Brainier Mouse (Quiz 3) Flashcards
1
Q
How many neurons/nerve cells does the human brain have?
A
Approximately 100 billion
2
Q
What are neurons?
A
Nerve cells linked in networks to give rise to a variety of mental and cognitive attributes
3
Q
When were the foundations of understanding the molecular and genetic mechanisms of learning and memory made?
A
In 1949 with Canadian psychologist Donald O. Hebb
4
Q
Who is Donald O. Hebb?
A
Canadian psychologist who came up with a simple idea to explain how memory is represented and stored in the brain.
5
Q
What is Hebb’s learning rule?
A
A memory is produced when two connected neurons are active simultaneously in a way that strengthens the synapse. At a synapse, information in the form of neurotransmitters flows from the presynaptic cell to the post synaptic cell.
6
Q
What is the synapse?
A
The site where two nerve cells touch each other
7
Q
What happens at the synapse?
A
Neurotransmitters flow from presynaptic to postsynaptic cell
8
Q
What are neurotransmitters?
A
Chemicals that provide information
9
Q
What are the names of the two nerve cells (neurons) that are connected to each other over a synapse?
A
Presynaptic and postsynaptic cell
10
Q
What is the hippocampus?
A
A sea horse-shaped region of the brain from the Greek for “horse-headed sea monster.” Crucial brain structure for memory formation in both humans and animals.
11
Q
What happens to the nerve cells in the hippocampus when stimulated by a series of high-frequency electrical pulses?
A
The nerve cells become more tightly linked—increase in synaptic strength. (Discovered by Tim VP Bliss and Terje Lomo in University of Oslo)
12
Q
When do nerve cells in the hippocampus become more tightly linked (increase in synaptic strength)?
A
When stimulated by a series of high-frequency electrical pulses. (Discovered by Tim VP Bliss and Terje Lomo in University of Oslo)
13
Q
What is long-term potentiation (LTP)?
A
The increase in synaptic strength in the nerve cells in the hippocampus when stimulated by a series of high-frequency electrical pulses. Can last for hours, days, or weeks
14
Q
What happens when you apply a low-frequency stimulation to the hippocampal pathway?
A
Produces a long-lasting decrease in the strength of connections there
15
Q
What is long-term depression (LTD)?
A
The long-lasting reduction in strength of connections in the hippocampus. Has nothing to do with clinical depression.
16
Q
What are the two terms for increase and decrease in synaptic strength?
A
Long-term potentiation (LTP) and long-term depression (LTD)
17
Q
What are the leading candidate mechanisms for storing and erasing learned information in the brain?
A
The strengthening and weakening of synaptic connections through LTP- and LTD-like processes
18
Q
Do LTP and LTD come in many different forms?
A
Yes.
19
Q
Where does the phenomena of LTP and LTD occur?
A
In many brain regions—hippocampus, neocortex (the “gray matter”), amygdala (structure involved in emotion), etc.
20
Q
What is the neocortex?
A
A brain region known as “gray matter.” LTP and LTD occur here.
21
Q
What is the amygdala?
A
A brain region/structure involved in emotion. LTP and LTD occur here.
22
Q
What does the induction of the major forms of LTP and LTD require?
A
The activation of NMDA receptors, which sit on the cell membranes of postsynaptic neurons.
23
Q
Where are NMDA receptors located?
A
On the cell membranes of postsynaptic neurons
24
Q
What happens when NMDA receptors are activated?
A
The induction of major forms of LTP and LTD
25
What are NMDA receptors?
Minuscule pores most scientists think are made up of four protein subunits that control the entry of calcium ions into neurons (basically, they’re proteins)
26
What does the name of NMDA receptors derive from?
N-methyl-D-aspartate
27
What is N-methyl-D-aspartate?
An artificial chemical that happens to bind to NMDA receptors
28
Why are NMDA receptors perfect candidates for implementing synaptic changes of Hebb’s learning rule?
Because they require 2 separate signals to open: 1. the binding of the neurotransmitter glutamate and 2. an electrical change called membrane depolarization. They are the ideal molecular switches to function as “coincidence detectors” to help the brain associate 2 events.
29
What are “coincidence detectors”?
NMDA receptors—help the brain associate 2 events
30
What did Richard G.M. Morris of University of Edinburgh find when rats’ brains were infused with drugs that block the NMDA receptor?
They cannot learn how to negotiate a test called a Morris water maze as well as other rats.
31
What do the drugs that block the NMDA receptor produce and what does this indicate?
Sensory-motor and behavioral disturbances, indicating the delicate line between drug efficacy and toxicity
32
What are knock-out mice, and what do scientists do with these mice?
Mice in which one gene has been selectively inactivated, or “knocked out.” Lacks a particular gene in every cell and tissue. Scientists study health and behavior of such animals to deduce function of the gene.
33
What is the drawback of knockout mice?
They die at or before birth because the genes they lack are required for normal development
34
What did the author, Joe Tsien, devise to solve the issue of knockout mice?
A way to delete a subunit of the NMDA receptor in only a specific region of the brain.
35
What did Tsien’s mice lack?
A critical part of the NMDA receptor termed the NR1 subunit in a part of their hippocampus known as the CA1 region
36
Why was it convenient that Tsien had knocked out the gene in the CA1 region?
Because that is where most LTP and LTD studies have been conducted and because people with brain damage to that area have memory deficits
37
What did Tsien find about his knockout mice?
They lost the capacity to change the strength of neuronal connections in the CA1 regions of their brains—exhibited abnormal spatial representation and had poor spatial memory: couldn’t remember their way around a water maze. Also show impairment in several other, nonspatial memory tasks
38
Are the experiences with Tsien’s knockout mice conclusive about NMDA receptors being crucial for memory? Why or why not?
No. They only supported it. Could have been that the drugs used to block the receptors could have exerted their effects through other molecules in addition to NMDA receptors and the memory deficits of knockout mice might have been caused by another unexpected abnormality independent of LTP/LTD deficits. SO. Decided to try to increase function of NMDA receptors in mice to see whether an alteration improved animals’ learning and memory
39
How are Doogie mice different from other mice?
They have been genetically engineered to make more than the usual amount of a key subunit of a protein called the N-methyl-D-aspartate (NMDA) receptor
40
What does the NMDA receptor do?
Helps to strengthen the connection between 2 neurons that happen to be active at the same time. There is a theory that such strengthening is the basis for learning and memory.
41
How smart are Doogie mice?
They won’t do differential equations, but they are better than normal mice at distinguishing between objects they have seen before and at recalling how to find a platform in a tank of murky water
42
How does genetic alteration of Doogie mice make them smarter?
NMDA receptors of Doogie mice stay open nearly twice as long as those of normal mice. Extra time helps them form a new memory more effectively
43
Could the same technique be used to enhance people’s ability to learn and remember?
Theoretically possible. But learning and memory in humans are much more complex. Scientific and technical barriers as well as the safety and ethical issues surrounding human genetic engineering need to be addressed. More likely that pharmaceutical companies will first attempt to develop drugs that interact with NMDA receptor to boost memory ability in people with memory deficits.
44
What is the object-recognition task?
To recognize a familiar object over a novel one
45
What is the Morris water maze?
Put a mouse into a circular pool that was 1.2m in diameter and filled with murky water. Placed a nearly invisible, clear Plexiglas platform that was almost as tall as the water was deep so it was hidden beneath the surface. Surrounded the pool with a black shower curtain that had certain landmarks on it (red dot). Mice generally swim around until they find the platform to pull themselves out of the water and rest (they don’t like to get wet)
46
What happened with Doogie mice in the object-recognition task?
Doogie mice were more likely than normal mice to recognize a familiar object over a novel one.
47
What happened with Doogie mice in the Morris water maze?
Doogie mice located submerged platform faster than normal mice. Also, when they took out the platform but kept the landmarks like the red dot, Doogie mice spent more time than normal mice in the quarter of the pool where the platform had been, indicating they remembered where it should be.
48
What did Tsien focus on when increasing the function of NMDA receptors?
Focused on different parts of the NMDA receptor, the NR2A and NR2B subunits
49
What is the difference in NMDA receptors in diverse animals (young vs adults)? What might this difference account for?
Remain open longer in younger individuals than in adults (birds, rodents, primates, etc). This may account for the fact that young animals are usually able to learn more readily and remember what they have learned longer than their older counterparts.
50
What happens to NMDA receptors as individuals mature?
They begin to switch from making NMDA receptors that contain NR2B subunits to those that include NR2A subunits.
51
What have laboratory studies shown about receptors with NR2B vs NR2A subunits?
NR2B subunits stay open longer than those with NR2A. Age-related switch could explain why adults find it harder to learn new information.
52
What did Tsien do to specifically increase NR2B’s (or the gene’s) ability to make the protein in the adult brain?
Took a copy of the gene that directions production of NR2B and linked it to a special piece of DNA that served as an on switch to specifically increase the gene’s ability to make the protein in the adult brain. Injected this gene into fertilized mouse eggs, where it was incorporated into the chromosome and produced genetically modified mice carrying extra copy of NR2B gene.
53
How long could NMDA receptors from genetically engineering mice remain open (for increasing NMDA function)?
Open for roughly 230 milliseconds, almost twice as long as those of normal mice.
54
What did Tsien find about neurons in the hippocampi of adult mice when increasing NR2B in the adult brain?
Neurons in hippocampi of adult mice were capable of making stronger synaptic connections that those of normal mice of the same age. Their connections resembled those in juvenile mice.
55
What is the main concept of making a dumb mouse?
Remove part of a key receptor from its brain
56
What is the main concept of making a smart mouse?
Add an extra copy of part of a key receptor to its brain
57
What are the specific steps to making a dumb mouse?
1. Breed 2 mice. Gene for NMDA receptor subunit NR1 flanked by “cut” sites called LoxP. Gene for Cre enzyme attached to an on switch that operates only in the brain. 2. Birth: offspring mouse has both genes (LoxP, NR1, LoxP, Cre on DNA). 3. Cre enzyme, which is made only in the CA1 region of the hippocampus, binds to LoxP sites and splices out the NR1 gene and one LoxP site. 4. Conditional knockout mouse lacks NR1 gene in CA1 but has gene elsewhere in body.
58
What are the specific steps to making a smart mouse?
1. Isolate fertilized egg (nucleus from egg and from sperm). 2. Microinject gene encoding NMDA receptor subunit NR2B into either nucleus (brain specific on switch and gene for NMDA receptor subunit NR2B attached on DNA). 3. Allow fertilized egg to divide. 4. Introduce several embryos produced this way into a female mouse. 5. Birth: only some offspring carry the introduced gene. 6. Doogie mouse: NR2B gene active only in brain.
59
What can link two events in time (a prerequisite for laying down a memory)?
NMDA receptors because they open only when they receive 2 signals.
60
What 2 signals do NMDA receptors need to open?
1. Binding of glutamate released by presynaptic cell; 2. Electrical stimulation by input from another neuron that expels magnesium from the channel of the receptor.
61
What in the NMDA receptors strengthens the synapse?
The inrush of calcium actives biochemical cascades that eventually strengthen the synapse.
62
T or F: Genetically modified smart mice remembered objects 2-3 times longer than their normal counterparts did.
F. 4-5 times longer
63
What did Tang and Tsien find when they tested the ability of mice to learn to associate a mild shock to their paws with being in a particular type of chamber or hearing a certain tone?
Found that the Doogie mice were more likely to “freeze”—indication they remembered fear—than were normal mice when they returned the animals to the chamber or placed them the tone several days later. Suggested Doogie mice had better memory
64
What is the difference between learning and memory?
They represent different stages of the same gradual and continuous process whose steps are often not easy to distinguish.
65
What is fear-extinction learning?
A classic behavioral experimental paradigm
66
What did Tang and Tsien do in the fear-extinction learning of smart mice?
Conditioned mice in a shock chamber then placed animals back into fear-causing environment—but without the paw shocks—again and again. Most animals take 5 or so repetitions to unlearn link between being in shock chamber and receiving shock. Doogie mice learned to be unafraid after only 2 repetitions, also learned not to fear tone faster than normal mice.
67
What kinds of skills does the Morris water maze involve?
Cognitive factors, including analytical skills, learning and memory, and the ability to form strategies
68
What are the implications of the experiments with the Doogie mice (Hebb’s, suggestion)?
Bore out predictions of Hebb’s rule; suggested NMDA receptor is a molecular master switch for many forms of learning and memory
69
Do these findings mean we will soon be able to genetically engineer smarter children or devise “genius” pills?
No. Intelligence is a complex trait that involves many factors (reasoning, analytical skills, ability to generalize previously learned information).
70
Does the central role of NMDA receptors imply it is the only molecule involved in learning and memory?
No. Probably many molecules to be identified in the following years.
71
What do the various kinds of intelligence mean for enhancement?
Type and degree of enhancement must be highly dependent on nature of learning and memory skills involved in a particular task. (i.e. mice will never be able to play piano but may have easier time finding food)
72
What may NR2B be for the future?
A new drug target for treating various age-related memory disorders
73
What would be an immediate application of NR2B?
To search for chemicals that would improve memory by boosting activity or amount of NR2B molecules in patients who have healthy bodies but whose brains have begun to be ravaged by dementia during aging——boost memory function of the remaining healthy neurons by modulating and enhancing the cells’ NR2B activity
74
In applying NR2B to humans, what will need to be considered? What have the results been so far?
Possible side effects of such drugs. Increased NR2B activity in Doogie mice did not appear to cause toxicity, seizures, or strokes
75
Why has nature arranged for the amount of NR2B to taper off with age?
Possibly that the switch from NR2B to NR2A prevents brain’s memory capacity from becoming overloaded. Tsien favors that the decrease is evolutionarily adaptive for populations because it reduces likelihood that older individuals—who presumable have already reproduced—will compete successfully against younger ones for resources such as food.
76
What is the implications of the idea that natural selection doesn’t foster optimum learning and memory ability in adult organisms?
Genetically modifying mental and cognitive attributes such as learning and memory can open an entirely new way for targeted genetic evolution of biology and perhaps civilization with unprecedented speed.
77
What are the different tests Tsien and Tang did to test smart mice?
Behavioral tests. Tested remembering seeing objects (if seen, they’d focus on the unseen), ability to learn to associate shock with being in a chamber or hearing a certain tone, fear-extinction test (fear in chamber —\> unlearn link between chamber and receiving a shock), Morris water maze
78
What two people have teamed up to form a company based on the discovery of Doogie mice?
Joe Z. Tsien of Princeton University and Charles Hsu, venture capitalist
79
What is the company of Tsien called, and where is it located?
Eureka Pharmaceuticals in Hsu’s office at Walden Group in San Francisco
80
What is Eureka Pharmaceuticals first order of business?
To use gene technology called genomics to identify molecules that are potential targets for drugs to treat central nervous system disorders such as memory loss and dementia. 1st target: the NMDA receptor
81
What have several pharmaceutical companies tested as possible stroke drugs?
Various compounds that decrease activity of NMDA receptors because when brain is starved of blood, nerve cells can release too much glutamate, a chemical cells use to communicate. In excitoxicity, excess glutamate binds to NMDA receptors on other nerve cells, allowing tons of calcium to flood into other cells. Together with a lack of oxygen, this causes cells to die.
82
What is glutamate?
A chemical cells use to communicate
83
What is excitoxicity?
Excess glutamate binds to NMDA receptors on other nerve cells, allowing calcium to flood into other cells.
84
Has the search for NMDA-receptor blockers been successful as stroke drugs?
No. Very disappointing.
85
What is the problem with searching for NMDA-receptor blockers as stroke drugs?
Problem is finding a chemical that binds to precisely the right spot on the NMDA receptor and in just the right way without causing other neurological effects (phencyclidine PCP or angel dust also binds to the receptor—illicit hallucinogenic drug)
86
What is the more likely scenario since scientists’ enthusiasm for developing drugs that might boost learning and memory by activating the receptor has been blunted?
Developing drugs that subtly modulate the activity of NMDA receptor without binding to it directly
87
What is brain-derived neurotrophic factor (BDNF)?
A naturally occurring chemical that increases the likelihood that parts of the NMDA receptor will have a phosphate group tacked onto them as NMDA receptors with phosphate groups are more likely to be active than those without such groups.
88
Label.
