Saturday, December 03, 2005
Changes in AMPA subunit expression in the mouse brain after chronic treatment with the antidepressant maprotiline: a link between noradrenergic and glutamatergic function?
Tan CH, He X, Yang J, Ong WY.
Department of Pharmacology, National University of Singapore, 119260, Singapore, Singapore.
Potentiation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function has been proposed as being useful in the treatment of depression, but thus far, little is known about the possible changes in AMPA receptor expression in the brain, after antidepressant treatment. The present study was carried out to study the expression of AMPA receptor subunits in different brain regions of mice that had been chronically injected with maprotiline. The latter is a modified tricyclic antidepressant that functions as a noradrenaline uptake inhibitor. Daily intraperitoneal injection with 10 mg/kg maprotiline for 30 days resulted in significantly increased GluR1 and GluR2/3 subunit expression in the nucleus accumbens and dorsal striatum as detected by immunohistochemistry; and significantly increased GluR1 and GluR2/3 expression in the hippocampus, as demonstrated by Western blot analysis. No change, or a decrease in GluR2 expression was detected in all the brain regions by both immunohistochemistry and Western blots. The increase in GluR1 and GluR2/3, but no increase in GluR2 subunits suggests that there could be an increase in calcium permeability of AMPA receptors in limbic/striatal brain regions after maprotiline treatment. This could lead to increased synaptic activity or plasticity in the hippocampus and striatum, and may underlie the therapeutic effect of maprotline, and possibly, other antidepressant drugs.
Monday, September 13, 2004
We may suspect but we do not know that LTP forms the neural basis of learning for any task in any animal. But perhaps a sub-Galilean murmur may be forgiven in this anniversary year: surely, it must. Tim Bliss
Monday, November 17, 2003
Notes on Presentation
1. Black background, white Ariel font with keywords in pastel colours.
2. Picture on front page.
3. Lots of figs. Give Dorsal|_Ventral on anatomical figs. repeat pics with different manipulations (film effect).
4. "The Plan (Following the Bergman & Zoghbi mandates): 1. Motion perception & area MT. 2. Neural correlates of decision-making. 3. A challenge."
4. "Behaviour, behaviour, behaviour."
5. "Necessary, sufficient, causality."
6. "Now you might argue (--> counter argument). This is a critical point of logic."
7. "A hallmark signature of a decision-making structure should be ..."
Notes from Neuroscience 2003
1. Feedback on Poster:
a. Important to show whether there are GluR-C subunits in the basolateral amygdala. If there are no GluR-C subunits there, the LTP data is not relevant.
b. It makes perhaps more sense to leave the basolateral amygdala out of the initial paper. It would be good to include the thalamic afferents to the LA, though.
c. Fear conditioning is necessary and sufficient for publication. If there is a GluR-C-deficit in fear conditioning, that might warrant independent publication.
d. Would be interesting to look at a theta protocol a la Hoffman in the LA.
e. Extinction is BLA dependent, so could be interesting behavioural measure.
2. Wood has made a circular T-maze (see below). Might be what we want for the in vivo recordings. Spoke to Emma and she said I could visit the Edinburgh lab in January to see how they run the maze. We could be build two mazes, one for Heidelberg in vivo recordings and one for Oxford for lesion studies ++.
3. Jia has looked at synaptic function in GluR-C mice (see below). Not so interesting. They took notes from our poster.
4. Meeting with Andreas Luthi and Vidar Jensen: GluR-A and GluR-C mice have impaired cortical and thalamic LTP in the LA. This confirms the Oslo data. He is ready to publish. Wants to do lots more with the GluR-Cs in the new year. We had a great meeting and decided to leave planning to Rolf.
5. Meeting with Andy Mead (who published on the GluR-As last year): With his paradigm of conditional reward, the GluR-As are impaired. Cytotoxic lesions of the BLA in the rat impairs this (Everitt..). So the prediction would be that the GluR-Cs would be able to solve a task that relied on conditional reward (CS+ = tone previously paired with food reward). This would need to be validated with BLA lesions in the mouse. Andy is joining Merck in January 2004 and so his research on this will dry up.
Synaptic function and seizure tolerance in GlurR3 knockout mice.
Y.Meng; M.Cortez; C.Snead; Y.Zhang; J.Meng; Z.Jia*
1. Brain and Behavior, The Hosp. for Sick Children, 2. Dept. of Physiology, Univ. of Toronto, Toronto, ON, Canada,
AMPA glutamate receptors are the principal mediators of the fast excitatory synaptic transmission and they are important for synaptic changes involved in normal physiological as well as pathological processes, including long term potentiation (LTP) and epilepsy. AMPA receptors are heteromeric complexes composed of a combination of four distinct subunits (GluR1-4 or GluRA-D), with a vast majority of the receptors being assemblies of GluR1/2 or GluR2/3. While GluR1 and GluR2 are studied extensively, little is known about the function of GluR3. To address the in vivo role of GluR3, we conducted a series of experiments using knockout mice deficient in the expression of GluR3. We show that the GluR3 knockout mice are altered in several aspects of synaptic regulation, including hippocampal LTP. In addition, the knockout mice exhibited alterations in electrocortical responses and susceptibility in seizure generation. These results demonstrate a role for GluR3 in synaptic regulation and epileptogenesis.
Support Contributed By: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and Hospital for Sick Children Foundation.
Citation: Y.Meng, M.Cortez, C.Snead, Y.Zhang, J.Meng, Z.Jia. Synaptic function and seizure tolerance in GlurR3 knockout mice.. Program No. 894.2. 2003 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience
Excitotoxic lesions of the hippocampus impair performance on a continuous alternation T - maze task with short delays but not with NO delay.
Div. Neurosci, Univ. Edinburgh, Edinburgh, United Kingdom
Damage to the rodent hippocampus produces deficits on spatial memory tasks such as the discrete-trial T-maze alternation task (Aggleton et al., 1986). In a sample phase, animals are given access to one arm of the T-maze. This is followed, after a delay, by a choice phase in which both arms are open; animals are rewarded for entering the previously blocked arm. In a recent study, a continuous version of the task was used to examine hippocampal CA1 pyramidal cell activity in rats during T-maze alternation (Wood et al., 2000). The T-maze was modified so that the ends of the goal arms were connected to the base of the central stem. No delay was interposed between successive trials - rather, the rats ran in a continuous "figure-of-8" pattern. Cells with place fields on the central stem of the maze showed differential firing depending on whether the rat was performing a right-turn or left-turn trial. This differential neural activity provides a potential mechanism by which the hippocampus might contribute to solving spatial alternation tasks. However, one question that remains is whether this continuous version of the T-maze is hippocampal-dependent. To test this, hippocampal-lesioned and sham-operated rats were trained on the continuous T-maze task with no delay between the 40 daily trials. The number of days taken to reach criterion (90% correct alternation on 8/10 consecutive days) did not differ between groups. However, when a delay of 10s between trials was introduced by confining the rats to the base of the central stem using moveable barriers, the lesioned rats were significantly impaired compared to shams. Thus, the hippocampus appeared necessary only if a delay was introduced and the animals forced to pause between trials. Ongoing experiments are examining how introducing a delay affects the differential activity of CA1 pyramidal cells seen during the continuous task.
Support Contributed By: BBSRC
Citation: J.A.Ainge, E.R.Wood. Excitotoxic lesions of the hippocampus impair performance on a continuous alternation T - maze task with short delays but not with NO delay.. Program No. 91.1. 2003 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience
Tuesday, October 28, 2003
Oivind on amygdala AP5 story: could be because calcium entry is provided by other receptor subtypes (A alone or C alone) In the spinal cord there are no GluRBs so Ca2+ is provided through A/C receptors. In addition, calcium (im-?) permeable GluRB mice have 30% LTP with AP5 in the hippocampus. Calcium entry could also be provided through voltage-dependent channels (L-type?).
Sunday, October 26, 2003
Wanted to ask your advice on something. I have been thinking about additional amygdala-dependent tasks that we might want to put the mutants through. The task that might be quite interesting to have a look at is the Conditioned Taste Aversion, for a number of reasons:
1. CTA is impaired by electrolytic amygdala lesions (Dunn and Everitt, 1988).
2. CTA acquisition is impaired after intra-amygdalar injection of AP5 (Aguado et al, 1994).
3. CTA is impaired by injection of CREB antisense (Lamprecht et al, 1997).
4. CTA is impaired by injection of MAP kinase inhibitor ICag (Berman et al 1998).
5. CTA is impaired by mGluR7 ablation (Masugi et al 1999).
6. CTA expression is impaired after intra-amygdalar injection of 0.5 ul CNQX (Yasoshima et al 2000).
7. CTA learning is followed by MAP kinase phosphorylation in the amygdala (Swank 2000).
8. CTA is impaired in PKA (RIIbeta) mutants, that selectively express the deletion in the basolateral amygdala (Koh et al, 2003).
9. CTA is not affected by aspiration lesions of the prefrontal cortex or the cingulate gyrus (Fresquet et al 2003).
In addition, very few studies have included LTP recordings alongside CTA and CTA deficits are often accompanied by deficits in cue-conditioning or hyponeophagia, which is the cas in the GluRA-/- mice.
The hypothesis might be that an LTP-deficit in the BLA, as is the case in the GluRA-/- mice, would impair CTA learning. On the other hand, an LTP-deficit in the LA, as is the case in the GluRC-/- mice, might not impair CTA.
To test this I was thinking to test the As and the Cs who are due to go to Cardiff for CTA here in Oxford (unless you have a CTA protocol up and running in Cardiff already).
So I had two specific questions:
There seems to be some conflicting evidence for self-administration (bottles) or intraoral administration (cannula) (Yamamoto et al 2002), do you know which procedure is the preferred one (most amygdala-dependent) for mice?
Also, do you think it is a problem if the animals that are supposed to be tested for fear-conditioning in Cardiff does a LiCl CTA here in Oxford before they go? If it doesn't matter much if they get shock or nausea first, I would prefer to do the CTA as soon as possible (before New Orleans), since I could then include it on the poster and in the thesis.
Sorry about the long email, look forward to hear what you think.
Thursday, October 09, 2003
Huganir: Phosphorylation of GluR1 is required for LTP and spatial memory. CamKII, activated by NMDA stimulation, phosphorylates the amino acid Serine 845.
Thursday, August 28, 2003
Notes from Elke
GluR-D may be responsible for inserting B in cells in the adult animal (Zhu 2000, see also comment by Carroll and Malenka 2000). GluR-D is not found in the adult on principal cells, rather they form synapses on ihibitory GABA-ergic interneurons. Found in CA1 and also perhaps in the amygdala. The GluR-D KO has not been published yet. It may be interesting to do amygdala field-recordings and fear conditioning in the GluR-Ds. The hypothesis would be that they have increased LTP and perhaps increased levels of fear conditioning due to a lack of inhibition (similar to the Bolshakov's GRP KO, Shumyatsky 2002).
Friday, August 08, 2003
From Cohen & Eichenbaum, 2001
This chapter focuses on a candidate mechanism underlying memory and learning known as long/term potentiation (LTP). The chapter will first describe the historical background for current research and then evaluate in more detail the molecular and genetic approaches to the study of learning and memory. LTP was first discovered by Terje Lomo in the laboratory of Per Andersen at the University of Oslo. In 1972, Lomo together with Tim Bliss reported that in the rabbit hippocampal slice, repeated stimulations of afferent fibers resulted in an increase in magnitude of the responsiveness of the post-synaptic cell. Repetitive high-frequency electrical stimulation of cells projecting from the entorhinal cortex to the dentate gyrus resulted in an increased rise time (slope) of the excitatory synaptic potential (to a subsequent single pulse) of a dentate granule cell. In addition, they observed an increase in the population spike due to the recruitment of spike activity from a greater number of dentate cells (for review see Bliss and Lynch, 1988). The key feature of this phenomenon was that it lasted for several hours after the initial stimulation. In subsequent decades, considerable interest in LTP has been generated, not least because it provides a plausible mechanism for medium- to long-term memory storage.
Morris (1989) has described five fundamental properties that make LTP such a compelling/promising model of memory. First, LTP is found in the hippocampus, a brain structure widely accepted to be necessary for memory formation. Work from lesion studies (both natural and artificial) has long emphasised the central role of the hippocampus in memory. Second, LTP develops rapidly, a further necessary feature of a plausible memory mechanism. Third, it persists over time. LTP has been shown to last for weeks or more in in vivo preparations. Fourth, the effects of stimulation is synapse specific. Only those synapses that are activated during the initial stimulation are potentiated. Lastly, LTP possesses the feature of associativity described originally by Hebb (1949). In order to make a hippocampal neuron fire, at least 100 synapses need to be active simultaneously (Andersen & Trommold, 1995). Together, these properties make up the necessary requirements for LTP to be a model for memory.
However, the five features of LTP as described by Morris are not sufficient to LTP to a meaningful cellular model of memory. What is required is a specific correlation between LTP and memory as observed in the wake behaving animal. As the majority of LTP studies are conducted in the hippocampal slice preparation, this has proven a difficult condition to meet. Only recently, with the emergence of better in vivo techniques and more sophisticated imaging methods, has it become possible to study cellular changes directly as an animal learns a task or navigates an environment.
LTP has also been observed in non-hippocampal stuctures in the brain. Both the visual and motor cortices exhibit LTP ...
Induction/expression of LTP ...
The molecular mechanism that underlies LTP induction in CA1 is thought to involve a combination of specific synaptic events involving the neurotransmitter glutamate. Glutamate receptors are defined functionally into three classes, AMPA, NMDA and quisqualate/kainate receptors. Whereas AMPA receptors are believed to mediate normal synaptic transmission in the hippocampus, NMDA receptors are required for all types of LTP. AP5, a pharmacological NMDA antagonist, blocks LTP following high-frequency stimulation trains. AMPA and NMDA receptors also differ in their regulation of post-synaptic ion permeability. Activation of NMDA receptors increases the permeability of the cell to calcium (Ca++), potassium (K+) and sodium (Na+) ions. In contrast, activation of AMPA receptors increases the permeability to potassium (K+) and sodium (Na+) ions, but not to calcium (Ca++) ions.
Friday, June 27, 2003
What we could do of course, would be to lesion the mPFC in the GluR-A and test them on DRL-10. If the lesioned GluR-A mice are impaired, it would support Raymond Kesner's view that very short retention is mPFC-dependent.
We know that the spatial working memory deficit on the rewarded alternation on the T-maze is not frontal, because frontal lesions do not impair T-maze performance.
Thursday, June 19, 2003
good adjectives for science writing: compelling, valuable, striking, specific, controversial, notable.
Friday, May 16, 2003
The LeDoux people believe that the NR2B subunit is critical for integrating CS-US pairing in the LA during fear conditioning. Might well be worth it to test the NR2B transgenics for amygdalar plasticity in Oslo. See Blair et al, 2001.
Monday, May 12, 2003
From Risbrough et al, 2003
Mice are increasingly being used to further examine neural mechanisms underlying complex behaviors through the advent of transgenic technology (eg Gingrich and Hen, 2001). The FPS model in mice may offer substantial benefits in characterizing the mechanisms subserving the acquisition and expression of behaviors related to fear and anxiety. First, the FPS model, unlike typical conflict models of negative affective states, does not measure complex behavior that is modulated by competing drives. Thus, the FPS model may offer enhanced specificity of the interpretation of experimental manipulations without possible motivational (eg Vogel test), approach/avoidance, or locomotor activity confounds (eg elevated plus maze and open field) (Shekhar et al, 2001). This aspect of the FPS model is particularly important when using transgenic mice to describe effects of genes on anxiety-related behaviors, as subtle changes in locomotor activity or approach behavior could confound any putative 'anxiety' phenotype (Dulawa et al, 1999). Second, the model in mice could be used to further characterize the involvement of specific components in the acquisition of fear-related behaviors (eg CREB, Falls et al, 2000) as well as uncover new molecules and mechanisms involved in the expression and extinction of learned fear. Through the work of the Falls laboratory, FPS has been initially characterized in mice and has been shown to be amygdala dependent (Heldt et al, 2000). The next important step is to show that mouse FPS has similar underlying neurochemical systems to human anxiety, that is, shows predictive validity for identifying anxiolytic compounds.
Friday, May 02, 2003
Notes from Third Annual Meeting, Norway
1. GluRA and GluRB often co-locate.
2. It is possible that the GlurCs have Ca permeable GluRA subunits, which could explain why AP5 does not totally block LTP in the amygdala.
3. If the dentate projects to CA1, then how can the NR1-DG-KO have normal LTP in CA1 yet no LTP in the dentate? Is there an extra-DG afferent fiber tract to CA1?
4. Moral of the juvenile LTP story: GluRA-dendency increases with age.
Post-doc application: Finally we have a unique opportunity to investigate for the first time the effects of genetic manipulations in vivo.
Thursday, April 24, 2003
GluR-A-/- mice with conditional B-subunit deletion at P20 have about 20% potentiation in CA1. This level of LTP is similar to that found in the GluR-A-/- at P14, the so-called juvenile form of LTP. The presence of LTP in the AB double knockout may be due to this immature form of LTP, which might persist in these animals. The existence of LTP in CA1 at several months of age might be due to the lack of B-subunits from adolescence. From P40-60 these double-knockouts only use the C-subunit to allow current influx into the cell.
It is interesting to note that the AB double knockouts do not show PTP, which seems to require an A subunit. Furthermore, CA1 LTP in these animals is AP5 sensitive, just as is the case in P14 GluR-A-/- mice.
It would be interesting to test these animals on the T-Maze. A negative result on the T-Maze (that they are similar to the GluR-A-/- mice and thus cannot do rewarded alternation) would mean that juvenile LTP might be unrelated to working memory. It would also strengthen the hypothesis that the A subunit is required for spatial working memory.
On the other hand, a positive result on the T-Maze (that they can do rewarded alternation) would suggest that the A-subunit is necessary for spatial working memory. That would of course be even more interesting as it would mean that deletion of the B-subunit rescues the T-Maze deficit found in normal GluR-A-/- mice.
In the case of such a correlation it would provide further strengthening proof of the LTP hypothesis.
Tuesday, April 01, 2003
Sheena Josselyn's coordinates for electrolytic lesions (12 s of 1 mA) of the amygdala:
1) AP= -1.3, ML=+/-3.0 and DV 4.8
2) AP= - 1.7, ML = +/- 3.3 and DV = -4.8
Thursday, March 20, 2003
Sunday, March 02, 2003
Nick suggests one-way passive avoidance as a measure of fear learning in the GluR-C KOs. Also elevated plus maze, light dark box, successive alleys, and possibly shuttle-box avoidance (which we don`t currently have).
With regard to the NR1-DG-KOs and their selective LTP impairment on T-Maze, see Chapman 1999.
Tuesday, February 25, 2003
Monday, February 24, 2003
now huerta et al (2000) says that trace fear conditioning requires NMDA receptors in CA1. They base this on the fact that NR1-CA1-KO mice cannot learn a trace fear conditioning paradigm when the CS and the US are separated by 30s. This seems like a eminently relevant test, both for GluR1-KO and NR1-DG-KO.
list for medline search: glur1, ltp, amygdala mice, hippocampus mice, working memory, fear conditioning, nr1.
lynch and baudry (1984) proposed almost two decades ago that LTP is due to an increase in the number of synaptic glutamate receptors. at least according to the famous review paper by malinow and malenka (2002).
Monday, February 17, 2003
check out simon killcross on amygdala-dependent action-outcome contingency learning.
there are reciprocal connections between the basolateral amygdala and the orbito-frontal cortex. might underlie learning about expected outcomes. see schoenbaum, 1998.
Thursday, February 13, 2003
If fear conditioning is normal in the GluR-A-/- mice, why not try the Resident-Intruder Model of Aggression. Amygdala-dependent according to Demas et al, JNeurosci 1999.
Thursday, October 31, 2002
The long-term benefits of human generosity in indirect reciprocity
Wedekind C, Braithwaite VA.
Institute of Cell, Animal, and Population Biology, University of Edinburgh, West Mains Road, Scotland, United Kingdom. firstname.lastname@example.org
Among the theories that have been proposed to explain the evolution of altruism are direct reciprocity and indirect reciprocity. The idea of the latter is that helping someone or refusing to do so has an impact on one's reputation within a group. This reputation is constantly assessed and reassessed by others and is taken into account by them in future social interactions. Generosity in indirect reciprocity can evolve if and only if it eventually leads to a net benefit in the long term. Here, we show that this key assumption is met. We let 114 students play for money in an indirect and a subsequent direct reciprocity game. We found that although being generous, i.e., giving something of value to others, had the obvious short-term costs, it paid in the long run because it builds up a reputation that is rewarded by third parties (who thereby themselves increase their reputation). A reputation of being generous also provided an advantage in the subsequent direct reciprocity game, probably because it builds up trust that can lead to more stable cooperation.
Monday, October 21, 2002
Although ANOVA is an extension of the two group comparison embodied in the t-test, understanding ANOVA requires some shift in logic. In the t-test, if we wanted to know if there was a significant difference between two groups we merely subtracted the two means from each other and divided by the measure of random error (standard error). But when it comes to comparing three or more means, it is not clear which means we should subtract from which other means.
For example, with five means,
Mean 1 = 7.0
Mean 2 = 6.9
Mean 3 = 11.0
Mean 4 = 13.4
Mean 5 = 12.0
we could compare Mean 1 against Mean 2, or against Mean 3, or against Mean 4, or against Mean 5. We could also compare Mean 2 against Mean 3 or against Mean 4, or against Mean 5. We could also compare Mean 3 against Mean 4, or against Mean 5. Finally, we could compare Mean 4 against Mean 5. This gives a total of 10 possible two-group comparisons. Obviously, the logic used for the t-test cannot immediately be transferred to ANOVA.
Instead, ANOVA uses some simple logic of comparing variances (hence the name 'Analysis of Variance'). If the variance amongst the five means is significantly greater than our measure of random error variance, then our means must be more spread out than we would expect due to chance alone.
F = variance among sample means/variance expected from sampling error
If the variance amongst our sample means is the same as the error variance, then you would expect an F = 1.00. If the variance amongst our sample means is greater than the error variance, you would get F > 1.00. What we need therefore is a way of deciding when the variance amongst our sample means is significantly greater than 1.00. (An F < 1.00 does not have much importance and is always > 0.0 because variance is always positive.)
The answer to this question is the distribution of the F-ratio. An F-ratio is merely the ratio of any two variances. In the case of the between groups ANOVA, the variances we are interested in are the two nominated above.
F distributions depend on the degrees of freedom associated with the numerator in the ratio and the degrees of freedom associated with the denominator. Figure 7.1 shows three different F distributions corresponding to three different combinations of numerator df and denominator df.
Figure 7.1. Different F distributions for different combinations of numerator and denominator degrees of freedom. Notice "variance expected from sampling error" is sometimes called "WITHIN" variance or "within-subjects" variance, which indicates where it comes from.
You will see that each distribution is not symmetrical and has a peak at about F = 1.00. With degrees of freedom = 3 and 12, a calculated F-value greater than 3.49 will be a significant result (p < .05). If the calculated F- value is greater than 5.95, the result will be significant at the = .01 level. With 2 and 9 df, the corresponding values are 4.26 and 8.02. (You will be pleased to know, that there are no one-tailed tests in ANOVA.)
Variance was covered earlier but as a reminder . . .
variance = standard deviation squared
In ANOVA terminology, variance is often called Mean Square. That is, variance is equal to Sums of Squares divided by N-1. N-1 is approximately the number of observations, so variance is an average Sums of Squares or Mean Square for short.
Type I and Type II errors
When we set at a specified level (say, 0.05) we automatically specify how much confidence (0.95) we will have in a decision to "fail to reject Ho if it really is the true state of affairs. To put a more rational meaning on these numbers, consider doing the exact same experiment, each using a different random sample, 100 times. [Recall the discussion of the nature of a sampling distribution Ð which this sort of repetition idea gives rise to.] If we set = 0.05 (and consequently 1 - = 0.95), then in our 100 experiments, we should expect to make an incorrect decision in 0.05 x 100 or 5 of these experiments (= 5% chance of error), and a correct one 95% of the time if Ho is really true. Thus, states what chance of making an error (by falsely concluding that the null hypothesis should be rejected) we, as researchers, are willing to tolerate in the particular research context.
That is, our basis for making a decision about our sample being a "reasonable estimate" of a population value, is whether the sample event is particularly unlikely or not. Now, it happens, of course, that now and again, unusual, rare and unlikely events do occur just by chance and do not necessarily imply something meaningful has occurred or that something has caused this event to occur. In our example sampling distribution, just by chance you might have drawn 0, 0, 0, and 0. According to our decision making rules, this is so unlikely to have occurred by chance that we should reject Ho in favour of the alternative. You must have been peeking when you drew out the squares!!! But if it was a truly random selection, we would be making a Type I error. We would claim we have evidence of a selection rule being used (i.e., peeking) but would in fact be wrong in concluding this.
When we consider the case where Ho is not the true state of affairs in the population (i.e., Ho is false), we move into an area of statistics concerned with the power of a statistical test. If Ho is false, we want to have a reasonable chance of detecting it using our sample information. Of course, there is always the chance that we would fail to detect a false Ho, which yields the Type II or error. However, error is generally considered less severe or costly than an error. We must be aware of the power of a statistical test Ð the test's ability to detect a false null hypothesis Ð because we want to reject Ho if it really should be rejected in favour of H1 Hence we focus on 1 - which is the probability of correctly rejecting Ho. See Ray and Howell for more discussion of these types of errors.
Corresponding nonparametric test
The corresponding analogue of the one-way between groups ANOVA is the Kruskal-Wallis one-way analysis of variance.
Post hoc tests
Once a significant F-value is obtained in an Analysis of Variance, your work is not yet over. A significant F-value tells you only that the means are not all equal (i.e., reject the null hypothesis). You still do not know exactly which means are significantly different from which other ones. You need to examine the numbers more carefully to be able to say exactly where the significant differences are. In the example above, the significant F-value would allow us to conclude that the smallest and largest means were significant different from each other, but what about Mean 2 and Mean 3 or Mean 2 and Mean 4? Hence we need post hoc tests.
The most widely used post hoc test in Psychology and the behavioural sciences is Tukey's Honestly Significant Difference or HSD test. There are many types of post hoc tests all based on different assumptions and for different purposes. Tukey's HSD is a versatile, easily calculated technique that allows you to answer just about any follow up question you may have from the ANOVA.
Post hoc tests can only be used when the 'omnibus' ANOVA found a significant effect. If the F-value for a factor turns out nonsignificant, you cannot go further with the analysis. This 'protects' the post hoc test from being (ab)used too liberally. They are designed to keep the experimentwise error rate to acceptable levels.
The term 'Bonferroni adjustment' is used to indicate that if we want to keep the experimentwise error rate to a specified level (usually = .05) a simple way of doing this is to divide the acceptable - level by the number of comparisons we intend to make. In the above example, if 10 pairwise comparisons are to be made and we want to keep the overall experimentwise error rate to 5% we will evaluate each of our pairwise comparisons against .05 divided by 10. That is, for any one comparison to be considered significant, the obtained p-value would have to be less than 0.005 - and not 0.05. This obviously makes it harder to claim a significant result and in so doing decreases the chance of making a Type I error to very acceptable levels.
The Bonferroni adjustment is becoming more common with computers calculating exact probabilities for us. Once when you had to look up a table to determine the probability of a particular t-, F-, or r-value, you usually only had a choice of .05 or .01. Occasionally, some tables would cater for other probabilities but there are rarely tables for .005!! So, Bonferroni adjustments were not widespread. Nowadays, however, with probabilities being calculated exactly it easy to compare each probability with the Bonferroni-adjusted - level. In the above example, you would be justified in doing 10 t-tests and considering a comparison significant if the p-value was less than 0.005.
The more likely you are to claim you have a significant result when you shouldn't have (i.e., a Type I error).
What goes in the "F ( , )"?
The information contained in the "F( , )" can be most easily found in the analysis of variance summary table under the "df" column. This information is the degrees of freedom (df) for your experiment. Specifically, the degrees of freedom in the numerator (between groups) and the degrees of freedom in the denominator (within groups or error). The first number is your between groups degrees of freedom followed by your within groups degrees of freedom. Because your degrees of freedom are dependent on the number of participants you have in each of your conditions, your degrees of freedom may change from analysis to analysis.
What comes after the "="?
The information that comes after the "=" is the actual value of that F. This value can be found in the analysis of variance summary table under the "F" column.
How Do I Know if the Analysis is Significant?
Simple. All you need to do to determine whether that particular analysis is significant is to, again, look at the analysis of variance summary table under the "Sig." column. The "Sig." column is your probability level for that particular analysis. Remember, any value in this column that is LESS than .05 is significant. All other values in that column that are greater than
.05 are NOT significant. But, I KNOW you remember all of this from your statistics class...right?
Sources of Variation
The sources of variation are: age, trials, the Age x Trials interaction, and two error terms. One error term is used to test the effect of age whereas a second error term is used to test the effects of trials and the Age x Trials interaction.
Degrees of Freedom
The degrees of freedom for age is equal to the number of ages minus one. That is: 2 - 1 = 1. The degrees of freedom for the error term for age is equal to the total number of subjects minus the number of groups: 8 - 2 = 6. The degrees of freedom for trials is equal to the number of trials - 1: 5 - 1 = 4. The degrees of freedom for the Age x Trials interaction is equal to the product of the degrees of freedom for age (1) and the degrees of freedom for trials (4) = 1 x 4 = 4. Finally, the degrees of freedom for the second error term is equal to the product of the degrees of freedom of the first error term (6) and the degrees of freedom for trials (4): 6 x 4 = 24.
General Hypothesis Tests
A statistical hypothesis is a statement about the distribution of the data variable X; equivalently, a statistical hypothesis specifies a set of possible distributions of X. In hypothesis testing, the goal is to see if there is sufficient statistical evidence to reject a presumed null hypothesis in favor of a conjectured alternative hypothesis. The null hypothesis is usually denoted H0 while the alternative hypothesis is usually denoted H1. A hypothesis that specifies a single distribution for X is called simple; a hypothesis that specifies more than one distribution for X is called composite.
An hypothesis test is a statistical decision; the conclusion will either be to reject the null hypothesis in favor of the alternative, or to fail to reject the null hypothesis. The decision that we make must, of course, be based on the data vector X. Thus, we will find a subset R of the sample space S and reject H0 if and only if X in R. The set R is known as the rejection region or the critical region. Usually, the critical region is defined in terms of a statistic W(X), known as a test statistic.
The ultimate decision may be correct or may be in error. There are two types of errors, depending on which of the hypotheses is actually true:
A type 1 error is rejecting the null hypothesis when it is true.
A type 2 error is failing to reject the null hypothesis when it is false.
Friday, September 20, 2002
Thursday, September 19, 2002
nick: task for complete control: reference memory animals, errorless run = working memory animals, sample run. xor, conditioned supression also relevant to amygdala profiling.
mark good: compare baseline freezing within subjects as a rough guide to whether there are amygdala-mediated deficits in the knockouts.
Tuesday, September 10, 2002
'Another reason that human nature doesn't rule out social progress is that many features of human nature have free parameters. This has long been recognized in the case of language, where some languages use the mirror-image of the phrase order patterns found in English but otherwise work by the same logic. Our moral sense may also have a free parameter as well. People in all cultures have an ability to respect and sympathize with other people. The question is, with which other people? The default setting of our moral sense may be to sympathize only with members of our clan or village. Over the course of history, a knob or a slider has been adjusted so that a larger and larger portion of humanity is admitted into the circle of people whose interests we consider as comparable to our own. From the village or clan the moral circle has been expanded to the tribe, the nation, and most recently to all of humanity, as in the Universal Declaration of Human Rights. It's an idea that came from the philosopher Peter Singer in his book The Expanding Circle. It's an example of how we can enjoy social improvement and moral progress even if we are fitted with certain faculties, as long as those faculties can respond to inputs. In the case of the moral sense the relevant inputs may be a cosmopolitan awareness of history and the narratives of other peoples, which allow us to project ourselves into the experiences of people who might otherwise be treated as obstacles or enemies.' Steven Pinker @ edge.org September 2002.
do brain stuff. quickly!
notes on flint
1. what is the multi-electrode device used by McHugh, 1996 and Rottenburg, 1996?
2. What has Maria Grazia Turri found?
3. "The success of neurogenetics is only possible in so far as the genetics tells something useful about processes within neurons. It has yet to throw light on how neuronal connections give rise to cognitive processes."
4. There needs to be closer interaction between molecular neuroscience and systems neuroscience before genetics can tell us anything interesting about cognitive function. (Does he need an electrophysiologist?)
(apply for 'mock' post-doc with flint?)
save graph in sigma plot as eps (mihght have to get driver from adobe)
then open in illustrator and (if size is not important) save in tiff format
for best resolution.
Wednesday, September 04, 2002
Place to consider for the future: The Addiction and Mental Health Centre, Toronto
Friday, August 30, 2002
Monday, August 19, 2002
The "tragedy of the commons" is often not that tragic, because we have evolved to punish defectors, even at a cost to ourselves. As Fehr points out in Nature, this type of "altruistic punishment" may have been one of the key factors in the early evolving hunter-gatherer societies at humanity's dawn some 100.000 years yonder. But which part of the brain does it?
Saturday, August 10, 2002
As a species, we appear to be biologically programmed to see patterns and conspiracies, and this tendency increases when we sense that we're in danger. ''We are hard-wired to overreact to coincidences,'' says Persi Diaconis. ''It goes back to primitive man. You look in the bush, it looks like stripes, you'd better get out of there before you determine the odds that you're looking at a tiger. The cost of being flattened by the tiger is high. Right now, people are noticing any kind of odd behavior and being nervous about it.''
Adds John Allen Paulos: ''Human beings are pattern-seeking animals. It might just be part of our biology that conspires to make coincidences more meaningful than they really are. Look at the natural world of rocks and plants and rivers: it doesn't offer much evidence for superfluous coincidences, but primitive man had to be alert to all anomalies and respond to them as if they were real.''
-- someone needs to do the brain stuff on this. see josh tenenbaum at mit.
Friday, July 19, 2002
Wednesday, April 03, 2002
Filial imprinting in domestic chicks is associated with spine pruning in the associative area, dorsocaudal neostriatum
Jörg Bock and Katharina Braun
European Journal of Neuroscience. Volume 11 Issue 7 Page 2566 - July 1999
Juvenile emotionally modulated learning events are fundamental for the normal development of socio-emotional competence and intellectual capabilities. Filial imprinting in the domestic chick provides a suitable model to investigate the neural mechanisms underlying such juvenile learning events. The forebrain area dorsocaudal neostriatum (Ndc), a multimodal integration area and presumed equivalent to mammalian parietotemporal association cortices, has been shown to be critically involved in this learning process. We investigated whether filial imprinting is associated with changes of synaptic connectivity in the Ndc. Quantitative measurements of spine densities of a large neuron type in the Ndc revealed a massive pruning of spine synapses after filial imprinting. Compared with 7-day-old naive control chicks, imprinted chicks displayed significantly lower spine frequencies on all dendritic segments. Since the average length of the dendritic segments did not change during imprinting, these results can be interpreted as a reduction of the absolute number of spine synapses on this neuron type. In a control region, the primary sensory forebrain area ectostriatum, spine density and dendritic length remained unchanged. These results indicate that synaptic pruning may represent a mechanism of selective synaptic reorganization in higher associative forebrain areas as a fundamental feature of juvenile learning events.
Four kick-ass studies:
1. Amygdala LTP correllated with behaviour (w/ Per)
2. Two-photon microscopy on activity-dependent AMPA morphology (w/ Andreas)
3. Conditional KOs and LTP tested in the same animals (w/ Per)
4. In vivo recording on LTP in KOs during learning tasks (w/ Bliss)
Thursday, March 07, 2002
Wednesday, March 06, 2002
Cell Press journals (inc. Neuron): cibanez/cibanez
J Neurosci: antonio/yolanda
Experimental Brain Research: won233oz/uii827ua
Animals without LTP: put them through procedures that have not been tested yet:
Then try to block the same with eg Ap5
Test the Gray/Falsh/Meltzer’s hypothesis that LTp is required for arousal, attention etc
Also try antipsychotic drugs and see if it can oblitarate the t maze result.
If LTP = Attention gating/enhancing? Construct a behavioural in vivo recording study where the animal is given shocks ahile under anastesia and check for differences in LTP levels.
whatever mechanisms that people use to check for long lasting changes of
anatomy in plasticity (increases in synapses, quantaol size, whatever) needs
to be checked in the KOs!!
check out who have done anxiety tests with the KOs and what they found. KOs should be more anxious. Why?
Monday, March 04, 2002
Irvine/San Diego Notes
1. The working memory version of the MWM.
2. Reversal in the MWM.
3. Win-switch on the radial maze.
4. “If you do nothing else, you have to do trace fear conditioning in these animals!”
5. Electrode recordings (Pennartz/Thompson).
6. Substance X: A GluR-A blocker.
7. Trace fear conditioning vs. delayed trace fear conditioning (Heinemann’s GluR2 KOs are impaired on delayed trace fear conditioning but not normal trace).
8. More non-spatial: Delay/Trace eye blink conditioning? (Fanselow; delay: Kirino has shown impairment in GluR delta 2 mutants.
9. Introduce delays in the T-maze?
10. Do the radial maze in the tank (Woodson) or with lights (Packard).
11. Novel/Spontaneous object recognition (Yee, Aggleton) J
12. LeDoux scores freezing manually!
1. T-maze/DRL/WM with the conditional knockouts.
2. Inject AP5 into GluRA-/- to control for intra-hippocampal rewiring.
3. Confocal imaging of GFP-tagged synaptogenesis following learning.
4. Amygdalar LTP and AMPA; ecologically valid fear conditioning.
5. Cortisol levels in urine to test fear conditioned learning.
6. In vivo recording during DRL or similar (Moser/Andersen).
7. Environmental enrichment (Tsien).
8. Differential reinforcement (Robbins).
9. Inhibitory avoidance (with shock).
10. One-trial vs. three-trial contextual fear conditioning (Tonegawa’s calcineurin
mutants are impaired using three but not one trial).
11. DMP in MWM (Steele & Morris, 1999).
12. Perhaps good WM performance is due to over-learning. Could be checked
by doing probe test earlier on. Would also be interesting to vary the ITI.
· Always take a step back and ask: What has this got to do with memory?
· Morris, 1996: Hippocampus and rule generalisation.
· If the hippocampus extracts rules, then the T-maze is a lot more hippocampus
dependent than is the MWM.
· The hippocampus is like a post office that delivers the mail, and then its job is done?
· Malenka/Malinow: The AMPA receptor is responsible for mRNA trafficking.
12 mRNAs have been identified in the dendrites of the Aplysia.
· “Fear conditioning is so simple that it can happen in the amygdala.”
· “If memories are laid down in the cortex, why are we looking in the hippocampus?”
misc to do
look up shi and malinow
olfactorily driven processes
submit abstract to fens 2002
has anyone actually done hippocampal lesions + DRL in mice? who? where?
see cammarota medina for inhibitory avoidance
check increase of ampa receptors in schaeffer collateral pathway
yogita (chudasama) about glur1 drug
get fear conditioning set-up in january
go to heidelberg in spring
check pain sensitivity and addiction in the KOs
ledoux in sci am
y-maze to peter
environmental enrichment, soc trans food pref, olfaction