Show:
Bipolar Disorder
Molecular Neurobiology
Methods
Tests
Results
100
What is a manic episode?
A period of elevated, euphoric or irritable mood
100
Of all the proteins known to be involved in regulating circadian rhythms, which is viewed as the central regulator?
Glycogen synthase kinase-3 B (GSK3B)
100
What is the "sucrose preference task"?
Used to test for depression and the effects on antidepressants on rodents. It gives the rodent a choice of water or sugar water, because by nature, rodents have an affinity for sweetness. This test screens for anhedonia by observing and recording a depressed rodents' likelihood to choose the sweet water over the regular water.
100
What does "hyperhedonic" state mean?
Very active self-gratification, highly aroused state of pleasure seeking
100
Which of the mice were less anxious or fearful? CLOCK mutants or wild-type?
CLOCK mutants
200
What are the two MAIN factors (or symptoms) that underlie bipolar disorder?
Depression and mania
200
What is the name of CLOCK's "binding partner" that has also been associated with bipolar disorder
BMAL1
200
What is the specific genetic manipulation to generate a CLOCK mutant mouse?
The mutation in these mice was created through N-ethyl-N-nitrosourea mutagenesis
200
Why do you think the researchers measured sucrose preference (shown in Fig 1d) as well as ICSS behavior?
The sucrose preference test was longitudinal measuring reward and behavior over a much longer period of time than the other tests relying on ICSS stimulation.
200
Anti-depressants have been shown to increase CLOCK expression in which region of the brain?
Hippocampus
300
One difference between depression and bipolar disorder?
No manic episodes in depression and anti-depressants are not used to treat bipolar patients
300
What method did the authors use to deliver a functional CLOCK protein directly to the VTA of adult Clock mutant mice?
Viral-mediated gene transfer
300
Explain what intracranial self-stimulation (ICSS) is
ICSS is a test in which rodents administer rewarding electrical stimulation through electrodes implanted into the brain
300
Explain the “cracker test” and what results were yielded between WT and CLOCK mutant mice?
The time to approach and eat a cracker in the presence of an aversive stimulus was measured for CLOCK mutant and WT mice. Mutant mice took less time indicating that they were less fearful.
300
How did the CLOCK mutant mice perform on the open field and elevated plus maze tasks as compared to wild-type mice?
In the elevated plus maze, the CLOCK mutant mice had more number of entries into the open ended arms of the maze than the WT mice, showing that they had less anxiety. As for the open field test, the CLOCK mutant mice spent more time in the center of the box as compared to WT mice.
400
Which symptoms of BPD might be particularly hard to model in nonhuman animals?
Manic episodes, mood changes, specific depressive states
400
State the hypothesis that the researchers of this study formed based on the knowledge that VTA neurons are active in CLOCK mutant mice
They hypothesized that although CLOCK is expressed throughout the brain, its loss from the VTA per se contributes to the manic-like state seen in the Clock mutant mice.
400
What is the difference between the ICSS threshold (shown in Fig 1b) and the rate of ICSS (shown in Fig 1c)?
The ICSS threshold is the level of ICSS beyond which mice show evidence of increased rewarding activity, it is a variable that can be raised or lowered (cocaine lowers it for example). The rate of ICSS is the frequency or intensity of rewarding activity engaged in by the mice, this is also a variable and therefore a focus of analysis.
400
Which conditions produced a genotype difference in the latency to eat a cracker (shown in Fig 2d)?
The presence of an aversive stimulus (bobcat urine)
400
How did the CLOCK mutant perform on the forced swim and learned helplessness task as compared to wild-type mice?
The CLOCK mutant mice started swimming earlier than the WT mice did in the FST. The CLOCK mutant mice also had fewer failures to get out of a confined space than the WT mice did.
500
Give an example of evidence that BPD is marked by disruptions in circadian rhythms, as mentioned in the article
1) Appearance of mania can cycle with a regular, even seasonal, pattern, further suggesting a circadian component to its pathology 2) Normalization of both sleep/wake cycles and social zeitgebers often is essential for mood stabilization, while disruptions in these rhythms can trigger manic episodes 3) Some successful treatments for mood disorders rely on altering the circadian cycle 4) Depression symptoms are also diurnal, being more prevalent during the winter months and in parts of the world that receive little sunlight for extended periods of time
500
What was previously known about activity in the VTA neurons of CLOCK mutant mice?
That CLOCK mutant animals display an increase in dopamine cell firing and bursting in the VTA, a critical component of the brain’s reward pathways
500
Explain how the open field and elevated plus maze tests work. What is the dependent variable measured in the open field test? What about the elevated plus maze?
-Both test for anxiety -Open field: Method for recording and scoring the general activity of an animal in a large, barren chamber -Elevated plus maze: An apparatus for recording defensiveness or anxiety in rats by assessing their tendency to avoid the two open arms of plus-sign shaped maze mounted some distance above the floor -Dependent variable: Both tests measure the amount of time spent in an anxiety-provoking space, such as the middle of an open field or unprotected arm of a raised platform
500
Explain how the Porsolt forced swim test and learned helplessness tasks work. What is the dependent variable measured in the forced swim test? What about the learned helplessness test?
- Both measure depression - In the FST: The DV was the time the mice were immobile, i.e. before they started to swim. This time was lower for the CLOCK mutant mice. - In learned helplessness: The DV was the number of times the mouse tried to get out of a confined space but could not. CLOCK mutant mice displayed fewer such times as compared to the WT.
500
How did administration of cocaine affect ICSS behavior in the wild-type mice? How about the mutant mice? (The results are shown in Fig 1b and 1c). How were the effects of cocaine different across the 2 genotypes?
- Both genotypes decreased ICSS thresholds as a result of administration of cocaine, however the decrease was observed at a lower dose of cocaine for the CLOCK mutant mice than was the case for the WT mice.