behavioral modulation by dopamine in drosophila
TRANSCRIPT
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Behavioral Modulation by Dopamine in Drosophila
Reporter: JSH CJ GC
2019-9-27
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CONTENT
1.Dopaminergic circuits in Drosophila — JSH
2. Dopamine and reward pathway in Drosophila
— CJ
3. Dopamine in regulating arousal and sleep in Drosophila
— GC
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01 Dopaminergic circuits in Drosophila
Sihui Jin
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Dopamine is an important neurotransmitter in mammals
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Why we choose Drosophila as a model system for the study of dopamine
The brain of Drosophila melanogaster is comprised
of 100,000 neurons.
Dopamine regulates the same behavioral functions
both in mammals and flies.
Drosophila genes can be replaced by their human
orthologs.
The genetic tool box is useful.
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Different genes regulate DA biology in Drosophila
S.Yamamoto and E.Seto. 2014
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DA synthesis TH(pale)、GTPCH(DYT1)、DDC(Ddc)
(embryonically lethal)
DA secretion VMATs
DA signal reception
and transduction
D1-like receptors (DopR and DopR2)
D2-like receptor (D2R)
non-canonical receptor (DopEcR)
DA reuptake DAT(fumin) 、(ebony、black、tan)
DA metabolism aaNAT
A set of genes involved in Dopamine Dynamics in Drosophila
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Development of the dopamine-containing neurons of the Drosophila brain
Shin M, Copeland JM et al. Neurosci. 2018 Hartenstein V, Cruz L et al. J Comp Neurol.2017
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The DA neuronal system in larval CNS
Maria Monastirioti. 1999
Three bilateral clusters, consisting of 4–6 neuronal
perikarya each, are located in DM, DL1, and DL2 positions
in the brain lobes.
The axonal projections of most of these DA cells extend
within the ipsilateral brain lobe following common axonal
tracts.
Sb, Abu, Th, ThL and AbL form two lateral rows,
symmetrically placed along the thoracic and abdominal
ganglia.
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Developmental increase of primary DA neurons from the larval period to adult
Hartenstein V. J Comp Neurol. 2017
Primary DA clusters of the larva persist into the adult brain. Mao Z, Davus RL. Front Neural Circuits. 2009
TH-GAL4>UAS-mCD8::GFP
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DA innervation of the mushroom body lobes, heel and calyx
Mao Z, Davus RL. Front Neural Circuits. 2009
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Three clusters of DA neurons of the adult brain innervate the different parts of MB
PAM
PPL2
PPL1
Aversive memory formation,
negative geotaxis, sleep, Inhibit
oviposition preference The vertical lobes
reward signaling, long-term and
short-term memory, promote
wakefulness, foraging behavior
Medial portion of
horizontal lobes
The calyx ?
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Dopamine
sex
sleep and
arousal aggression
reward
Learning
and
memory
locom
-otion
Behavioral paradigms modulated by dopamine in Drosophila
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Dopaminergic neurons control mating drive
Stephen X.Zhang, Dragana Rogulja et al. Neuron. 2016
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The dopaminergic mating drive signal is received exclusively by P1
Stephen X.Zhang, Dragana Rogulja et al. Neuron. 2016
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The dopaminergic neurons in the VNC substain copulation
Dopaminergic neurons signal
sustain copulation through
multiple dopamine receptors.
Michael A. Crickmore and Leslie B. Vosshall. Cell.2013
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Increased dopamine level enhances male–male courtship in Drosophila
Liu T and Dartvelle L er al. J Neurosci. 2008
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Increased DA levels in PPL2ab neurons leads to inter-male courtship behaviour
LG121 ∩ murashka-1 Chen SL and Chen YH et al. Scientific Reports.2017
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PPL2ab neuron initiates male-male courtship behaviour by motion cues
Chen SL and Chen YH et al. Scientific Reports.2017
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Reduction of DA levels enhances the attractiveness of males to other males
Chen SL and Chen YH et al. Scientific Reports.2017
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Dopamine modulates female sexual receptivity in Drosophila melanogaster
ovarian maturation and fecundity
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02 Dopamine and reward pathway in Drosophila
Jie Chen
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Reward circuitry across species
Kristin M. Scaplen and Karla R. Kaun , 2016
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Dopamine and
reward pathway
In mammal
In drosophila
Addiction
Reinforcement learning
Overview
Reward Prediction Error(RPE)
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In mammal Dopamine and Reward Prediction Error(RPE)
Mitsuko Watabe-Uchida et al. 2017
CS: conditioned stimulus
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Reinforcement learning (aversive ) In drosophila
Octopamine is necessary for the
acquisition of sugar memory
DA is necessary for acquisition but not
retrieval of electric shock memory
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Reinforcement learning (aversive ) In drosophila
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Reinforcement learning (aversive ) In drosophila
A subset of 12 DA neurons was identified in the PPL1 cluster could implant aversive memories
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Reinforcement learning (aversive ) In drosophila
Scott Waddell. 2010
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Reinforcement learning (reward ) In drosophila
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Reinforcement learning (reward ) In drosophila
DA signaling is functionally downstream of OA in appetitive memory processes
0273- and 0104-GAL4 lines express in
subsets of PAM-DA neurons
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Reinforcement learning (reward ) In drosophila
Thermo-activation with DDC-GAL4 induces appetitive memory
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Reinforcement learning (reward ) In drosophila
The PAM cluster neurons signal
reward for olfactory memory
The PAM neurons convey the reward
signal to the MB
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Reinforcement learning (reward ) In drosophila
Scott Waddell. 2010
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Q: Why is dopamine considered a reward signal in mammal but a aversive signal in
drosophila?
The prior conclusion that DA was only required for aversive learning was drawn
from studies using a TH-GAL4 line that does not express in all of the fly’s DA
neurons
The DA neurons that are omitted by TH-GAL4 are those in the PAM cluster that
signal rewarding reinforcement
A:
Q&A
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Addiction In drosophila
Ethanol is both aversive and rewarding to flies
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Addiction In drosophila
Dopamine is required for expression of ethanol reward
30 min after training 24hrs after training
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Addiction In drosophila
30 min after training 24hrs after training
The mushroom body is required for aversion and preference
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Addiction In drosophila
3IY: a competitive antagonist of tyrosine hydroxylase (TH)
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Addiction In drosophila
Drosophila responds synergistically to co-
administration of low doses of cocaine and
nicotine
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Addiction
Changes induced by drugs of abuse on the firing properties of dopamine (DA)-containing neurons
In mammal
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Bainton, R. J., Tsai, L. T. Y., Singh, C. M., Moore, M. S., Neckameyer, W. S., & Heberlein, U. (2000). Dopamine modulates acute responses to cocaine,
nicotine and ethanol in Drosophila. Current Biology, 10(4), 187-194. doi:Doi 10.1016/S0960-9822(00)00336-5
Burke, C. J., Huetteroth, W., Owald, D., Perisse, E., Krashes, M. J., Das, G., . . . Waddell, S. (2012). Layered reward signalling through octopamine and
dopamine in Drosophila. Nature, 492(7429), 433-437. doi:10.1038/nature11614
Claridge-Chang, A., Roorda, R. D., Vrontou, E., Sjulson, L., Li, H., Hirsh, J., & Miesenböck, G. (2009). Writing Memories with Light-Addressable
Reinforcement Circuitry. Cell, 139(2), 405-415. doi:10.1016/j.cell.2009.08.034
Heberlein, U., Tsai, L. T., Kapfhamer, D., & Lasek, A. W. (2009). Drosophila, a genetic model system to study cocaine-related behaviors: a review with focus
on LIM-only proteins. Neuropharmacology, 56 Suppl 1, 97-106. doi:10.1016/j.neuropharm.2008.07.023
Highfill, C. A., Baker, B. M., Stevens, S. D., Anholt, R. R. H., & Mackay, T. F. C. (2019). Genetics of cocaine and methamphetamine consumption and
preference in Drosophila melanogaster. PLoS Genet, 15(5), e1007834. doi:10.1371/journal.pgen.1007834
Kaun, K. R., & Rothenfluh, A. (2017). Dopaminergic rules of engagement for memory in Drosophila. Current Opinion in Neurobiology, 43, 56-62.
doi:10.1016/j.conb.2016.12.011
Krashes, M. J., DasGupta, S., Vreede, A., White, B., Armstrong, J. D., & Waddell, S. (2009). A Neural Circuit Mechanism Integrating Motivational State with
Memory Expression in Drosophila. Cell, 139(2), 416-427. doi:10.1016/j.cell.2009.08.035
Liu, C., Placais, P. Y., Yamagata, N., Pfeiffer, B. D., Aso, Y., Friedrich, A. B., . . . Tanimoto, H. (2012). A subset of dopamine neurons signals reward for odour
memory in Drosophila. Nature, 488(7412), 512-516. doi:10.1038/nature11304
Petruccelli, E., Feyder, M., Ledru, N., Jaques, Y., Anderson, E., & Kaun, K. R. (2018). Alcohol Activates Scabrous-Notch to Influence Associated Memories.
Neuron, 100(5), 1209-1223.e1204. doi:10.1016/j.neuron.2018.10.005
Scaplen, K. M., & Kaun, K. R. (2016). Reward from bugs to bipeds: a comparative approach to understanding how reward circuits function. J Neurogenet,
30(2), 133-148. doi:10.1080/01677063.2016.1180385
Schwaerzel, M., Monastirioti, M., Scholz, H., Friggi-Grelin, F., Birman, S., & Heisenberg, M. (2003). Dopamine and octopamine differentiate between
aversive and appetitive olfactory memories in Drosophila. Journal of Neuroscience, 23(33), 10495-10502. doi:https://doi.org/10.1523/JNEUROSCI.23-
33-10495.2003
Waddell, S. (2010). Dopamine reveals neural circuit mechanisms of fly memory. Trends in Neurosciences, 33(10), 457-464. doi:10.1016/j.tins.2010.07.001
Waddell, S. (2013). Reinforcement signalling in Drosophila; dopamine does it all after all. Curr Opin Neurobiol, 23(3), 324-329.
doi:10.1016/j.conb.2013.01.005
References
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03 Dopamine in regulating sleep and arousal in Drosophila
V.G.
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Outline
Sleep & Arousal in animal
Significance of sleep and arousal
Classification of arousal
Dopamine is a regulator of arousal in Drosophila
Sandman — “sleep switch”
Genetic study of dopamine effect on arousal
Neural study of dopamine effect on arousal
Sleep-wakefulness Center in the Drosophila
Classic animal model for sleep research
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Sleep & Arousal in animal
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Why sleep ?
Risks Benefits <
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Sleep-wake arousal
Environmentally stimulated arousal
(stress-induced arousal )
Classification of arousal
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Three key steps in the evolution of sleep-active neurons
海绵动物
刺胞动物
扁盘动物
蜕皮动物
两栖动物
(Henrik Bringmann , 2005)
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Sleep-controlling neural circuits identified in genetic model animals
(Henrik Bringmann , 2005)
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Sleep-wakefulness center in the Drosophila
• Mushroom body
• Dorsal paired medial neurons (DPM)
• Peptidergic neurons in the PI
• Exfl2 neurons of the dFB
• Ellipsoid body (EB)
(Sarah Ly et al , 2018)
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Genetic study of dopamine
effect on sleep-wake arousal
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Brain activity and behavioral performance depend on arousal level in
Drosophila and humans
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Methamphetamine
甲基苯丙胺
ICE
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(Andretic, van Swinderen, & Greenspan, 2005)
Wake-promoting and increased sexual arousal effects of methamphetamine in Drosophila
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(DA synthesis inhibitor)
(Andretic, van Swinderen, & Greenspan, 2005)
Visual perception is dependent on transmission from dopaminergic neurons
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Drosophila rest/activity mutant known as fumin ( fmn)
fmn mutants exhibit increased
locomotor activity fmn flies have normal life span
(Kume, Kume, Park, Hirsh, & Jackson, 2005)
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Functional characterization of dopamine transporter in Drosophila
(Ueno & Kume, 2014)
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fmn mutants have attenuated rest rebound after rest deprivation
Arousal threshold and rest
rebound are altered by fmn
fmn flies exhibit circadian
activity rhythms
Precise regulation of DAT may be
important for normal dopamine
homeostasis
(Ueno & Kume, 2014)
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Neural study of dopamine
effect on sleep-wake arousal
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Dopamine mediates arousal via DA1 in dFSB neurons
(Ueno et al., 2012)
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Dopamine neurons have connections with the dFSB
(Ueno et al., 2012)
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Six major clusters of TH
PPL1 and/or PPM3 clusters mediate the arousing effects of DA
(Liu, Liu, Kodama, Driscoll, & Wu, 2012)
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FSB-projecting PPM3 dopamine neuron regulates arousal
(Ueno et al., 2012)
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Neural study of dopamine effect on
Environmentally stimulated arousal
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Repetitive stress induces an extended state of locomotor hyperactivity
(Lebestky et al., 2009)
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DopR negatively regulates repetitive startle-induced hyperactivity
(Lebestky et al., 2009)
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Independent requirements for DopR in spontaneous versus stimulated activity
(Lebestky et al., 2009)
Control (Gal4/+)
Mutant (DopR/+)
Rescue (Gal4/+; DopR/+)
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DopR1 exerts opposite effects on different types of arousal by acting in
different circuits
(Lebestky et al., 2009)
cocaine cocaine
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Sandman — Sleep Switch
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Optogenetic stimulation of dopaminergic neurons
silences dFB neurons and promotes awakening
Dopamine inhibits dFB neurons via Dop1R2 and
the transient opening of a potassium conductance
(Pimentel et al., 2016)
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The targets of antagonistic modulation by dopamine—
Shaker and Sandman—have opposing effects on sleep
(Pimentel et al., 2016)
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Sleep switch model
(Jeffrey M Donlea , 2017 )
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EB dFB
MB
Stress-induced Arousal Sleep-wake Arousal Associative learning
Sandman DopR1
DANs
PPM3(part) X cluster Y cluster
dDAT
cocaine
DopR2
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Thank you