Rduke55
02-23-2006, 03:29 PM
With all the talk going on in the intelligence and race threads I thought I’d move this little gem up a few spots. I started my career in a Learning and Memory lab studying NMDA receptors. That seems like a lifetime ago but I’ll give it a shot.
Disclaimer: As I said in the other threads, genetics is only one component of what determines a person’s intelligence.
You may have read about the supermouse within the past couple of years called the Doogie mouse. This mouse was genetically engineered to be smarter than other, normal mice. It was in the popular media after Tsien’s Nature paper from 1999. To understand what he was talking about we have to do a little background on the neurobiology of learning and memory.
So, the brain can be thought of being made up of a whole crapload of neurons (nerve cells) talking to each other in circuits. In many ways, circuits in the brain are like muscles. The more you use a particular connection the stronger it gets, the less you use it the weaker it gets. But I’m already getting ahead of myself.
OK, neurons conduct information using electrical and chemical means. When a neuron is activated, it sends a brief electrical signal down its length to the synapse (a space between two neurons). Now the electrical signal can’t jump this gap so it needs to be transformed into something that can. The change in voltage due to the electrical signal causes the release of chemicals from the activated neuron that influences the neuron on the other side of the synapse, for our purposes we’ll just deal with the chemicals that excite the next neuron. These chemicals cause a small change in voltage in the next neuron. If enough of the chemical is released onto the next neuron its change in voltage passes a certain threshold and that neuron gets activated and sends an electrical signal down its length to its synapse with another neuron and so forth. Now, the key part here is that you need a certain amount of voltage change in the 2nd neuron for it to be activated. After all, you don’t want all of your neurons firing all willy-nilly at the slightest provocation. For the most part, you want circuits that are more important and used regularly to be easier to activate.
Basically, the more input a neuron gets from other neurons (either from multiple neurons dumping chemical on it simultaneously or a single neuron rapidly dunping chemical on it), the stronger those connections get. Hebb postulated in the late 1940’s that neurons have a “coincidence detector” that allows them to tell when they are being stimulated by more than one neuron (or rapidly by a single neuron). How does it do this? Well since Hebb’s day it’s been thought that the main coincidence detector on neurons is the n-methy-d-aspartate (NMDA) receptor. Basically this is a receptor that is activated by the neurotransmitter glutamate (our excitatory chemical). Once activated it increases the amount calcium in the cell which causes a whole bunch of changes making it easier for the neuron the get excited in the future. Looks like a great mechanism for “muscling up” our neurons.
But why doesn’t any signal cause strengthening of these connections? Because I said it’s a coincidence detector – that’s why! The coincidence detection comes in because glutamate alone can’t activate the receptor. The neuron already needs to have a certain voltage change. You dump glutamate on NMDA receptors while the neuron is not excited and you’ll get no response. Dump it on when the neuron is somewhat excited and they’ll activate.
So how does the nervous system know how much stimulation a neuron or circuit should be activated by? It has a learning mechanism built right in! It happens at the synapse. Let’s say I take, oh say, HLMencken and want to train him. I want him to crap his pants everytime I flash a light. So I take him and flash that light and he doesn’t care because he is a big tough guy and he’s not afraid of lights. But I give him an electric shock and he craps his pants. As anyone who has taken a general psych course, etc. knows I may be able to have him associate the light with the shock and eventually crap his pants to the light only (no shock). How does this work?
Let’s think of HL as only a few neurons (insert joke about his intelligence here). One neuron gets excited to a light flash. One neuron gets excited by the shock. Both synapse on a neuron that, when activated, trigger his bowel-releasing (we’ll call this neuron the BR neuron). Now normally when I give the shock, the shock neuron releases enough exciting chemical on the bowel-releasing neuron to activate it and pants are crapped. The light neuron alone does not release enough chemical on the BR neuron to activate it, therefore no pants are crapped to presentation of the light only.
However, if I pair the presentation of the light and the shock then every time the light neuron is giving its weak excitation to the BR neuron the shock neuron is giving it’s strong one. Therefore the glutamate that the light neuron is dumping on the synapse can activate the NMDA receptors (because the neuron is excited), calcium can increase in that cell and make changes so that the synapse between the light neuron and BR neuron is more sensitive (the “connection is stronger”) to the light neuron’s input. Eventually after repeating this process, the connection will be so strong that light alone will cause HLMencken to crap his pants.
This coincidence detection is how we learn at the cellular level. In this way, neurons that give their input on another neuron at about the same time get those connections strengthened.
OK, so what does all this have to do with smart mice? Well, all NMDA receptors aren’t the same. They vary in how easily they are activated, how long they stay activated, etc.
One type, we’ll call in NMDA receptor A only stays activated for a short time. Another type, we’ll call it NMDA receptor B, stays activated for a long time. That longer activation results in more a greater time window for coincidence detection and its “easier” to get LTP (because neurons that don’t normally coincide now do and also neurons may send more signals that coincide because of the longer window).
Typically during early development we have mostly Type B receptors because we’re wiring things up and want these changes to be easy and robust. After about 6 months of age we switch to mostly Type A receptors (presumably because we want most of what we changed to stay that way). What Tsien’s group did was use genetic engineering in mice (he called them the Doogie mouse, after Doogie Howser) to increase the amount of Type B receptors in certain areas of the brain.
These altered mice performed better at certain tasks (maze running, classical conditioning, object recognition, etc.) than normal mice suggesting that they learn better because of the high levels of Type B receptors.
Combine this information with what we know about how different promoters can influence expression of receptors (see The Monogamy Gene post) and you have a mechanism for genetics influencing intelligence through subtle manipulation of NMDA receptor levels.
Man, this may be rough to comprehend without figures, but I typed it so I’m posting it.
Disclaimer: As I said in the other threads, genetics is only one component of what determines a person’s intelligence.
You may have read about the supermouse within the past couple of years called the Doogie mouse. This mouse was genetically engineered to be smarter than other, normal mice. It was in the popular media after Tsien’s Nature paper from 1999. To understand what he was talking about we have to do a little background on the neurobiology of learning and memory.
So, the brain can be thought of being made up of a whole crapload of neurons (nerve cells) talking to each other in circuits. In many ways, circuits in the brain are like muscles. The more you use a particular connection the stronger it gets, the less you use it the weaker it gets. But I’m already getting ahead of myself.
OK, neurons conduct information using electrical and chemical means. When a neuron is activated, it sends a brief electrical signal down its length to the synapse (a space between two neurons). Now the electrical signal can’t jump this gap so it needs to be transformed into something that can. The change in voltage due to the electrical signal causes the release of chemicals from the activated neuron that influences the neuron on the other side of the synapse, for our purposes we’ll just deal with the chemicals that excite the next neuron. These chemicals cause a small change in voltage in the next neuron. If enough of the chemical is released onto the next neuron its change in voltage passes a certain threshold and that neuron gets activated and sends an electrical signal down its length to its synapse with another neuron and so forth. Now, the key part here is that you need a certain amount of voltage change in the 2nd neuron for it to be activated. After all, you don’t want all of your neurons firing all willy-nilly at the slightest provocation. For the most part, you want circuits that are more important and used regularly to be easier to activate.
Basically, the more input a neuron gets from other neurons (either from multiple neurons dumping chemical on it simultaneously or a single neuron rapidly dunping chemical on it), the stronger those connections get. Hebb postulated in the late 1940’s that neurons have a “coincidence detector” that allows them to tell when they are being stimulated by more than one neuron (or rapidly by a single neuron). How does it do this? Well since Hebb’s day it’s been thought that the main coincidence detector on neurons is the n-methy-d-aspartate (NMDA) receptor. Basically this is a receptor that is activated by the neurotransmitter glutamate (our excitatory chemical). Once activated it increases the amount calcium in the cell which causes a whole bunch of changes making it easier for the neuron the get excited in the future. Looks like a great mechanism for “muscling up” our neurons.
But why doesn’t any signal cause strengthening of these connections? Because I said it’s a coincidence detector – that’s why! The coincidence detection comes in because glutamate alone can’t activate the receptor. The neuron already needs to have a certain voltage change. You dump glutamate on NMDA receptors while the neuron is not excited and you’ll get no response. Dump it on when the neuron is somewhat excited and they’ll activate.
So how does the nervous system know how much stimulation a neuron or circuit should be activated by? It has a learning mechanism built right in! It happens at the synapse. Let’s say I take, oh say, HLMencken and want to train him. I want him to crap his pants everytime I flash a light. So I take him and flash that light and he doesn’t care because he is a big tough guy and he’s not afraid of lights. But I give him an electric shock and he craps his pants. As anyone who has taken a general psych course, etc. knows I may be able to have him associate the light with the shock and eventually crap his pants to the light only (no shock). How does this work?
Let’s think of HL as only a few neurons (insert joke about his intelligence here). One neuron gets excited to a light flash. One neuron gets excited by the shock. Both synapse on a neuron that, when activated, trigger his bowel-releasing (we’ll call this neuron the BR neuron). Now normally when I give the shock, the shock neuron releases enough exciting chemical on the bowel-releasing neuron to activate it and pants are crapped. The light neuron alone does not release enough chemical on the BR neuron to activate it, therefore no pants are crapped to presentation of the light only.
However, if I pair the presentation of the light and the shock then every time the light neuron is giving its weak excitation to the BR neuron the shock neuron is giving it’s strong one. Therefore the glutamate that the light neuron is dumping on the synapse can activate the NMDA receptors (because the neuron is excited), calcium can increase in that cell and make changes so that the synapse between the light neuron and BR neuron is more sensitive (the “connection is stronger”) to the light neuron’s input. Eventually after repeating this process, the connection will be so strong that light alone will cause HLMencken to crap his pants.
This coincidence detection is how we learn at the cellular level. In this way, neurons that give their input on another neuron at about the same time get those connections strengthened.
OK, so what does all this have to do with smart mice? Well, all NMDA receptors aren’t the same. They vary in how easily they are activated, how long they stay activated, etc.
One type, we’ll call in NMDA receptor A only stays activated for a short time. Another type, we’ll call it NMDA receptor B, stays activated for a long time. That longer activation results in more a greater time window for coincidence detection and its “easier” to get LTP (because neurons that don’t normally coincide now do and also neurons may send more signals that coincide because of the longer window).
Typically during early development we have mostly Type B receptors because we’re wiring things up and want these changes to be easy and robust. After about 6 months of age we switch to mostly Type A receptors (presumably because we want most of what we changed to stay that way). What Tsien’s group did was use genetic engineering in mice (he called them the Doogie mouse, after Doogie Howser) to increase the amount of Type B receptors in certain areas of the brain.
These altered mice performed better at certain tasks (maze running, classical conditioning, object recognition, etc.) than normal mice suggesting that they learn better because of the high levels of Type B receptors.
Combine this information with what we know about how different promoters can influence expression of receptors (see The Monogamy Gene post) and you have a mechanism for genetics influencing intelligence through subtle manipulation of NMDA receptor levels.
Man, this may be rough to comprehend without figures, but I typed it so I’m posting it.