Olfactory input increases visual sensitivity in zebrafish: a possible function for the terminal nerve and dopaminergic interplexiform cells
Departments of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, USA
* Author for correspondence (e-mail: leili{at}uky.edu)
Accepted 24 March 2003
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Summary |
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Key words: centrifugal pathway, terminal nerve, dopamine, olfactory stimulation, retina, visual sensitivity, zebrafish, Danio rerio
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Introduction |
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In fish retinas, the DA-IPC is the only cell type that synthesizes dopamine
(Witkovsky and Dearry, 1992).
DA-IPCs synapse with virtually all other retinal cell types
(Dowling and Ehinger, 1978
;
Yazulla and Zucker, 1988
;
Yazulla and Studholme, 1997
).
Dopamine functions as a major neuromodulator in the retina
(Dowling, 1986
;
Negishi et al., 1990
). One of
the important effects of dopamine is to modulate glutamate receptor
sensitivity (Knapp and Dowling,
1987
; Knapp et al.,
1990
). In the outer retina, dopamine regulates retinomotor
movements (Dearry and Burnside,
1986
). It also plays a role in rodcone or horizontal cell
coupling via the modulation of gap junctions
(Krizaj et al., 1998
). In the
inner retina, dopamine modulates potassium currents of ON bipolar cells
(Fan and Yazulla, 2001
) and
the spike frequency of ganglion cells
(Vaquero et al., 2001
).
So far, the function of the olfactory bulb-retina connection remains
enigmatic. It has been speculated that the TN transmits olfactory information
to other brain areas. Since FMRFamide and GnRH are the major transmitters, it
has been hypothesized that the TN plays a role in the physiological mechanisms
involved in sexual behavior (Demski and
Northcutt, 1983; Schreibman
and Margolis, 1987
;
Oelschlager et al., 1998
).
Recent studies have suggested a role of TN input in visual function.
Via a dopamine mechanism, for example, FMRFamide and GnRH alter the
size of the receptive fields of horizontal cells
(Umino and Dowling, 1991
).
FMRFamide and GnRH also affect spike activity of retinal ganglion cells
(Walker and Stell, 1986
).
Weiss and Meyer (1988
) have
demonstrated that olfactory stimuli modulate the amplitude of the b-wave in
the electroretinogram (ERG), suggesting that FMRFamide and GnRH may have a
role in the regulation of bipolar cell activity.
In the present study, we have evaluated the effect of olfactory stimulation on visual sensitivity in zebrafish. Our data suggest that there is a functional connection between the olfactory organ and the neural retina. It seems likely that both the TN and DA-IPCs are anatomical candidates that play a role in the modulation of visual sensitivity by olfactory stimulation.
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Materials and methods |
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Behavioral assay
Zebrafish visual sensitivity was assessed using a behavioral assay based on
the visually mediated escape response when they encounter a threatening object
(Li and Dowling, 1997; see
also Fig. 2). The behavioral
test apparatus consisted of a transparent circular container surrounded by a
rotating drum. A black segment was marked on white paper that covered the
inside of the drum and served as a threatening stimulus. The drum was
illuminated from above with a halogen lamp (maximum intensity, 475 µW
cm-2), and was turned at 10 rotations min-1 by a motor.
The fish were viewed on a monitor attached to an infrared video camera.
|
Normally zebrafish swim in circles along the wall of a circular container. However, when challenged by a black segment revolving around the container, the fish show an escape response, i.e. they rapidly reverse the direction of swimming. To evaluate behavioral visual sensitivity, we measured the threshold of the light intensity required for the fish to react to the black segment with an escape response. The testing light was always started at a dim light level. If no escape responses were observed (within three encounters between the fish and the rotating black segment), the light intensity was increased by removing neutral density filters (in steps of 0.5 log unit) until the fish showed the escape response.
Olfactory stimulation
Amino acids are basic odorants for zebrafish. Analyzing activation patterns
of the glomuruli and their cross-adaptation using electro-olfactography led to
the proposal to divide the amino acids as olfactory stimuli into four groups:
short-chained neutral, long-chained neutral, basic, and acidic (Friedrich and
Korsching, 1997,
1998
;
Caprio and Byrd, 1984
;
Michel and Lubomudrov, 1995
;
Zippel et al., 1993
,
1997
). In the present study,
we examined the effect of representatives of each of the four groups:
L-alanine, L-methionine, L-arginine and
L-aspartic acid, on zebrafish visual sensitivity. The effect of
amino acids on visual sensitivity was determined by comparing the threshold
light intensities before and after amino acid administration at which an
escape response occurs.
Amino acids were dissolved in regular tank water, and the pH of the solution was adjusted to 7.0. Following pre-odor visual threshold measurements, 1.0 ml of odor solution was slowly injected into 200 ml water of the experimental container. The final concentrations of each amino acid were 0, 10-6, 10-5, 10-4 and 10-3 mol l-1. Post-odor threshold measurements were made within 30 s after amino acid administration. The experimenter was not aware of the concentration of the amino acids used in each experiment. Data obtained before and after each amino acid or sham stimulation were compared by a paired Student's t-test.
Electroretinographic recording
Procedures for electroretinographic (ERG) recordings were similar to those
described (Brockerhoff et al.,
1995; Li and Dowling,
1997
). The zebrafish was anesthetized with 4% 3-aminobenzoic
methylesther and immobilized with 10% gallamine triethiodide. The zebrafish
was placed on its ventral side at a 45° slanting angle on a wet sponge and
most of its body was covered with a wet paper towel. A slow stream of fish
water was directed via a spout into the mouth to keep the fish
oxygenized. A beam of halogen light (maximum light intensity 670 µW
cm-2) was directed by a mirror system to the eye of the fish. The
light intensity was controlled by neutral density filters.
ERGs were recorded after 30 min of dark adaptation. First, we determined the lowest light intensity that evoked a b-wave of at least 10 µV. The fish received five light stimuli of 10 µs with an inter-stimulus interval of 5 s. The light intensity was initially set at a dim level, and was increased in 0.5 log steps until a 10 µV b-wave was recorded. Following this pre-odor visual threshold measurement, the fish was allowed to dark-adapt for about 2 min, then a solution of 50 µl of either tank water or methionine dissolved in tank water was released over the nasal cavity contralateral to the recorded eye. Within 10 s after olfactory stimulation, the threshold light intensity to evoke a 10 µV b-wave was again determined. This experiment was carried out twice during the day, in the early (06.0009.00 h) and late morning (09.0012.00 h).
Bulbectomy
Zebrafish were anesthetized with 4% 3-aminobenzoic methylester. Under a
dissecting microscope, the olfactory bulbs were severed by a microblade
inserted approximately 1 mm caudal of the nasal cavities. The blade was
lowered at a slanting angle of approximately 45° in the caudal direction,
and was pulled along a trench of approximately 1 mm on each side of the
midline in the lateral direction. In all cases the olfactory bulbs were
severed, and sometimes a part of the telencephalon was ablated as well. The
fish were allowed to recover for 57 days before threshold measurements
were made. No obvious differences in swimming behavior were observed between
control and experimental animals.
Administration of drugs
DA-IPCs were destroyed by coinjections of 6-hydroxydopamine (6-OHDA) and
pargyline (Lin and Yazulla,
1994; Li and Dowling,
2000b
). Approximately 2 µl of a 1:1 mixture solution (5 µg
ml-1) was injected into the vitreous of each eye. The injection was
repeated the next day. Visual threshold measurements were performed after 2
weeks of 6-OHDA injections when the DA-IPCs were completely or nearly
completely depleted. SCH23390 (a dopamine D1 receptor antagonist)
and sulpiride (a D2 receptor antagonist) were dissolved in
phosphate-buffered saline (PBS) and PBS/HCl, respectively, and were further
diluted in PBS. The final concentrations of SCH23390 and sulpiride were
estimated to be approximately 100 µmol l-1. All chemicals were
obtained from Sigma (St Louis, MO, USA).
Immunostaining
Specimens were fixed in 4% paraformaldehyde in PBS. Both the TN cell bodies
and TN axons were stained with a polyclonal antibody against FMRFamide
(Chemicon, CA, USA). DA-IPCs were stained with an antibody against tyrosine
hydroxylase (Chemicon, CA, USA). Rhodamine- and FITC-conjugated secondary
antibodies (Sigma) were used to visualize FMRFamide and tyrosine hydroxylase
antibodies, respectively.
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Results |
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The above-described experiments were carried out in the early morning when
zebrafish are least sensitive to light, due to a circadian effect
(Li and Dowling, 1998). In a
separate experiment, we examined whether olfactory stimulation increases
visual sensitivity when the zebrafish are most sensitive to light, i.e. in the
late afternoon. In the late afternoon hours, application of amino acids
(methionine, 10-3 mol l-1) produced no effect on
behavioral visual sensitivity (t(16)=-2.06,
P>0.05; not shown). This suggests that olfactory stimulation by
amino acids could not increase the absolute visual sensitivity level when it
was already at its peak, probably due to a ceiling effect.
In our behavioral test, the criterion used to score a visual threshold was
the escape response, elicited by the rotating black segment
(Li and Dowling, 1998). We
have, of course, to be aware that zebrafish show some spontaneous turning
behavior, which cannot readily be discerned from visually mediated escape
responses. To test if the increase in visual sensitivity was confounded by an
increase in spontaneous turning behavior, we recorded the number of turns
before and after amino acid administration in the absence of visual cues. This
experiment was performed in the dark in order to exclude any reaction by the
fish to other unspecified visual stimuli, in the absence of the black segment.
In the dark, the number of changes in swimming direction before and after
amino acid administration was similar (t(23)=1.23,
P>0.2; not shown).
Olfactory stimulation increases ERG sensitivity in the early
morning
To investigate further the effect of olfactory stimulation on retinal
sensitivity, we recorded full-field ERGs in dark-adapted zebrafish. ERG has
been widely used in the evaluation of outer retinal sensitivity
(Dowling, 1987). We compared
light intensities required to evoke threshold (10 µV) b-waves before and
after olfactory amino acid stimulation. In the early morning, application of
amino acids (methionine 10-3 mol l-1) decreased the
b-wave threshold by approximately 0.4 log units
(t(34)=4.19, P<0.001)
(Fig. 4). The effect of
methionine on ERG sensitivity, however, was seen only in the experiments
carried out in the early morning, when the visual sensitivity of zebrafish is
at its lowest level (Li and Dowling,
1998
). When tested at a later time (09.0012.00 h),
methionine did not have any effect on the light threshold for the b-wave
(Fig. 4).
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Bulbectomy eliminates the modulation of visual sensitivity by amino
acids
Fish possess at least two classes of chemoreceptors, olfactory receptors
located in the epithelium in the nasal cavity and taste receptors located in
the oral cavity, on the gills, barbells or fins
(Hara, 1992;
Marui and Caprio, 1992
). To
distinguish if the effect of amino acid stimulation on vision is mediated by
olfactory or gustatory pathways, we measured visual sensitivity in zebrafish
after bulbectomy. Bulbectomy resulted in a strong reduction of FMRFamide
immunostaining in the forebrain, midbrain and retina
(Fig. 5). This suggests that
the TN is the main supplier for FMRFamide in those areas (see also
Pinelli et al., 2000
). While
methionine increased visual sensitivity in control fish, it was not effective
in bulbectomized fish (Fig. 6;
Table 1). This strongly
suggests that the effect of amino acids on visual sensitivity is indeed
mediated by the olfactory system.
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Dopamine mediates olfactory signals in the retina
In the retina, the target cells of the TN are DA-IPCs
(Zucker and Dowling, 1987). We
examined the effect of dopamine depletion on the modulation of visual
sensitivity by olfactory stimulation. DA-IPCs were destroyed by intraocular
injections of 6-OHDA. Depletion of dopamine in the retina resulted in
elevation of the absolute visual threshold. This may be due to blockage of rod
signaling transmission to the inner plexiform layer (see also
Li and Dowling, 2000b
). In
6-OHDA-treated animals, the effect of olfactory stimulation on vision was no
longer evident. Following methionine application the absolute visual threshold
of 6-OHDA-treated animals remained virtually unchanged from the visual
threshold measured before amino acid administration
(t(22)=-1.82, P>0.08)
(Fig. 6;
Table 1).
To investigate further the dopaminergic mechanism underlying the olfactory-visual interaction, we measured visual sensitivity following olfactory stimulation using zebrafish in which either dopamine D1 or D2 receptor activity was blocked (using the dopamine D1 antagonist SCH23390 or the D2 antagonist sulpiride). Following methionine stimulation, the visual sensitivity of SCH23390-injected fish increased significantly (t(5)=-4.0, P<0.05), similar to control fish sham-injected with PBS. However, no obvious threshold changes were observed in sulpiride-injected fish (t(5)=-1.58, P>0.1) (Fig. 6; Table 1), which suggests that in the retina, olfactory signals are mediated by dopamine via its D2 receptors.
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Discussion |
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The fact that amino acids decrease visual thresholds only at higher doses
might seem problematic. We know from both electro-olfactogram and imaging
studies that they stimulate the olfactory nerve at much lower doses, i.e. from
10-9 mol l-1 (Hara,
1992; Michel and Lubomudrov,
1995
; Zippel et al.,
1993
,
1997
;
Friedrich and Korsching,
1997
). Valentincic et al.
(2000
) have also shown that
bullhead catfish can be trained to search for food when exposed to amino acids
in concentrations as low as 10-7 mol l-1. The
fundamental difference is that we determined the amino acid concentration that
affects visual sensitivity, not the lowest concentration that can be detected
by the olfactory system.
The ERG data confirmed that olfactory stimulation increases visual
sensitivity. The b-wave threshold was decreased after application of
methionine. Similarly, Weiss and Meyer
(1988) reported that in fish
the b-wave amplitude was increased after presenting food extracts as olfactory
stimuli. It is likely that the increase of ERG sensitivity after olfactory
stimulation is due to changes in the activity of the retinal bipolar cells. We
know that the b-wave in dark-adapted fish mainly arises from activity of ON
bipolar cells and of glial Müller cells, which both are characterized by
a potassium flux (Stockton and Slaughter,
1989
; Miller and Dowling,
1970
). These potassium currents are modulated by dopamine
(Fan and Yazulla, 2001
). The
only source of dopamine in the fish retina is the DA-IPC
(Witkovsky and Dearry, 1992
).
DA-IPCs receive input from the TN (Stell
et al., 1984
; Zucker and
Dowling, 1987
), which in turn receives input from the olfactory
bulbs (Yamamoto and Ito,
2000
). Thus, the TN projection to the DA-IPC seems to provide an
ideal pathway for the dopaminergic modulation of the bipolar cells after
olfactory stimulation, and thus to modulate ERG threshold.
Using a psychophysical assay, Davis et al.
(1988) found that bilateral
ablation of the olfactory bulb and telencephalon had no effect on the response
threshold to a conditioned stimulus, i.e. a spot of red light on a dark
background. They concluded, therefore, that the TN had no role in the
regulation of visual sensitivity. It is noteworthy that they did not offer
olfactory stimulants, so their conclusion only applies to spontaneous TN
activity. In a previous study, Li and Dowling
(2000a
) examined the effect of
bulbectomy on visual sensitivity in zebrafish. They found that following short
dark adaptation the visual threshold of bulbectomized fish was similar to that
in control fish. However, following prolonged dark adaptation their visual
threshold started to fluctuate and was sometimes more than 3 log units higher
than before. In control fish, on the other hand, prolonged dark adaptation had
no such effect. It is not clear why these studies
(Davis et al., 1988
;
Li and Dowling, 2000a
)
elicited different results. There may be several reasons, e.g. the
characteristics of the stimulus (Davis and colleagues used red light, Li and
Dowling white light), the duration of the dark adaptation, or the time of day
when the experiment was performed. As we demonstrated here, the effect of
olfactory stimulation on vision was observed only in the early morning when
the circadian visual sensitivity is low. When repeated in the late morning or
late afternoon, the effect was diminished.
Olfactory modulation of visual sensitivity is mediated by a
dopaminergic mechanism
Dopamine is an important neural modulator in the retina
(Dowling, 1986;
Witkovsky and Dearry, 1992
).
Dopamine release is under the control of light
(Weiler et al., 1997
;
Kirsch and Wagner, 1989
) and a
circadian clock (Doyle et al.,
2002
; Ribelayga et al.,
2002
). Although many questions remain about the mechanism of
retinal dopamine functions, one of the main pictures emerging is that dopamine
plays a role in the modulation of neural circuitry during light and dark
adaptation (Dowling, 1986
;
Witkovsky and Dearry, 1992
).
This seems to be true for short-term reactions to ambient illumination
changes, as well as for long-term adaptation during the circadian cycle.
TN input may play a crucial role in short-term and/or long-term light/dark
adaptation. Umino and Dowling
(1991) have shown that both
GnRH and FMRFamide have effects on horizontal cells by either simulating or
antagonizing, respectively, the effects of dopamine. Retinal ganglion cells
increased their spontaneous activity in the dark after administration of both
GnRH and FRMRamide (Stell et al.,
1984
). Interestingly, retinal GnRH content depends on diurnal and
seasonal factors and on the state of light/dark-adaptation
(Ball et al., 1989
). We found
that olfactory stimulation increased visual sensitivity only in the early
morning, not in the late afternoon when visual sensitivity and retinal
dopamine release are already high (Li and
Dowling, 1998
; Ribelayga et
al., 2002
). This shift of visual sensitivity from an early morning
state to a late afternoon state could be blocked by a dopamine D2
antagonist. Manglapus et al.
(1999
) found, using ERG
measurements, that in Japanese quail retinas dopamine D2 agonist
administered at night simulated the daytime state of the retina with respect
to b-wave amplitude and rodcone dominance. A D2 antagonist
administered during the day, on the other hand, shifted the retina
functionally to a state of night time. It is possible that changes of b-wave
threshold, as seen in the present study and by Manglapus et al.
(1999
), or changes of b-wave
amplitude as seen by Weiss and Meyer
(1988
), are due to
dopaminergic modulation of outer retinal first-order elements, such as
photoreceptor cells, that possess D2 receptors
(Stella and Thoreson,
2000
).
The increase of absolute visual sensitivity in response to olfactory
stimulation also suggests that dopamine is needed for the modulation of rod
signaling transmission. It has been demonstrated that dopamine plays a role in
the regulation of rod signaling transmission in the inner retina. In zebrafish
with the DA-IPCs destroyed, rod signaling transmission to the inner plexiform
layer was blocked (Li and Dowling,
2000b), possibly due to desensitization of dopamine receptors
located on the retinal bipolar cells. Fan and Yazulla
(2001
) demonstrated that in
6-OHDA treated goldfish, the modulatory effect of dopamine on outward
potassium current of bipolar cells is diminished. Similarly, in night
blindness b mutants, which are characterized by degeneration of TN fibres
and DA-IPCs (Li and Dowling
2000a
), the effect of dopamine on the outward potassium current is
lost (Yu and Li, 2003
).
TN is the prime candidate for olfactory modulation of visual
sensitivity
We propose that the olfactoretinal branch of the TN is involved in
transmitting olfactory signals to the retina. Although this hypothesis awaits
conclusive proof, we present here four lines of evidence in favor of it. (1)
Although other centrifugal pathways have been described in different fish
species, the TN is the only direct anatomical pathway between olfactory bulb
and retina thus far identified (Stell et
al., 1984). (2) Depletion of dopamine or intraocular injections of
a dopamine D2 antagonist prevents the modulation of visual
sensitivity by olfaction. So far the only centrifugal pathway described in
zebrafish that synapses onto the DA-IPCs is the TN
(Li and Dowling, 2000a
). (3)
FMRFamide and GnRH alter the activity of both outer and inner retinal neurons
(Walker and Stell, 1986
;
Umino and Dowling, 1991
).
Except for the TN, no other brain areas have been reported to send fibers to
the retina that contain FMRFamide or GnRH. (4) The visual defect displayed by
olfactory bulbectomized or dopamine-depleted fish mimic to some extent the
visual defect of a mutant zebrafish, night blindness b, in which the
olfactoretinal centrifugal pathway is disrupted. The characteristics of
night blindness b mutants are a reduced number of DA-IPCs, fewer
FMRFamide fibers in the retina and, in the behavioral assay, intermittent
decreases in visual sensitivity after prolonged dark adaptation
(Li and Dowling, 2000a
).
Although olfactory bulb neurons synapse onto TN cell bodies
(Yamamoto and Ito, 2000), so
far no obvious changes in the electrophysiological characteristics of the TN
have been recorded as a result of chemosensory stimulation
(Fujita et al., 1991
).
Recently, Folgueira et al.
(2002
) have shown in trout
that the nucleus subglomerulosis is a link between the visual and chemosensory
systems. Interestingly, this nucleus projects to the optic tectum. It is known
that the optic tectum is involved in the visual perception of objects and has
a role in visually mediated escape responses
(Springer et al., 1977
;
Herrero et al., 1998
).
Although chemosensory stimuli could modulate visual functions at the level of
the optic tectum, we can exclude this explanation for our findings, because
destruction of the retinal DA-IPCs and intraocular application of the
D2 antagonist sulpiride eliminate the effect of amino acids on
visual function. This demonstrates that the olfacto-visual transduction
described here is located in the retina. Furthermore, visual sensitivity is
commonly assumed to be a function of the retina. A lesion of the optic tectum
can eliminate the escape response
(Springer et al., 1977
);
however, this will be an all-or-none effect, i.e. it will not influence the
visual threshold under which an escape response can be elicited. Finally, the
nucleus subglomerulosis receives gustatory, not olfactory information
(Folgueira et al., 2002
).
Conclusion
The zebrafish has recently become a genetic model for visual and olfactory
physiology (Baier, 2000),
behavioral and developmental neurobiology
(Fetcho and O'Malley, 1997
;
Gahtan and O'Malley, 2001
),
and circadian biology (Cahill,
2002
). In the present study, we provide in vivo evidence
for functional olfactory-retinal sensory integration. We present several lines
of evidence that the TN and DA-IPCs are the anatomical components for
olfactoretinal centrifugal modulation.
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Acknowledgments |
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