Behavioral Modulation by Dopamine in Drosophila

Reporter: JSH CJ GC

2019-9-27

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

01 Dopaminergic circuits in Drosophila

Sihui Jin

Dopamine is an important neurotransmitter in mammals

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.

Different genes regulate DA biology in Drosophila

S.Yamamoto and E.Seto. 2014

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

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

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.

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

DA innervation of the mushroom body lobes, heel and calyx

Mao Z, Davus RL. Front Neural Circuits. 2009

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 ?

Dopamine

sex

sleep and

arousal aggression

reward

Learning

and

memory

locom

-otion

Behavioral paradigms modulated by dopamine in Drosophila

Dopaminergic neurons control mating drive

Stephen X.Zhang, Dragana Rogulja et al. Neuron. 2016

The dopaminergic mating drive signal is received exclusively by P1

Stephen X.Zhang, Dragana Rogulja et al. Neuron. 2016

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

Increased dopamine level enhances male–male courtship in Drosophila

Liu T and Dartvelle L er al. J Neurosci. 2008

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

PPL2ab neuron initiates male-male courtship behaviour by motion cues

Chen SL and Chen YH et al. Scientific Reports.2017

Reduction of DA levels enhances the attractiveness of males to other males

Chen SL and Chen YH et al. Scientific Reports.2017

Dopamine modulates female sexual receptivity in Drosophila melanogaster

ovarian maturation and fecundity

02 Dopamine and reward pathway in Drosophila

Jie Chen

Reward circuitry across species

Kristin M. Scaplen and Karla R. Kaun , 2016

Dopamine and

reward pathway

In mammal

In drosophila

Addiction

Reinforcement learning

Overview

Reward Prediction Error（RPE）

In mammal Dopamine and Reward Prediction Error（RPE）

Mitsuko Watabe-Uchida et al. 2017

CS: conditioned stimulus

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

Reinforcement learning (aversive ) In drosophila

Reinforcement learning (aversive ) In drosophila

A subset of 12 DA neurons was identified in the PPL1 cluster could implant aversive memories

Reinforcement learning (aversive ) In drosophila

Scott Waddell. 2010

Reinforcement learning (reward ) In drosophila

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

Reinforcement learning (reward ) In drosophila

Thermo-activation with DDC-GAL4 induces appetitive memory

Reinforcement learning (reward ) In drosophila

The PAM cluster neurons signal

reward for olfactory memory

The PAM neurons convey the reward

signal to the MB

Reinforcement learning (reward ) In drosophila

Scott Waddell. 2010

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

Addiction In drosophila

Ethanol is both aversive and rewarding to flies

Addiction In drosophila

Dopamine is required for expression of ethanol reward

30 min after training 24hrs after training

Addiction In drosophila

30 min after training 24hrs after training

The mushroom body is required for aversion and preference

Addiction In drosophila

3IY: a competitive antagonist of tyrosine hydroxylase (TH)

Addiction In drosophila

Drosophila responds synergistically to co-

administration of low doses of cocaine and

nicotine

Addiction

Changes induced by drugs of abuse on the firing properties of dopamine (DA)-containing neurons

In mammal

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

03 Dopamine in regulating sleep and arousal in Drosophila

V.G.

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

Sleep & Arousal in animal

Why sleep ?

Risks Benefits <

Sleep-wake arousal

Environmentally stimulated arousal

（stress-induced arousal ）

Classification of arousal

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)

Sleep-controlling neural circuits identified in genetic model animals

(Henrik Bringmann , 2005)

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)

Genetic study of dopamine

effect on sleep-wake arousal

Brain activity and behavioral performance depend on arousal level in

Drosophila and humans

Methamphetamine

甲基苯丙胺

ICE

(Andretic, van Swinderen, & Greenspan, 2005)

Wake-promoting and increased sexual arousal effects of methamphetamine in Drosophila

(DA synthesis inhibitor)

(Andretic, van Swinderen, & Greenspan, 2005)

Visual perception is dependent on transmission from dopaminergic neurons

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)

Functional characterization of dopamine transporter in Drosophila

(Ueno & Kume, 2014)

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)

Neural study of dopamine

effect on sleep-wake arousal

Dopamine mediates arousal via DA1 in dFSB neurons

(Ueno et al., 2012)

Dopamine neurons have connections with the dFSB

(Ueno et al., 2012)

Six major clusters of TH

PPL1 and/or PPM3 clusters mediate the arousing effects of DA

(Liu, Liu, Kodama, Driscoll, & Wu, 2012)

FSB-projecting PPM3 dopamine neuron regulates arousal

(Ueno et al., 2012)

Neural study of dopamine effect on

Environmentally stimulated arousal

Repetitive stress induces an extended state of locomotor hyperactivity

(Lebestky et al., 2009)

DopR negatively regulates repetitive startle-induced hyperactivity

(Lebestky et al., 2009)

Independent requirements for DopR in spontaneous versus stimulated activity

(Lebestky et al., 2009)

Control (Gal4/+)

Mutant (DopR/+)

Rescue (Gal4/+; DopR/+)

DopR1 exerts opposite effects on different types of arousal by acting in

different circuits

(Lebestky et al., 2009)

cocaine cocaine

Sandman — Sleep Switch

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)

The targets of antagonistic modulation by dopamine—

Shaker and Sandman—have opposing effects on sleep

(Pimentel et al., 2016)

Sleep switch model

(Jeffrey M Donlea , 2017 )

EB dFB

MB

Stress-induced Arousal Sleep-wake Arousal Associative learning

Sandman DopR1

DANs

PPM3（part） X cluster Y cluster

dDAT

cocaine

DopR2

Thank you