 billion neurons, and some of these cells can connect up to 10,000 others, meaning the number of neuron connection pathways in your brain is almost endless. Once a memory pathway is generated, the storage of this memory can take up to a year, meaning your hippocampus is busy day and night. However, once the memory is stored, the hippocampus is no longer needed for its recall as the circuit can be activated by itself. So, removing HM’s hippocampus did not damage these old pre-formed memories – mad!

Give me (synaptic) strength: LTP/LTD

Memories are basically just specific connections between different neurons, but what defines these connections? How does this trace standout from a bog-standard neuron connection? Well, as we know, the junction between two neurons is called a synapse and the strength of synapses can be altered based on neuron activity. If a synapse is used a lot, it undergoes long-term potentiation (LTP); making that synaptic connection easily activated by action potentials. If a synaptic connection is not used, the connection is weakened in a process called ‘long-term depression’ (LTD). LTP and LTD can occur to varying extents due to the number of alterations which can be made at a synapse so across the brain, each synapse can be different strengths. In a memory pathway, LTP occurs at the synapses between the neurons

within the circuit, making them ‘standout’ for the other connections these neurons have. Think of this as all the roads in your local area mapped out, and your route to work standing out amongst the many twists and turns of streets and avenues. Your memory traces standout from lots of other connections as the strength between junctions is amplified.

Synapses are ‘chemical junctions’ and involve the release of chemicals called ‘neurotransmitters’ from the pre-synaptic neuron terminal which activate receptors on the post-synaptic neuron terminal (more deets in Synapses post). A few different changes at the synapse can make it stronger when it undergoes LTP. The main changes include:

  1. Changing the amount of neurotransmitter released: the more neurotransmitters available, the more chance they will open the receptors on the post synaptic membrane

  2. Adding more excitatory receptors on the post-synaptic membrane: if you have more receptors on the post-synaptic membrane that increase the chance of initiating an action potential, more neurotransmitters can bind and increase the burst signal in the receiving neuron.

Together, these changes increase the chance that an action potential will be triggered in the receiving neuron. In the neuron pathways which make a memory, initiation of one neuron will lead to a cascade of activation of the other neurons in the memory trace. An example of this mechanism in action is when you hear a song from years ago and it takes you back to the school disco dancing madly with your mates and eating so many sweets you needed fillings. The good days.

Synaptic strengthening is not permanent. Synapses that have undergone LTP can also undergo LTD if they are not used as much as  neuron communication requires a lot of energy. Your brain doesn’t want to waste time thinking about the conversation you had about what shoes you were going to wear for a party 10 years ago, so these synapses undergo LTD. This reverses the LTP alterations mentioned above so that connection is less likely to result in action potential initiation. LTD is vital during development as it stops all synapses being hyper active and is important for making the strong LTP synapses standout from background firing at other synapses. Also, LTD helps make room for new, more ‘important’ memories. So, the information you revised relentlessly to pass your final school exams is probably long lost due to the mechanism of LTD.

 

The roles of LTP and LTD are reversed at inhibitory synapses. LTP will inhibit action potentials if a strength of an inhibitory GABA synapses is increased as this enhanced activation causes the post-synaptic neuron to prevent burst activity. LTD at this type of synapse lessens this inhibitory signal, making it more likely than a synapse can be activated elsewhere on the neuron.

Forget Me Nots: Memory Impairment

“Where did I put my keys?”

“What is this person’s name who is waving at me?”

“What on earth happened last night?”

We all forget things; we are humans, not super computers. And as you have just read, forgetting bits of information is a natural process to make room for new, more important memories in order to use that finite brain power wisely. However, there are some occasions when memory loss can be extremely debilitating. Below are a few examples of extreme cases of memory loss and how these conditions affect the brain.

1. Alzheimer’s disease

Alzheimer’s disease is a type of dementia with the heart-breaking symptom of progressive memory loss. Patients with the disease normally forget more recent events and how to perform basic tasks before losing long term memories. This is caused by the death of neurons, which starts with the death of cells in the EC and hippocampus. This includes removing the neuron precursor cells which can transform into new neurons. Therefore, patients are unable to solidify new memories into long-term storage. Eventually, neurons in the frontal cortex die, breaking up memory pathways throughout the brain.

2. Amnesia

There are two types of amnesia: anterograde and retrograde. The former is when patients cannot make any new memories (like patient HM and people with Alzheimer’s disease) and the latter is when patients forget past events. Retrograde amnesia can occur following head trauma and stroke, and little is known about the neurological mechanisms behind this. It is still debated whether retrograde amnesia is caused by impairment to memory storage or memory retrieval i.e. if the memory is wiped from the brain or if the patient just cannot access it. Recent evidence is pointing towards the issue being with retrieval as mice with drug-induced amnesia can have their previously-learnt fear switched back on when individual neurons are activated.

3. Alcohol Blackout

Many of us have woken up following a few too many tipples and had the sinking dread trying to remember what you said or did. Well, with every alcoholic drink you have, your hippocampus gets less and less good at transforming your experiences into long-term memories. When experiencing a blackout, it is thought your hippocampal cells completely stop firing. But, as your short-term memory (lasting 30 seconds) is still intact, you can continue to have conversations which can convince others you are fully aware (although you normally end up repeating yourself A LOT). Taking an individual back to a place they experienced their blackout can trigger some recall as blackout is normally partial. However, the long-term effects of excessive alcohol consumption can cause irreparable damage to your hippocampus and affect memory formation for life.

Take Home Message to Remember

Making memories is a complex process involving neurons from across the brain. However, the hippocampus is where all memory formation begins. Activating this region transfers present experiences into long-term memories, with this transfer of data taking months to years. Memory pathways are formed due to the strengthening of individual synapses and the more this is remembered, the more likely it will stay with you for a long time. Those memories that don’t serve you any purpose or have no emotional attachment can be weakened by LTD; making storage space for incoming, novel memories. As humans, we hold our memories in great esteem as they help define who we are and where we have come from. So, losing those vital memories and associations can be devastating for the individual and those who love them. A lot of research is being done on memory conditions and how memories are stored and recalled with the hopes of resolving some of these issues in the future. Ways to improve memory are thought to be to get a good night’s sleep and keep your brain active by socialising and solving problems. So keep on chatting about all those funny times your mates embarrassed themselves to keep those really important memory traces active and alive.

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