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. 2004 Feb 4;24(5):1217-25.
doi: 10.1523/JNEUROSCI.1569-03.2004.

Dopamine and glutamate control area-restricted search behavior in Caenorhabditis elegans

Thomas Hills  1 , Penelope J Brockie, Andres V Maricq
Affiliations

Dopamine and glutamate control area-restricted search behavior in Caenorhabditis elegans

Thomas Hills et al. J Neurosci. .

Abstract

Area-restricted search (ARS) is a foraging strategy used by many animals to locate resources. The behavior is characterized by a time-dependent reduction in turning frequency after the last resource encounter. This maximizes the time spent in areas in which resources are abundant and extends the search to a larger area when resources become scarce. We demonstrate that dopaminergic and glutamatergic signaling contribute to the neural circuit controlling ARS in the nematode Caenorhabditis elegans. Ablation of dopaminergic neurons eliminated ARS behavior, as did application of the dopamine receptor antagonist raclopride. Furthermore, ARS was affected by mutations in the glutamate receptor subunits GLR-1 and GLR-2 and the EAT-4 glutamate vesicular transporter. Interestingly, preincubation on dopamine restored the behavior in worms with defective dopaminergic signaling, but not in glr-1, glr-2, or eat-4 mutants. This suggests that dopaminergic and glutamatergic signaling function in the same pathway to regulate turn frequency. Both GLR-1 and GLR-2 are expressed in the locomotory control circuit that modulates the direction of locomotion in response to sensory stimuli and the duration of forward movement during foraging. We propose a mechanism for ARS in C. elegans in which dopamine, released in response to food, modulates glutamatergic signaling in the locomotory control circuit, thus resulting in an increased turn frequency.

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Figures

Figure 1.
Figure 1.
C. elegans does an ARS in response to food deprivation. A, The ARS assay. Worms were transferred from a plate seeded with food to a transition plate (no food) where any residual food attached to the worm was removed. The worm was then transferred to the observation plate (no food) where the turn frequency was recorded. B, A wild-type worm path for the first 5 min (left) of food deprivation. Each circle represents the position of the center of the worm at 1 sec intervals. The single arrow shows a high-angled turn. The open arrow shows a region of “running.” A 5 min worm path after 30 min (right) of food deprivation shows a complete absence of high-angled turns. C, The distribution of turning angles on a food-free agar plate. Positive and negative values represent the amplitude of the turn to the right or left, respectively. The black line represents 6000 turns (cumulative from 20 worms) during the first observation period. The gray line represents 6000 turns during the last observation period. The distributions are significantly different by the Kolmogorov–Smirnov test (p < 0.05). The boxed inset shows the region of interest for high-angled turns, in absolute value between 50 and 180°. D, The frequency of high-angled turns per millimeter for the first (0–5 min) and last (30–35 min) observation periods (n = 10; n refers to plates unless otherwise stated). E, The ARSi, representing the ratio of mean turns for the first and last observation periods, after 0, 2, or 50 sec of food exposure after 29 min of food deprivation (n = 8). Worms exposed to food just before the second observation period show significantly more turns than worms not exposed to food. *Statistical difference (p < 0.05).
Figure 3.
Figure 3.
Dopaminergic signaling is required for ARS. A, dat-1::GFP expression in a wild-type transgenic worm. B, dat-1::GFP expression in a transgenic worm that also expressed dat-1::ICE. C, D, Apoptotic bodies (arrowheads) in transgenic ced-1 mutants that expressed both dat-1::GFP and dat-1::ICE. Nomarski (C) and Nomarski plus GFP fluorescence (D). E, G, I, The frequency of high-angled turns for the first (black) and last (gray) observation periods in wild-type worms (n = 10) and transgenic worms that expressed dat-1::ICE (n = 10) (E); in mock-ablated transgenic dat-1::GFP worms (n = 20) and laser-operated transgenic worms in which either the ADE (n = 6), CEP (n = 8), PDE (n = 9), ADE and CEP (n = 5), ADE and PDE (n = 5), or CEP and PDE (n = 7) neurons were ablated (G); and in wild-type worms (n = 10) and transgenic dat-1::ICE worms (n = 10) in either the presence or absence of exogenous 10 mm dopamine (I). F, H, J, The ARSi for turns for worms shown in E (F), G (H), and I (J). *Statistical difference from self (E, G, I) by Student's t test or from wild-type (F, H, J) by repeated-measures ANOVA (p < 0.05). **Statistical difference from wild-type by Student's t test (G).
Figure 4.
Figure 4.
The dopamine antagonist raclopride eliminates ARS. A, Frequency of high-angled turns for wild-type worms in the presence of various concentrations of exogenous dopamine. Concentrations higher than 10 mm led to paralysis during the observation period. No visibly paralyzed worms were included in the analysis. B, The frequency of high-angled turns in wild-type worms in either the presence or absence of exogenous dopamine and raclopride (n = 8). C, The frequency of high-angled turns for the first (black) and last (gray) observation periods for wild-type worms in either the presence or absence of exogenous raclopride (n = 10). D, The ARSi shows a significant reduction in the turning ratio between the first and last observation periods. *Statistical difference from self (C) by Student's t test or from wild-type (D) by repeated-measures ANOVA (p < 0.05).
Figure 2.
Figure 2.
Defects in glutamatergic signaling alter ARS. A, The mean number of high-angled turns per millimeter during the first (black) and last (gray) 5-min observation period for wild-type worms; eat-4(ky5), glr-1(ky176), and glr-2(ak10) mutants; and transgenic glr-1 (glr-1 Rescue) and glr-2 (glr-2 Rescue) mutants that expressed an introduced wild-type glr-1 or glr-2 transgene, respectively (n = 10). B, The ARSi. *Statistical difference from self in A by Student's t test or from wild-type in B by repeated-measures ANOVA (p < 0.05).
Figure 5.
Figure 5.
cat-2 mutants are defective in ARS. A, The frequency of high-angled turns during the first and last 5 min observation periods for wild-type worms and cat-2(e1112) mutants in either the presence or absence of exogenous dopamine. B, The ARSi. *Statistical difference from self (A) by Student's t test or from wild-type or cat-2(e1112) plus dopamine (B) by repeated-measures ANOVA (p < 0.05).
Figure 6.
Figure 6.
Dopamine fails to increase turning in worms defective in glutamatergic signaling. A, The frequency of high-angled turns for worms observed on plates with 10 mm exogenous dopamine (gray) or on control plates without dopamine (black) (n = 10). B, The ratio of turns in the presence of dopamine to turns on control plates. *Statistical difference from self (A) by Student's t test or from wild-type (B) by ANOVA (p < 0.05).
Figure 7.
Figure 7.
A model that describes the control of ARS. A, A diagrammatic representation, reconstructed from White et al. (1986), of the neural circuit proposed to control ARS that shows the position of the dopaminergic sensory neurons (CEP, PDE, and ADE) relative to the command interneurons that express GLR-1 and GLR-2 (AVA, AVB, AVD, AVE, and PVC). Postsynaptic interneurons that express serotonin (RIG), octopamine (RIC), and those involved in the tap response (DVA) (Rankin et al., 1990) are also shown. Sensory neurons (triangles), interneurons (hexagons), and motor neurons (circles) are shown. The → and | represent chemical synapses and gap junctions, respectively. B, We propose a model in which food activates dopaminergic sensory neurons, causing them to release dopamine onto downstream neurons. This may lead to the modulation of glutamate receptors in the postsynaptic cell via an unidentified intermediate, or to increased glutamate release from presynaptic glutamatergic neurons. The activation of glutamate receptors results in an increased frequency of high-angled turns.
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