A genetically-encoded fluorescent sensor enables rapid and specific detection of dopamine in flies, fish, and mice

Sun, Fangmiao; Zeng, Jianzhi; Jing, Miao; Zhou, Jingheng; Feng, Jiguang; Owen, Scott F.; Luo, Yichen; Li, Funing; Yamaguchi, Takashi; Yong, Zi-hao; Gao, Yijing; Peng, Wanling; Wang, Lizhao; Zhang, Siyu; Du, Jiulin; Lin, Dayu; Xu, Min; Kreitzer, Anatol C.; Cui, Guohong; Li, Yulong

doi:10.1101/332528

Cited by 72 publications

(105 citation statements)

References 88 publications

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“…To address this question, we next turned to direct measurements of dopamine using a recently developed genetically encoded dopamine sensor, GRABDA, an improved version based on GRABDA1m (Sun et al, 2018), with additional point mutations in the inserted circularly permuted EGFP. A dopamine sensor (DA2m) was expressed in neurons in the ventral striatum, and fluorescent signals were measured through an optical fiber implanted in the ventral striatum ( Fig.…”

Section: The Dynamics Of Dopamine Concentration In the Ventral Striatmentioning

confidence: 99%

A unified framework for dopamine signals across timescales

Kim

Malik

Mikhael

et al. 2019

Preprint

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Rapid phasic activity of midbrain dopamine neurons are thought to signal reward prediction errors (RPEs), resembling temporal difference errors used in machine learning. Recent studies describing slowly increasing dopamine signals have instead proposed that they represent state values and arise independently from somatic spiking activity. Here, we developed novel experimental paradigms using virtual reality that disambiguate RPEs from values. We examined the dopamine circuit activity at various stages including somatic spiking, axonal calcium signals, and striatal dopamine concentrations. Our results demonstrate that ramping dopamine signals are consistent with RPEs rather than value, and this ramping is observed at all the stages examined. We further show that ramping dopamine signals can be driven by a dynamic stimulus that indicates a gradual approach to a reward. We provide a unified computational understanding of rapid phasic and slowly ramping dopamine signals: dopamine neurons perform a derivative-like computation over values on a moment-by-moment basis.

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Section: The Dynamics Of Dopamine Concentration In the Ventral Striatmentioning

confidence: 99%

A unified framework for dopamine signals across timescales

Kim

Malik

Mikhael

et al. 2019

Preprint

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“…Another limitation is the inability to directly measure the amount of monoamine release as genetically encoded calcium indicators measure axonal activity, which does not necessary correlate with the amount of monoamine release due to release regulation at the presynapse and reuptake by transporters. More recently, engineered monoamine G protein‐coupled receptors (GPCR) have been developed as fluorescent reporters for extracellular monoamine concentration, enabling direct monitoring of released monoamine dynamics in specific brain regions …”

Section: Genetic Tools For the Interrogation Of Dopamine And Serotonimentioning

confidence: 99%

“…More recently, engineered monoamine G protein-coupled receptors (GPCR) have been developed as fluorescent reporters for extracellular monoamine concentration, enabling direct monitoring of released monoamine dynamics in specific brain regions. 36,37…”

Section: Genetic Tools For the Interrogation Of Dopamine And Serotonimentioning

confidence: 99%

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

Yagishita

2019

Psychiatry Clin Neurosci

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Pharmacological studies of antidepressants and atypical antipsychotics have suggested a role of dopamine and serotonin signaling in depression. However, depressive symptoms and treatment effects are difficult to explain based simply on brain‐wide decrease or increase in the concentrations of these molecules. Recent animal studies using advanced neuronal manipulation and observation techniques have revealed detailed dopamine and serotonin dynamics that regulate diverse aspects of motivation‐related behavior. Dopamine and serotonin transiently modulate moment‐to‐moment behavior at timescales ranging from sub‐second to minutes and also produce persistent effects, such as reward‐related learning and stress responses that last longer than several days. Transient and sustained effects often exhibit specific roles depending on the projection sites, where distinct synaptic and cellular mechanisms are required to process the neurotransmitters for each transient and sustained timescale. Therefore, it appears that specific aspects of motivation‐related behavior are regulated by distinct synaptic and cellular mechanisms in specific brain regions that underlie the transient and sustained effects of dopamine and serotonin signaling. Recent clinical studies have implied that subjects with depressive symptoms show impaired transient and sustained signaling functions; moreover, they exhibit heterogeneity in depressive symptoms and neuronal dysfunction. Depressive symptoms may be explained by the dysfunction of each transient and sustained signaling mechanism, and distinct patterns of impairment in the relevant mechanisms may explain the heterogeneity of symptoms. Thus, detailed understanding of dopamine and serotonin signaling may provide new insight into depressive symptoms.

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“…We proceeded to examine the dynamics of active CB 1 upon the CB 1 agonist, WIN 55,212-2 (WIN), application using live SIM imaging. Previously, several probes have been developed to detect neuromodulator receptor activations, such as dopamine (DA), norepinephrine (NE), and acetylcholine (Ach) 22,23,24 . An agonist-induced conformational change of these GPCRs alters the arrangement of the associated cpGFP and results in a fluorescence change.…”

Section: Active Cb 1 Tightly Associate With Mps and Display Less Dynamentioning

confidence: 99%

Organized cannabinoid receptor distribution in neurons revealed by super-resolution fluorescence imaging

Yang

Tian

et al. 2020

Preprint

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G-protein-coupled receptors (GPCRs) play important roles in cellular functions. However, their intracellular organization is largely unknown. Through investigation of the cannabinoid receptor 1 (CB 1 ), we discovered periodically repeating clusters of CB1 hotspots within the axons of neurons. We observed these CB 1 hotspots interact with the membrane-associated periodic skeleton (MPS) forming a complex crucial in the regulation of CB 1 signaling. Furthermore, we found that CB 1 hotspot periodicity increased upon CB 1 agonist application, and these activated CB1 displayed less dynamic movement compared to non-activated CB 1 . Our results suggest that CB 1 forms periodic hotspots organized by the MPS as a mechanism to increase signaling efficacy when being activated.

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A genetically-encoded fluorescent sensor enables rapid and specific detection of dopamine in flies, fish, and mice

Abstract: (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Cited by 72 publications

References 88 publications

A unified framework for dopamine signals across timescales

A unified framework for dopamine signals across timescales

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

Organized cannabinoid receptor distribution in neurons revealed by super-resolution fluorescence imaging

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