Neuroscientists have long been fascinated by why a person can't remember recent events after a brain injury, such as after a fall. Yet, that same person might still be able to recall the exact ingredients to their chocolate-chip cookie recipe. It has led to theories on how we learn and store information in that complicated computer called our brains. Part of this appears to be due to long-term potentiation.
Long-term potentiation (LTP) is a mechanism in mammals, such as people, believed to enable learning and making long-term memories. LTP is a process where synapses strengthen through repetition. LTP occurs in various areas of the brain, but most research has focused on the glutamate synapse.
"Use it or lose it" is a frequent warning regarding our memories and the way we learn. It brings up images of tiny brain cells lifting weights to stay in shape while others shrivel and die. A more technical term for this is synaptic plasticity, where synapses get stronger or weaker depending on if they are needed. Long-term potentiation is on the complicated "weight lifting" side of synaptic plasticity.
Discovery Of Long-Term Potentiation
"Keep my neurons firing" has become an everyday phrase in modern society. People tell friends they are trying to prevent dementia by playing games like Sudoku or crosswords. But while Camillo Golgi discovered neurons in 1908, the mechanism of how this "firing" allowed learning and memories was unknown.
But in 1966, Terje Lømo, a neuroscientist, began work studying the hippocampus of rabbits. The work led to the discovery of long-term potentiation. Two years later, he and Tim Bliss did a systematic study on this discovery and observed the muscle impulse activity in mammalian brains (rats).
The activity wasn't random but had patterns within adaptive ranges. These patterns created a stronger connection between two neurons. That a stronger, better signal between two neurons is instrumental to learning and creating memories rather than birthing new brain cells.
To make a crude mixed analogy: imagine two neurons exercising by playing catch. But their game of catch creates a mobile signal. It starts weak, a lousy 2G; information passes between them slowly, and pages don't always load. Then, after some practice, it gets to EDGE. But the more those neurons work, the better they get until they've made a 4G connection (and beyond) between them.
Neurons building and strengthening connections wasn't an entirely new concept. For example, Santiago Ramón y Cajal suggested in 1894 that learning involved better connections between neurons rather than making more of them. In addition, the famous Hebbian theory was brought out in 1949 by Donald Hebb. His theory is summed up with the catchy phrase, "Cells that fire together wire together."
But while Cajal and Hebb were on the right track, their ideas were incomplete. The discovery of LTP opened up the mystery behind the firing and began to help us understand why some thoughts are temporary, and other information is retained and built upon. Yet, even to this day, LTP is not fully understood. For starters, it doesn't occur the same way in all parts of the brain.
Long Term Potentiation At The Glutamate Synapse
As adorable as it is to imagine our neurons playing catch or firing little laser guns at each other, long-term potentiation is a wee bit (a lot) more complicated. Nor does this game of catch operate in the same manner in all areas of the brain. But the easiest way to dive into LTP is at the glutamate synapse of the hippocampus because that's where the most research has been done.
LTP: NMDA Receptor, AMPA Receptor, And Depolarization
Folks love a good acronym, and that includes neuroscientists. Thus, in the glutamate synapse receptors: NMDA and AMPA. So the best way to visualize these receptors is as tiny tunnels in the pathway of our game of catch. These tunnels allow the "balls" to pass through with enough glutamate. These "balls" are things like magnesium and calcium.
The body takes in sensory input: sight, smell, sounds, touch, and taste. The sensory input is transmitted to the hippocampus through signals. The glutamate receptors are then activated. A low amount of activity will get the AMPA receptor going. However, the NMDA receptor is harder to please. It doesn't open very far and promptly gets itself blocked by a magnesium ion (one of our balls).
The brain doesn't have a plunger to pop that magnesium ion out of our NMDA "tunnel." Instead, it uses depolarization to remove the magnesium ion. However, this is only possible by strengthening the signal by either:
- Stimulating it with a strong signal
- Repeating a signal
It's like teaching a child not to touch a hot fireplace. There are two ways this lesson is going to be learned:
- The kid touches the hot fireplace and screams in pain
- The parent keeps saying, "No, hot," every time the child reaches out to touch the fireplace
Example A is a strong signal: it teaches most kids instantly that fireplaces are hot and dangerous.
Example B is a weak signal: less painful and hazardous to the child but takes much longer (and makes parents question their life choices).
The first "No, hot" isn't enough stimulation to get that magnesium ion to budge. For Example B to work, it needs to be performed repeatedly until a large amount of glutamate is released. The extra glutamate keeps the AMPA receptor open longer, allowing enough sodium into the cell that there is depolarization. The magazine is popped out, and now calcium (other balls) can get through.
LTP is now in its first phase. The child is starting to learn that the fireplace is hot. However, if better weather arrives before the LTP reaches its second phase, this lesson might be forgotten by the time winter rolls back around. Then the learning process must be repeated, perhaps not entirely from scratch, but nearly.
Long Term Potentiation And Memories
Phase 1 of long-term potentiation is known as short-term memory. To put it crudely, the information hangs out in a temporary storage locker in the hippocampus. Only until it reaches phase 2 will the information be considered important enough to be sent to the cortex for a long-term storage compartment. Once stored in the cortex, it is now a long-term memory.
We witness these differences between phase 1 and phase 2 in people with brain injuries and mental deterioration conditions. A person that falls off their horse, for example, might sustain a head injury bad enough that they start losing recent memories. At first, they can't remember the fall. But by the next day, they may have forgotten the entirety of the past week.
Yet, this same injured person will still be able to tell you exactly how to make their favorite chocolate chip cookie recipe. The recipe was taught to them when they were small, maybe by their grandmother, and they have been making these cookies for decades. That information is locked in the cortex, safe and sound, while the hippocampus is dumped out of its lockers.
In the case of a temporary injury, such as falling off the horse, the hippocampus eventually gets back to work, and more long-term memories can be formed. However, if lesions have formed due to injury or disease, the brain struggles or can't make new memories. Yet it might still be able to retain older memories. We see this phenomenon in people with Alzheimer's.
Synaptic Plasticity
Synaptic strength is not a constant but can both be strengthened or weakened. The term for this is synaptic plasticity, and it is often compared to going to the gym. So when you go to the gym regularly, your muscle tone and strength typically increase, as does your cardiovascular fitness. But then maybe you get busy and don't go for a month, and your fitness decreases.
While the brain is not a muscle, it does require "exercise" to keep the mechanism of long-term potentiation ticking along. But even a well-exercised brain will have some connections weakening while others are strengthening.
For example, if you don't use a skill for a while, say, a second language, your proficiency in that skill drops. However, this doesn't mean you haven't been exercising your brain. For example, during that period, you might have been learning the guitar or become obsessed with making sourdough.
Thus, while certain connections in our brain were getting stronger––how to play the guitar, how to bake the ultimate sourdough loaf––other connections were getting weaker. Or to return to the gym: it's like taking up spin classes because you became bored with swimming. But after a year on the bike, you jump back in the pool to find that your swimming fitness has declined despite still being in shape.
However, what is weird about this example is that you will not have forgotten how to swim. Admittedly, it is more challenging because your muscles are no longer being used that way. But the body still knows what needs to be done not to drown. Oddly enough, your ability to “not drown” after a prolonged period of not swimming is believed to be related to the same process as forgetting.
Thus, as annoying as it is to "forget" things, synaptic plasticity can be a healthy process when kept in balance. We don't need all the information we take in forevermore. It is not a big deal if you can't remember the grocery list you wrote in January 2004.
Instead, our brains let tired connections go and reset them so they can be used again for something else, like the grocery list. Or it pairs it down, so we only use the necessary bits, such as with the swimming. This reset or pair-down process is done through a mechanism known as long-term depression.
Long Term Depression: The Opposite Of LTP
Long-term depression (LTD) in neuroscience is not the same as the serious mental health illness known as chronic depression. Instead, LTD is a mechanism in mammals that runs opposing to long-term potentiation.
LTD is not fully understood. While it is seen as part of the process of forgetting, it plays a crucial role in our motor memory, back to swimming. When first learning this skill, it involves a lot of concentration. When swimming was new, a distraction, such as somebody calling out our name, could cause us to lose focus and panic.
But once we've mastered the ability to swim, it requires nearly zero conscious thought to stay afloat. Some people do it on their backs, chatting to the seagulls, without a care in the world. Somehow, LTD carves away all the information we don't need and retains essential aspects to our muscle memory. Thus, the "moving" the knowledge to our muscle memory allows us to multitask.
LTD can also make memories clearer, sharpening the essential parts of the "story," creating a greater contrast while allowing other elements to fall away. This might be why someone might have, say, a crystal-clear memory of making chocolate chip cookies with grandma for the first time. However, they don't know the day, month, or even their exact age. Instead, it is more, "I must have been somewhere between six and eight."
While the research into LTP is still ongoing, some aspects of it are fairly well established. For instance, neuroscientists know that, like LTP, long-term depression can occur by various mechanisms, but the most studied is in the glutamate receptors. Thus, we return to the NMDA and AMPA, where the NMDA is blocked by the magnesium ion.
But unlike LTP, there isn't enough stimulation to unblock the magnesium ion. Interestingly, there is some low-intensity stimulation. In fact, there is enough to allow some calcium into the NMDA. But it isn't enough cause long-term potentiation. Instead, it activates a cellular cascade that results in the removal of the AMPA receptors, reducing the amount of glutamate receptors. Thus, the connection weakens.
LTP, LTD, Synaptic Placidity, Learning, And Memory
While LTP and LTD are thought to play major roles in how we learn and form memories, the brain is a complicated organ. Even the roles of LTP and LTD in synaptic placidity are not absolute. The explanations above are simplistic, and neuroscientists are still researching and debating the full impact of these processes. There are also other chemicals at play.
Yet LTP and LTD do seem to have a wide-reaching impact. There is a huge amount of evidence to support these mechanical processes as significant contributors to behavioral learning and spatial memory. Thus, research into them extends into a multitude of conditions, including Alzheimer's, trauma, the development of pain pathways, and drug addiction.
Conclusion
Long-term potentiation is a mechanical process that is involved in the strengthening of synaptic connections between neurons. It is believed that this is part of how we learn and create memories. It is the opposing process to long-term depression, weakening the connections between neurons. Thus, LTP and LTD are believed to be a major part of the phenomena synaptic plasticity.
Links
https://www.sciencedirect.com/topics/neuroscience/long-term-potentiation
https://www.nature.com/articles/s41598-020-71528-3
