Imagine being home on a moonless night when the power unexpectedly goes out. You are shrouded by silent darkness, instantly blind to your surroundings. Yet despite this sensory deprivation, you can navigate somewhat effortlessly around the futon, through the doorway of the kitchen, and across to the middle drawer where your lighter is stored, avoiding walls, furniture, and other familiar obstacles along the way. How, without vision or echolocation, did you remember where everything was in relation you and to everything else?
The brain's "spatial memory," as this ability is called, relies on the operation of neural "maps." Critical to these maps are specialized neurons known as "place cells," which are located in the hippocampal formation. These cells show place-specific firing patters; that is, a given place cell will become highly activated only when an animal is at a specific location within a particular environment. Theoretically, networks of place cells, each activated in a distinct but partially overlapping spatial region, form maps of every environment encountered. If an environment is experienced repeatedly, the map will be committed to long-term memory; the brain can then deduce its animal's location by interpreting the activation of place cells along the relatively stable map.
Importantly, place cell activation patterns are based on spatial clues. In the introductory example, you could navigate in darkness only because you knew your relative position at the time of the power outage. If, however, you were to close your eyes and twirl around on your toes, and open your eyes immediately after the outage began, your internal map (and thus you), would be spatially bewildered. Yet if you were to grope and fumble until you found the futon, your map would reorient, allowing you to immediately intuit the rest of your spatial world.
What about when two environments have similar spatial cues? For example, imagine two parallel streets in San Francisco, each lined by eminent Victorians, peppered with sushi restaurants, cafes, and liquor stores, a MUNI rail cutting a rugged metallic swath down the middle of each street. The spatial cues of these two environments would activate a somewhat overlapping pattern of place cells, yet the subtle differences on each street (an Indian-Pakistani restaurant on the north side of one, a pirate store on the south side of the other) would allow you to recognize the differences and navigate each uniquely. How does your brain recognize such relatively small differences to construct the distinct maps the environments deserve?
Researchers at the University of Bristol and MIT published a report in the early online edition of Science on June 7 that explored this question. The group focused on the role of a particular region of the hippocampal formation, the dentate gyrus, and found it to be crucial for distinguishing between similar locations. The dentate gyrus does not contain place cells, but it does serve as an interface between the hippocampus (where the place cells are located) and the rest of the brain (which would provide the sensory information, the spatial cues). Thus, it may provide the neural input necessary for "map" construction.
The group removed the NMDA receptor, a protein crucial for synaptic plasticity (the process by which the connection between two neurons adapts to become stronger or weaker, thus enabling learning and memory), specifically from the dentate gyrus. Although these mice perform normally in several learning and memory tasks, they had trouble discriminating between similar yet distinct environments. At the neuronal level, their place cells showed decreased spatial specificity, becoming activated in a significantly broader range.
This type of deficit is similar to what has been previously observed in aged animals; these results may thus help explain the disorientation experienced by some older people, who often struggle to adapt to new spatial locations. Perhaps a major component of their impairment is an age-related dysfunction in the dentate gyrus, which makes it difficult to encode subtle differences and form unique place cell maps for similar yet distinct places. Such individuals would also lose their bearings as a result of changes to familiar environments; e.g., a few years ago I moved some of my grandmother's icons around on her computer's desktop, and she was completely bewildered until I dragged them all back to their original, recognizable locations.
Reference:
McHugh TJ et al. "Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network" Science. [Published online June 7 2007, DOI: 10.1126/science.1140263]
Showing posts with label NMDA. Show all posts
Showing posts with label NMDA. Show all posts
Friday, June 8, 2007
Friday, June 1, 2007
Of Molecules and Memory, Pt. II
This is Part II of a two-part series; click here for Part I.
Now for some neurobiological background on memory, on the biological changes that occur at synapses when "internal representations" are modified. A key experimental paradigm to understand is called long term potentiation (LTP), which is thought to simulate what happens in the brain during learning. Basically, experimenters take a slice of the hippocampus (a structure with a critical role in declarative learning and memory), and use an electrode to induce strong activity (i.e. a high frequency of action potentials) in a group of neurons located in a specific area of the hippocampus (called CA3). These regions project to neurons in another region (CA1), and connections between these regions are believed to be involved in learning and memory. Moreover, the experimental stimulation is thought to be similar to the kind of stimulation neurons receive during intense activity (e.g. learning), and results in the "potentiation," or strengthening, of the synapses between CA3 and CA1 neurons. In other words, the CA3 neurons become more effective at stimulating the post-synaptic CA1 neurons.
The hippocamal synapses at which LTP is thought to occur are excitatory (meaning their activation makes it more likely for the post-synaptic cell to fire an action potential), and use a small neurotransmitter called glutamate. Glutamate is by far the most prevalent excitatory neurotransmitter in the brain, and in most cases activates a mixture of NMDA and AMPA receptors on the surface of the post-synaptic cell. Now, I'm going to try to delve deep into the biology of NMDA receptors (with some hyperlinked help), because they have some quite unique features that are critical for synaptic plasticity (and by extension, learning, knowledge, and humanity).
NMDA receptors are ion channels (proteins that span the membrane and conduct specific charged particles into or out of a cell). Because NMDA is at excitatory synapses, it allows positively charged ions (like sodium and potassium) to flow into the neuron. One of the special features of NMDA receptors is they will only conduct these ions under very specific circumstances: 1) glutamate must be present (indicating the activation of an incoming neuron which has released glutamate) and 2) the neuron must already be somewhat "depolarized" (indicating the activation of other synapses from nearby cells; remember that each neuron receives thousands of inputs). Thus, NMDA channels at synapse A will only open if 1) synapse A's presynaptic neuron is activated and 2) the post-synaptic cell is already somewhat activated by activity at synapses B, C, and D. This specificity confers on the receptor the capacity to act as a molecular coincidence detector, only opening when the pre- and post-synaptic cell are activated in unison, e.g. if the synapse is highly active.
When the NMDA channel does open, it allows not only the entrance of sodium (Na+) and potassium (K+), which depolarize the cell, but also of calcium (Ca++). If the NMDA receptors are induced to open repeatedly in a short period of time, the levels of Ca++ in the cell will become high enough that they activate specific biochemical pathways. First, in the "early phase," the pathways lead to an increase of functional AMPA receptors (the other major kind of glutamate receptor, which cause activation of the post-synaptic cell but does not conduct calcium, nor act as a coincidence detector) on the post-synaptic cell, which means that when a certain amount of glutamate is released into the synapse, it will have a stronger effect because there are more receptors for it to act upon. However, this potentiation is short-lived unless other changes take place.
Persistently high calcium levels will eventually lead to "late phase" LTP, which involves changes in the expression of certain genes (i.e. the rate at which certain proteins are produced). This results in enduring changes such as reshaping the architecture of the dendrite, changing the number of functional receptor proteins, and even building new synapses. A structural change has now ensued, allowing synaptic potentiation to last for days, weeks, months, or even longer.
Thus, the NMDA receptor allows certain synapses--those which are frequently activated--to become more effective. Theoretically, when these changes occur at multiple synapses in a neural circuit, the activity and connectivity of the circuit is modified, thus changing the "internal representation" which the circuit underlies, and generating a "memory." But are these truly the molecular mechanisms of memory, particularly forms of memory relevant to mammalian behavior?
This brings us back to the paper, which intervenes directly with these molecular pathways and then measures the effects on memory. The focus of the study was a protein called cyclin-dependent kinase 5 (Cdk5) (a "kinase" is a protein which attaches a phosphate group (PO4) to a molecule (phosphorylation), a process which significantly alter the molecule's ability to interact with other molecules).
After using sophisticated genetic tools to remove the gene for Cdk5 in adult mice, the experimenters subjected both normal and "mutant" (those lacking Cdk5) mice to a number of well-established memory tests. In the first set of tests, the mice are trained to learn that an aversive stimulus (usually an electrical shock to the feet) is associated with a particular context (e.g. a room) or cue (e.g. a light or tone); these tests are called contextual and cued fear-conditioning, respectively. Once the association in learned, the neutral stimulus alone (the room or the light) is sufficient to elicit a state of fear (usually determined by observing whether the mouse becomes immobile or "freezes").
In another test, the "Morris water maze," a mouse is placed in a circular pool of opaque water (about 4-5 ft in diameter, typically clouded with milk powder or white paint) that contains a platform hidden about 1 cm below the surface. As rodents are highly averse to swimming, they desperately swim around in search of an exit until they find the platform and can "escape." A series of static visual cues are placed around the edge of the pool, which the rodent uses to determine and, after repeated trials, learn the spatial location of the platform. During the course of training, rodents should require progressively less time to find the platform; once learned, the spatial memory should endure after the training has been completed. This ability to remember the location of the platform depends on the hippocampus; if the hippocampus is damaged, the animals never learn the task.
After a bit more probing, the group found evidence showing that Cdk5, by phosphorylating NR2B-containing NMDA receptors, was leading to the degradation of the receptor. Consequently, in the absence of Cdk5, levels of this specific class of NMDA receptors were increased, thus significantly affecting learning behavior, possibly through effects on synaptic plasticity.
And thus, by intervening with a molecular pathway, and tracking the effects using well-established memory tasks, this group linked a molecule to memory. Together with the anatomical circuits into which the neurons are embedded, these molecular pathways directly explain the behavior.
One of the main reasons I wanted to devote this post to reductionism is that I realized that in most of my posts on cognitive neuroscience, I more or less treat the brain like a "black box," which I'm worried may mislead people into thinking that the field of neuroscience doesn't know much about how the brain works. While there is an unimaginable amount of information that is yet to be revealed and understood, there is an amazing amount which we do know--so much that the wealth of available knowledge tends to intimidate me from attempting to explain it in a blog (which is why this post is so monstrously long; congratulations to those who have made it this far). As Eric Kandel, James Schwartz, and Thomas Jessell announce in their introduction to Principles of Neural Science,
Reference:
Hawasli AH et al "Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation" Nature Neuroscience. Published online 27 May 2007.
Now for some neurobiological background on memory, on the biological changes that occur at synapses when "internal representations" are modified. A key experimental paradigm to understand is called long term potentiation (LTP), which is thought to simulate what happens in the brain during learning. Basically, experimenters take a slice of the hippocampus (a structure with a critical role in declarative learning and memory), and use an electrode to induce strong activity (i.e. a high frequency of action potentials) in a group of neurons located in a specific area of the hippocampus (called CA3). These regions project to neurons in another region (CA1), and connections between these regions are believed to be involved in learning and memory. Moreover, the experimental stimulation is thought to be similar to the kind of stimulation neurons receive during intense activity (e.g. learning), and results in the "potentiation," or strengthening, of the synapses between CA3 and CA1 neurons. In other words, the CA3 neurons become more effective at stimulating the post-synaptic CA1 neurons.
The hippocamal synapses at which LTP is thought to occur are excitatory (meaning their activation makes it more likely for the post-synaptic cell to fire an action potential), and use a small neurotransmitter called glutamate. Glutamate is by far the most prevalent excitatory neurotransmitter in the brain, and in most cases activates a mixture of NMDA and AMPA receptors on the surface of the post-synaptic cell. Now, I'm going to try to delve deep into the biology of NMDA receptors (with some hyperlinked help), because they have some quite unique features that are critical for synaptic plasticity (and by extension, learning, knowledge, and humanity).
NMDA receptors are ion channels (proteins that span the membrane and conduct specific charged particles into or out of a cell). Because NMDA is at excitatory synapses, it allows positively charged ions (like sodium and potassium) to flow into the neuron. One of the special features of NMDA receptors is they will only conduct these ions under very specific circumstances: 1) glutamate must be present (indicating the activation of an incoming neuron which has released glutamate) and 2) the neuron must already be somewhat "depolarized" (indicating the activation of other synapses from nearby cells; remember that each neuron receives thousands of inputs). Thus, NMDA channels at synapse A will only open if 1) synapse A's presynaptic neuron is activated and 2) the post-synaptic cell is already somewhat activated by activity at synapses B, C, and D. This specificity confers on the receptor the capacity to act as a molecular coincidence detector, only opening when the pre- and post-synaptic cell are activated in unison, e.g. if the synapse is highly active.
When the NMDA channel does open, it allows not only the entrance of sodium (Na+) and potassium (K+), which depolarize the cell, but also of calcium (Ca++). If the NMDA receptors are induced to open repeatedly in a short period of time, the levels of Ca++ in the cell will become high enough that they activate specific biochemical pathways. First, in the "early phase," the pathways lead to an increase of functional AMPA receptors (the other major kind of glutamate receptor, which cause activation of the post-synaptic cell but does not conduct calcium, nor act as a coincidence detector) on the post-synaptic cell, which means that when a certain amount of glutamate is released into the synapse, it will have a stronger effect because there are more receptors for it to act upon. However, this potentiation is short-lived unless other changes take place.
Persistently high calcium levels will eventually lead to "late phase" LTP, which involves changes in the expression of certain genes (i.e. the rate at which certain proteins are produced). This results in enduring changes such as reshaping the architecture of the dendrite, changing the number of functional receptor proteins, and even building new synapses. A structural change has now ensued, allowing synaptic potentiation to last for days, weeks, months, or even longer.
Thus, the NMDA receptor allows certain synapses--those which are frequently activated--to become more effective. Theoretically, when these changes occur at multiple synapses in a neural circuit, the activity and connectivity of the circuit is modified, thus changing the "internal representation" which the circuit underlies, and generating a "memory." But are these truly the molecular mechanisms of memory, particularly forms of memory relevant to mammalian behavior?
This brings us back to the paper, which intervenes directly with these molecular pathways and then measures the effects on memory. The focus of the study was a protein called cyclin-dependent kinase 5 (Cdk5) (a "kinase" is a protein which attaches a phosphate group (PO4) to a molecule (phosphorylation), a process which significantly alter the molecule's ability to interact with other molecules).
After using sophisticated genetic tools to remove the gene for Cdk5 in adult mice, the experimenters subjected both normal and "mutant" (those lacking Cdk5) mice to a number of well-established memory tests. In the first set of tests, the mice are trained to learn that an aversive stimulus (usually an electrical shock to the feet) is associated with a particular context (e.g. a room) or cue (e.g. a light or tone); these tests are called contextual and cued fear-conditioning, respectively. Once the association in learned, the neutral stimulus alone (the room or the light) is sufficient to elicit a state of fear (usually determined by observing whether the mouse becomes immobile or "freezes").
In another test, the "Morris water maze," a mouse is placed in a circular pool of opaque water (about 4-5 ft in diameter, typically clouded with milk powder or white paint) that contains a platform hidden about 1 cm below the surface. As rodents are highly averse to swimming, they desperately swim around in search of an exit until they find the platform and can "escape." A series of static visual cues are placed around the edge of the pool, which the rodent uses to determine and, after repeated trials, learn the spatial location of the platform. During the course of training, rodents should require progressively less time to find the platform; once learned, the spatial memory should endure after the training has been completed. This ability to remember the location of the platform depends on the hippocampus; if the hippocampus is damaged, the animals never learn the task.
These tests always seem much more brutal when I explain them like this, although at least they're not as cruel as testing the LD50 of LSD for elephants.Anyways, the experimenters found that mice lacking Cdk5 performed significantly better in both sets of tests, indicating improved hippocampal learning abilities. The group then explored the mechanisms underlying these behavioral changes, and found that LTP was enhanced in the absence of Cdk5. Moreover, the mice had higher numbers of a subset of NMDA receptors--those containing a subunit called NR2B (NMDA Receptor 2B).
After a bit more probing, the group found evidence showing that Cdk5, by phosphorylating NR2B-containing NMDA receptors, was leading to the degradation of the receptor. Consequently, in the absence of Cdk5, levels of this specific class of NMDA receptors were increased, thus significantly affecting learning behavior, possibly through effects on synaptic plasticity.
And thus, by intervening with a molecular pathway, and tracking the effects using well-established memory tasks, this group linked a molecule to memory. Together with the anatomical circuits into which the neurons are embedded, these molecular pathways directly explain the behavior.
One of the main reasons I wanted to devote this post to reductionism is that I realized that in most of my posts on cognitive neuroscience, I more or less treat the brain like a "black box," which I'm worried may mislead people into thinking that the field of neuroscience doesn't know much about how the brain works. While there is an unimaginable amount of information that is yet to be revealed and understood, there is an amazing amount which we do know--so much that the wealth of available knowledge tends to intimidate me from attempting to explain it in a blog (which is why this post is so monstrously long; congratulations to those who have made it this far). As Eric Kandel, James Schwartz, and Thomas Jessell announce in their introduction to Principles of Neural Science,
"Neural science is attempting to link molecules to mind--how proteins responsible for the activities of individual nerve cells are related to the complexities of neural processes. Today it is possible to link the molecular dynamics of individual nerve cells to representations of perceptual and motor acts in the brain and to relate these internal mechanisms to observable behavior."Again, I do not believe that molecular mechanisms can alone explain cognition. I would certainly never be satisfied by saying that memory arises from the activity of NMDA receptors and calcium signaling, but these molecular processes are essential for understanding the larger phenomenon, and I thought it was time I showed them their due respect.
Reference:
Hawasli AH et al "Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation" Nature Neuroscience. Published online 27 May 2007.
Subscribe to:
Posts (Atom)
