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Transient Dysregulation of Dopamine Signaling in a Developing Drosophila Arousal Circuit Permanently Impairs Behavioral Responsiveness in Adults

View Article: PubMed Central - PubMed

ABSTRACT

The dopamine ontogeny hypothesis for schizophrenia proposes that transient dysregulation of the dopaminergic system during brain development increases the likelihood of this disorder in adulthood. To test this hypothesis in a high-throughput animal model, we have transiently manipulated dopamine signaling in the developing fruit fly Drosophila melanogaster and examined behavioral responsiveness in adult flies. We found that either a transient increase of dopamine neuron activity or a transient decrease of dopamine receptor expression during fly brain development permanently impairs behavioral responsiveness in adults. A screen for impaired responsiveness revealed sleep-promoting neurons in the central brain as likely postsynaptic dopamine targets modulating these behavioral effects. Transient dopamine receptor knockdown during development in a restricted set of ~20 sleep-promoting neurons recapitulated the dopamine ontogeny phenotype, by permanently reducing responsiveness in adult animals. This suggests that disorders involving impaired behavioral responsiveness might result from defective ontogeny of sleep/wake circuits.

No MeSH data available.


Transient activation of dopamine during development decreases behavioral responsiveness to mechanical stimuli in adults. (A) Timeline of experiment. Th-Gal4/UAS-TrpA1 flies were exposed to elevated temperatures (31°C) during their late pupal stage, which activates dopaminergic neurons specifically. Behavioral experiments were then performed on adult males at room temperature, using the Drosophila ARousal Tracking (DART) system. (B) Adult flies were placed in individual tubes with access to food, and their responsiveness to mechanical stimuli (vibrating motors) was monitored hourly over 3 days and nights using DART. (C) Average speed (mm/s) of Th-Gal4/UAS-TrpA1 flies (N = 32) to hourly mechanical vibrations for day (light gray) and night (dark gray). (D) Average speed of identically treated UAS-TrpA1/+ genetic controls (N = 32). (E) Average speed of identically treated Th-Gal4/+ genetic controls (N = 32). (F) Average daytime responsiveness of treated Th-Gal4/UAS-TrpA1 animals (maroon) compared to genetic controls (gray). (G) Average responses are compared to each other by zeroing the baseline (pre-stimulus) speed, and summarized average daytime responsiveness (mm/s ± SEM) is shown in the histogram. (H) Average nighttime responsiveness of treated Th-Gal4/UAS-Gal4 animals (maroon) compared to genetic controls (gray). (I) Average nighttime responsiveness (mm/s ± SEM) for the three strains. ***P < 0.001, by one-way ANOVA, adjusted for multiple comparisons by Post Hoc Tukey’s test.
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Figure 1: Transient activation of dopamine during development decreases behavioral responsiveness to mechanical stimuli in adults. (A) Timeline of experiment. Th-Gal4/UAS-TrpA1 flies were exposed to elevated temperatures (31°C) during their late pupal stage, which activates dopaminergic neurons specifically. Behavioral experiments were then performed on adult males at room temperature, using the Drosophila ARousal Tracking (DART) system. (B) Adult flies were placed in individual tubes with access to food, and their responsiveness to mechanical stimuli (vibrating motors) was monitored hourly over 3 days and nights using DART. (C) Average speed (mm/s) of Th-Gal4/UAS-TrpA1 flies (N = 32) to hourly mechanical vibrations for day (light gray) and night (dark gray). (D) Average speed of identically treated UAS-TrpA1/+ genetic controls (N = 32). (E) Average speed of identically treated Th-Gal4/+ genetic controls (N = 32). (F) Average daytime responsiveness of treated Th-Gal4/UAS-TrpA1 animals (maroon) compared to genetic controls (gray). (G) Average responses are compared to each other by zeroing the baseline (pre-stimulus) speed, and summarized average daytime responsiveness (mm/s ± SEM) is shown in the histogram. (H) Average nighttime responsiveness of treated Th-Gal4/UAS-Gal4 animals (maroon) compared to genetic controls (gray). (I) Average nighttime responsiveness (mm/s ± SEM) for the three strains. ***P < 0.001, by one-way ANOVA, adjusted for multiple comparisons by Post Hoc Tukey’s test.

Mentions: We investigated whether a transient developmental increase in dopamine activity during Drosophila development (Figure 1A) affected behavioral responsiveness in adults, by using a newly developed paradigm to measure behavioral responsiveness to mechanical stimuli in flies, the DART system (16) (Figure 1B). We utilized a heat-inducible genetic construct [TrpA1 (20)] to induce depolarization in dopaminergic neurons during late pupation (21, 22). We found that this transient increase of presynaptic dopamine activity resulted in decreased responsiveness to mechanical stimuli in these flies as adults (Figure 1C), compared to similarly treated genetic controls (Figures 1D,E). This effect was evident as significantly decreased average speed of the treated flies in response to mechanical stimuli during the day (F(2,93) = 119, P < 0.001, Tukey’s) (Figures 1F,G) and night (F(2, 93) = 52.43, P < 0.001, Tukey’s) (Figures 1H,I), suggesting a general deficit in arousal. Average walking speed, however, was not significantly affected by this treatment (day: F(2, 93) = 11.76, P = 0.9494, Tukey’s; night: F(2, 93) = 27.53, P = 0.0689, Tukey’s) (Figure 2A), suggesting that the deficit is more specifically related to behavioral responsiveness than baseline activity.


Transient Dysregulation of Dopamine Signaling in a Developing Drosophila Arousal Circuit Permanently Impairs Behavioral Responsiveness in Adults
Transient activation of dopamine during development decreases behavioral responsiveness to mechanical stimuli in adults. (A) Timeline of experiment. Th-Gal4/UAS-TrpA1 flies were exposed to elevated temperatures (31°C) during their late pupal stage, which activates dopaminergic neurons specifically. Behavioral experiments were then performed on adult males at room temperature, using the Drosophila ARousal Tracking (DART) system. (B) Adult flies were placed in individual tubes with access to food, and their responsiveness to mechanical stimuli (vibrating motors) was monitored hourly over 3 days and nights using DART. (C) Average speed (mm/s) of Th-Gal4/UAS-TrpA1 flies (N = 32) to hourly mechanical vibrations for day (light gray) and night (dark gray). (D) Average speed of identically treated UAS-TrpA1/+ genetic controls (N = 32). (E) Average speed of identically treated Th-Gal4/+ genetic controls (N = 32). (F) Average daytime responsiveness of treated Th-Gal4/UAS-TrpA1 animals (maroon) compared to genetic controls (gray). (G) Average responses are compared to each other by zeroing the baseline (pre-stimulus) speed, and summarized average daytime responsiveness (mm/s ± SEM) is shown in the histogram. (H) Average nighttime responsiveness of treated Th-Gal4/UAS-Gal4 animals (maroon) compared to genetic controls (gray). (I) Average nighttime responsiveness (mm/s ± SEM) for the three strains. ***P < 0.001, by one-way ANOVA, adjusted for multiple comparisons by Post Hoc Tukey’s test.
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Figure 1: Transient activation of dopamine during development decreases behavioral responsiveness to mechanical stimuli in adults. (A) Timeline of experiment. Th-Gal4/UAS-TrpA1 flies were exposed to elevated temperatures (31°C) during their late pupal stage, which activates dopaminergic neurons specifically. Behavioral experiments were then performed on adult males at room temperature, using the Drosophila ARousal Tracking (DART) system. (B) Adult flies were placed in individual tubes with access to food, and their responsiveness to mechanical stimuli (vibrating motors) was monitored hourly over 3 days and nights using DART. (C) Average speed (mm/s) of Th-Gal4/UAS-TrpA1 flies (N = 32) to hourly mechanical vibrations for day (light gray) and night (dark gray). (D) Average speed of identically treated UAS-TrpA1/+ genetic controls (N = 32). (E) Average speed of identically treated Th-Gal4/+ genetic controls (N = 32). (F) Average daytime responsiveness of treated Th-Gal4/UAS-TrpA1 animals (maroon) compared to genetic controls (gray). (G) Average responses are compared to each other by zeroing the baseline (pre-stimulus) speed, and summarized average daytime responsiveness (mm/s ± SEM) is shown in the histogram. (H) Average nighttime responsiveness of treated Th-Gal4/UAS-Gal4 animals (maroon) compared to genetic controls (gray). (I) Average nighttime responsiveness (mm/s ± SEM) for the three strains. ***P < 0.001, by one-way ANOVA, adjusted for multiple comparisons by Post Hoc Tukey’s test.
Mentions: We investigated whether a transient developmental increase in dopamine activity during Drosophila development (Figure 1A) affected behavioral responsiveness in adults, by using a newly developed paradigm to measure behavioral responsiveness to mechanical stimuli in flies, the DART system (16) (Figure 1B). We utilized a heat-inducible genetic construct [TrpA1 (20)] to induce depolarization in dopaminergic neurons during late pupation (21, 22). We found that this transient increase of presynaptic dopamine activity resulted in decreased responsiveness to mechanical stimuli in these flies as adults (Figure 1C), compared to similarly treated genetic controls (Figures 1D,E). This effect was evident as significantly decreased average speed of the treated flies in response to mechanical stimuli during the day (F(2,93) = 119, P < 0.001, Tukey’s) (Figures 1F,G) and night (F(2, 93) = 52.43, P < 0.001, Tukey’s) (Figures 1H,I), suggesting a general deficit in arousal. Average walking speed, however, was not significantly affected by this treatment (day: F(2, 93) = 11.76, P = 0.9494, Tukey’s; night: F(2, 93) = 27.53, P = 0.0689, Tukey’s) (Figure 2A), suggesting that the deficit is more specifically related to behavioral responsiveness than baseline activity.

View Article: PubMed Central - PubMed

ABSTRACT

The dopamine ontogeny hypothesis for schizophrenia proposes that transient dysregulation of the dopaminergic system during brain development increases the likelihood of this disorder in adulthood. To test this hypothesis in a high-throughput animal model, we have transiently manipulated dopamine signaling in the developing fruit fly Drosophila melanogaster and examined behavioral responsiveness in adult flies. We found that either a transient increase of dopamine neuron activity or a transient decrease of dopamine receptor expression during fly brain development permanently impairs behavioral responsiveness in adults. A screen for impaired responsiveness revealed sleep-promoting neurons in the central brain as likely postsynaptic dopamine targets modulating these behavioral effects. Transient dopamine receptor knockdown during development in a restricted set of ~20 sleep-promoting neurons recapitulated the dopamine ontogeny phenotype, by permanently reducing responsiveness in adult animals. This suggests that disorders involving impaired behavioral responsiveness might result from defective ontogeny of sleep/wake circuits.

No MeSH data available.