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The Journal of Neuroscience, October 15, 1998, 18(20):8534-8538
Decreased Odor Avoidance after Electric Shock in
Drosophila Mutants Biases Learning and Memory Tests
Thomas
Préat
Institut Alfred Fessard, Centre National de la Recherche
Scientifique, 91190 Gif-sur-Yvette, France
 |
ABSTRACT |
The Drosophila mutants amnesiac,
dunce (dnc), and rutabaga
were isolated after associative conditioning tests, during which animals were trained to associate the presence of an odor with that of
electric shocks (ES). In the absence of conditioning, the odor
avoidance (OA) of these mutants was shown to be normal, indicating that
their poor associative conditioning performance was attributable to
specific learning or memory deficits. However, I show that the
OA of the mutants is greatly decreased after their exposure to ES. This
effect can last for hours. These results strongly suggest that part of
the defect displayed by these mutants in associative conditioning tests
does not correspond to a learning or memory deficit but might arise
from abnormal sensitivity to stressful stimuli. I looked at the OA
after ES of two previously characterized dnc
mutants. Df(1)N79f specifically
decreases Dnc expression in the mushroom bodies, leading to a normal
level of learning but decreased memory.
Df(1)N79f mutants displayed a normal
OA after ES. Df(1)N64j15 affects the
entire brain expression of Dnc, leading to decreased learning and
memory. Df(1)N64j15 animals showed a
strong decrease of their OA after ES. Thus, the lack of Dnc
"general" expression is most likely responsible for the OA defect,
which would be responsible for the apparent learning defect after
conditioning. In contrast, the Dnc phosphodiesterase accumulated in the
mushroom bodies would be involved specifically in memory formation.
Key words:
Drosophila melanogaster; learning and memory
mutants; cAMP; stress sensitivity; odor avoidance; conditioning
controls
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INTRODUCTION |
Several mutations affecting
associative learning and memory have been characterized in
Drosophila, including dunce (dnc), rutabaga (rut), amnesiac
(amn), and linotte (lio) (Dudai et
al., 1976 , 1984; Quinn et al., 1979; Dura et al., 1993).
dnc and rut encode, respectively, a
phosphodiesterase and an adenylate cyclase (Chen et al., 1986; Levin et
al., 1992), two enzymes involved with the cAMP pathway.
amn encodes a putative neuropeptide that might regulate
adenylate cyclase activity (Feany and Quinn, 1995), and lio
encodes a putative tyrosine kinase (Dura et al., 1995) involved in
adult brain development (Simon et al., 1998). Despite recent progress
(Zhong and Wu, 1991; Qiu and Davis, 1993; Dauwalder and Davis, 1995),
the precise physiological roles of the Drosophila proteins
Amn, Dnc, and Rut are not fully understood. In particular, although Dnc
and Rut accumulate in the mushroom bodies (Nighorn et al., 1991; Han et
al., 1992), an insect structure involved in learning and memory (Erber
et al., 1980; Davis, 1993; Hammer, 1993; de Belle and Heisenberg,
1994), they are also expressed in other parts of adult brain (Nighorn
et al., 1991; Han et al., 1992) in which their possible roles
are unknown.
The conditioning protocols originally used to isolate and characterize
most of Drosophila learning and memory mutants associate an
odor with electric shocks (ES) (Quinn et al., 1974; Tully and Quinn,
1985). Naturally, before the abnormal performance of the mutants
could be linked to a learning or memory defect, it was shown that
untrained mutants could react normally to the stimuli used for the
conditioning and, in particular, that their odor avoidance (OA) was
normal (Dudai et al., 1976, 1984; Quinn et al., 1979; Dura et
al., 1993). However, the possibility that ES presentation during
conditioning could itself affect odor perception was never explored.
This issue is crucial when one needs to compare a putative learning or
memory mutant with a reference wild-type stock, because the ES might
differentially affect the two groups. Thus, to characterize a mutant
deficient in associative learning or memory, it is essential to
separate a bona fide learning or memory defect (related to the
association of stimuli) from behavioral deficits merely related to
abnormal perception of the stimuli after the conditioning treatment. I
show here that the mutants amn, dnc, and
rut display a very strong decrease of their OA after their
exposure to ES. Two deficiencies affecting different sets of
dnc transcripts allowed the separation of memory defects
from nonspecific deficits.
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MATERIALS AND METHODS |
All of the mutant stocks have a Canton-S background. This issue
is important, because different wild-type backgrounds lead to different
learning and memory aptitudes (Tully and Quinn, 1985). The three
ethylmethane sulfonate mutations amn, dnc, and
rut were originally induced in a Canton-S background. The
background of the two P mutants rutP2080
and lio1 was "cantogenized" by
outcrossing w1118
rutP2080/w1118
females and w1118,
lio1/+ females to
w1118/Y (Canton-S) males for
five generations. The lio2 mutant was
cantogenized by outcrossing w1188,
lio1/lio2 females
to w1118/Y,
lio1/lio1
(Canton-S) males for five generations. The
wa
Df(1)N79f/w+Y × CD(1), y w f and
Df(1)N64j15/w+Y × CD(1), y w f (Canton-S) stocks were provided by Ronald
Davis (Baylor College of Medicine, Houston, TX). A cantogenized
wa
Df(1)N79f/w+Y × CD(1),y w f (Canton-S) stock was generated by outcrossing for nine generations wa
Df(1)N79f/w1118
females to w1118/Y (Canton-S)
males. A
w1118/w+Y × CD(1),y w f (Canton-S) stock was also generated.
For associative memory tests, flies were conditioned with the Pavlovian
procedure developed by Tully and Quinn (1985), with a few adaptations.
During training, groups of 50-100 flies were first exposed for 60 sec
to a first odor (odor A) (either undiluted 3-octanol or
4-methylcyclohexanol), during which time they received ES (1.5 sec
pulses of DC). After a 45 sec rest period, flies were exposed for 60 sec to the second odor (odor B), which was not paired with ES.
Flies were then kept for 30 or 90 min in a vial with regular solid
food. For memory testing, flies were transported to the choice point of
a T maze, allowed to choose between the two odors for 120 sec, and
counted. The performance index represents a normalized probability of
correct choice. A score of 0 thus corresponds to a 50:50
distribution.
For OA tests, flies were treated in the upper chamber as for the
associative conditioning, except that presentation of the second odor
was omitted and replaced by exposure to air. For OA testing, treated
animals were transported to the choice point of the T maze, allowed to
choose between the new odor and air, and counted. A performance index
was calculated as for associative conditioning. An index of 0 corresponds to a 50:50 distribution. An index of 100% corresponds to
complete avoidance of the odor. Odors were used undiluted as by de
Belle and Heisenberg (1994). Two groups of the same stock were run
successively, and the side of the test tube with odor was alternated.
To remove odor traces from the previous run before each new experiment
and in the absence of flies, odor and fresh air, respectively, were
aspirated through the relevant test tube for 1 min.
The correct perception of ES requires the presence of humid air (Tully
and Quinn, 1985), and various voltage-humidity set-ups have been
adopted as regular working conditions. In the present study, unless
specified, 120 V-70% humidity was used (medium-humidity condition). A 60 V-90% humidity set-up was also used
(high-humidity condition).
Statistical significance of the differences between two means,
corresponding to mutant and control, were assessed with Student's t test. Comparisons among multiple means (see Fig. 1) were
assessed with one-way ANOVA.
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RESULTS |
The olfactory associative conditioning protocol that produces the
strongest learning scores consists of the following sequence (Fig.
1A) (Tully and Quinn,
1985). A first odor is presented to a group of flies paired with pulses
of ES. After a rest period, a second odor is presented in the absence
of shock. To measure the association between the first odor and ES,
flies are brought to a choice point from which they have free access to
two compartments, each filled with one of the odors previously used
during training. Animals, having learned and remembered the odor-ES
association, will tend to avoid the corresponding odor.
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Figure 1.
A, Half hour memory of normal
[Canton-S (CS)] and mutant stocks. Flies were trained
in the grid tube (position 1) and tested at the
choice point (position 2). Bars represent
mean ± SE performance index. These scores match previously
published values (Tully and Quinn, 1985; Dura et al., 1993).
**p < 0.01; ***p < 0.001;
one-way ANOVA. n = 4 groups. B, OA
of normal and mutant stocks after ES. OA to octanol
(position 2) after presentation of ES combined
with methylcyclohexanol (position 1) (see
Materials and Methods). Left, CS,
lio1, amn,
rut1, and
dnc1, 120 V were used together
with medium humidity. Right, CS,
lio2, and
rutP2080, 60 V were used with high
humidity. Note the similar scores displayed by Canton-S under both
conditions. This experiment was performed blind as to genotype.
*p < 0.05; **p < 0.01;
***p < 0.001; one-way ANOVA. n = 6 groups.
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A major drawback of this procedure is that flies make their olfactory
choice after having received strong ES, which might itself induce
behavioral changes unrelated to learning and memory, only indirectly
affecting learning and memory performances. In particular, because
unimpaired olfaction is a prerequisite for the correct interpretation
of results in the olfactory associative conditioning protocol, I tested
the OA of wild-type and mutant flies after presentation of ES (Fig.
1B). In this test, a first repellent odor is
presented to the flies in association with ES. The flies are then
brought to the choice point, where their reactivity to a second
repellent odor is measured. This protocol is thus similar to the
associative conditioning procedure, but the second odor is not
presented during the first phase, whereas the first odor, which has
been associated with the shocks, is not presented during the test. Such
control of the OA of the mutants is more relevant to the associative
conditioning protocol than the direct test of naive animals. The fact
that the second odor, used to test OA, is novel to the flies at the
time of testing precludes interference from phenomena related to
multiple presentations, such as habituation.
After presentation of ES combined with the first odor, the mutants
amn, dnc1,
rut1, and
rutP2080 displayed strongly reduced
avoidance of a second odor compared with normal flies (Fig.
1B). On the contrary,
lio1 and
lio2 behaved in the same way as wild-type
flies. Thus, although naive amn, dnc, and
rut mutants have been shown in previous studies to react
normally to odors (Dudai et al., 1976, 1984; Quinn et al.,
1979), their OA is dramatically reduced after presentation of ES, the
stimulus normally used for aversive conditioning.
The amn mutant was chosen, together with the reference
wild-type stock Canton-S, to analyze in more detail the effect of ES on
OA. amn displays an abnormal OA to odor B after presentation of ES, whether ESs are delivered in combination with fresh air or with
odor A (Fig. 2). This result indicates
that ES presentation is the main cause of the abnormal OA and not
preexposure to a first repellent odor. In the case of Canton-S,
avoidance of odor B is less efficient when ES is associated with air
rather than with odor A (Fig. 2). A plausible explanation for this is
that Canton-S flies, having learned the association between the air flow and ES, tend to avoid air during the test. Consequently, to
measure any learning-independent effects of ES on OA, it is imperative
to present ES associated with odor A, a condition which will not be one
of the options in the test.
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Figure 2.
OA of Canton-S (black) and
amn (light gray) strains after various
experimental conditions. Odor A is benzaldehyde, and the OA is measured
to methylcyclohexanol. No difference is detected between Canton-S and
amn after air presentation (t test;
p = 0.054; t = 2.2). After
presentation of odor A alone, amn avoidance is
marginally reduced (t test; *p = 0.041; t = 2.3), whereas it is strongly reduced
after presentation of ES (ES+air) (t
test; ***p = 0.0006; t = 4.9)
or ES combined with odor A (ES+odor A) (t
test; ***p = 0.0007; t = 4.8).
n = 6 groups.
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If amn displays a strong OA decrease after a 120 V ES
presentation, Canton-S is also affected at this voltage (Fig.
3). This is apparently attributable to
the degree of sensitivity, because Canton-S is unaffected at 60 V (with
medium humidity; see Materials and Methods), whereas amn
flies are abnormal. Thus, it seems that the threshold for ES
perturbation is lower in amn mutants than in normal flies.
At this stage, the nature of the physiological changes induced by ES
remains to be determined; ES could affect olfaction per se, or it could
produce a more general effect on brain activity. Whatever the case, the
concern is to understand to what degree the decreased OA affects the
performance of the mutants after associative conditioning. In
particular, could it account for part of the lasting deficit of
amn, which has been interpreted up to now as a memory
problem? Indeed, testing OA 1 hr after ES presentation shows no
amelioration of the amn defect (Fig.
4), which has only partially recovered at
24 hr.
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Figure 3.
OA after ES of Canton-S (black) and
amn (light gray) as a function of ES
intensity. No difference is detected at 30 V (t test;
p = 0.072; t = 2.0). A
significant difference is detected at 60 V (t test;
***p = 0.0005; t = 5.1) and at
120 V (t test; ***p = 0.0001;
t = 7.0). Odors as in Figure 2.
n = 6 groups.
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Figure 4.
OA of Canton-S (black) and
amn (light gray) as a function of the
delay between ES delivery and testing. A significant difference is
detected at all points: t = 0 hr, t
test; ***p = 0.0001; t = 7.0;
t = 1 hr, t test;
***p = 0.0003; t = 5.3;
t = 24 hr, t test; **p = 0.010; t = 3.7. Odors as in Figure 2.
n = 6 groups, except n = 4 groups at 24 hr.
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A fundamental issue now is to differentiate learning and memory defects
from unrelated deficits. The Dnc phosphodiesterase and the Rut adenylyl
cyclase are preferentially expressed in the mushroom bodies, but these
enzymes are also found in other parts of the brain (Nighorn et al.,
1991; Han et al., 1992). The mushroom body expression might indeed be
related to learning and/or memory, whereas the "general" expression
might be involved in the nonassociative response described here. To
test this hypothesis, I looked at the OA after ES of two dnc
deficiencies, which remove different sets of dnc transcripts
(Qiu and Davis, 1993). The first deficiency, Df(1)N79f, dramatically decreased Dnc
expression in the mushroom bodies. Individuals carrying this deficiency
displayed a normal OA after ES (Fig. 5).
On the contrary, Df(1)N64j15 affected the
general Dnc expression, as well as the mushroom body expression. These
animals showed a strong decrease of their OA after ES (Fig. 5).
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Figure 5.
OA after ES of
Df(1)N/w+Y males
(light gray) and control CD(1), y w f
sisters (black). Only
Df(1)N64j15/w+Y
males are affected (t test; **p = 0.005; t = 2.77). Odors as in Figure
1B. n = 12 groups for
N64j15; n = 16 groups for N79f. The standard
condition of 60 V-high humidity was used for this experiment.
wa
Df(1)N79f/w+Y
(Canton-S) males displayed a 90 min memory score of 30.6 ± 4.3 compared with 65.1 ± 5.4 for
w1118/w+Y
(Canton-S) control males (n = 6 groups;
t test; ***p = 0.0005;
t = 5).
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| |
DISCUSSION |
The present results strongly suggest that part of the learning and
memory deficits displayed by the mutants amn,
dnc, and rut in an associative conditioning
protocol could be attributable to effects of the ES on some aspect of
perception in the animals. It is possible that ES alters faculties in
the mutants required not only for the test but also for the training
phase of associative conditioning, and it is likely that these
faculties are progressively deteriorated as the shock pulses are
delivered. In summary, an altered physiology in the mutants after ES
presentation could lead to an apparent defect in associative
conditioning because of weaker acquisition during training and/or
because of poorer performance during the test.
This work highlights the need for two-step controls in associative
learning and memory experiments, especially in which a strong stimulus
is used to condition the animals. In particular, the effect of the
aversive unconditioned stimulus on the ability of the animals to
perceive the conditioned stimulus should be investigated. Thus,
although the mutants studied here have been shown to perform poorly
under many different associative conditioning protocols (Aceves-Pina
and Quinn, 1979; Folkers, 1982; Mariath, 1985), the unconditioned
stimulus was generally stressful.
Two strategies can now be adopted to differentiate learning and memory
defects from unspecific deficits. First, genetic dissection might
reveal that a specific protein isoform and/or expression in a
particular subdomain is involved in only one type of behavior. Such an
approach was performed successfully with dnc (Table
1) by testing two previously
characterized deficiencies (Qiu and Davis, 1993). Thus, a dramatic and
specific decrease in Dnc mushroom body product correlates with normal
OA after ES. These animals showed a specific memory defect. On the
contrary, elimination of the entire brain expression of Dnc leads to a
strongly reduced OA after ES. The fact that only the latter animals
showed an apparent learning deficit suggests that this might be a
secondary consequence of the nonassociative deficit induced by ES. In
this hypothesis, the Dnc phosphodiesterase accumulated in the mushroom
bodies would be involved specifically in memory formation.
Second, the mutants could be studied under conditions designed to
reduce stress to prevent the occurrence of nonspecific defects which
might interfere with the conditioning procedure. Thus, it has been seen
that dnc, which apparently displays a learning defect when
conditioned with a negative stimulus (ES), learns normally when a
positive stimulus (sugar) is used in association with odors (Tempel et
al., 1983). This observation supports the idea that Dnc is specifically
required for associative memory but not for associative learning.
| |
FOOTNOTES |
Received May 21, 1998; revised Aug. 3, 1998; accepted Aug. 7, 1998.
This work was supported by the Human Frontier Science Organization, the
Fondation pour la Recherche Médicale, the Association pour la
Recherche contre le Cancer, and the Centre National de la Recherche
Scientifique (ATIPE 7). Part of this work has been performed at
the Universität Würzburg (Lehrstuhl für Genetik, Am
Hubland, D-97074 Würzburg, Germany), and I thank researchers from
that laboratory for their valuable criticisms of this work. I thank
Ronald Davis for providing fly stocks and Jean-Maurice Dura, Yves
Fregnac, Martin Heisenberg, Raphael Hitier, Lucy Vincent, and
Jean-Didier Vincent for their helpful comments on a previous version of
this manuscript.
Correspondence should be addressed to Dr. Thomas Préat, Institut
Alfred Fessard, Centre National de la Recherche Scientifique, 91190 Gif-sur-Yvette, France.
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Top
Abstract
Introduction
