Hypothalamic dopamine neurons motivate mating through persistent cAMP signalling

Zhang, Stephen X.; Lutas, Andrew; Yang, Shang Fa; Díaz, Adriana; Fluhr, Hugo; Nagel, Georg; Gao, Shiqiang; Andermann, Mark L.

doi:10.1038/s41586-021-03845-0

Cited by 89 publications

(96 citation statements)

References 62 publications

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“…Later, bPAC from soil bacterium Beggiatoa was characterized with a higher light/dark activity ratio [ 26 ]. Recently, bPAC was further engineered to show strongly reduced dark activity, and a new biPAC with reduced dark activity was characterized [ 27 , 28 ]. Be Cyclop from Blastocladiella emersonii is a green light-activated guanylyl cyclase opsin with a very high L/D ratio [ 10 ], ideal for cGMP manipulation.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Modification of Light-Sensitive Phosphodiesterases from Choanoflagellates

et al. 2022

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Enzyme rhodopsins, including cyclase opsins (Cyclops) and rhodopsin phosphodiesterases (RhoPDEs), were recently discovered in fungi, algae and protists. In contrast to the well-developed light-gated guanylyl/adenylyl cyclases as optogenetic tools, ideal light-regulated phosphodiesterases are still in demand. Here, we investigated and engineered the RhoPDEs from Salpingoeca rosetta, Choanoeca flexa and three other protists. All the RhoPDEs (fused with a cytosolic N-terminal YFP tag) can be expressed in Xenopus oocytes, except the AsRhoPDE that lacks the retinal-binding lysine residue in the last (8th) transmembrane helix. An N296K mutation of YFP::AsRhoPDE enabled its expression in oocytes, but this mutant still has no cGMP hydrolysis activity. Among the RhoPDEs tested, SrRhoPDE, CfRhoPDE1, 4 and MrRhoPDE exhibited light-enhanced cGMP hydrolysis activity. Engineering SrRhoPDE, we obtained two single point mutants, L623F and E657Q, in the C-terminal catalytic domain, which showed ~40 times decreased cGMP hydrolysis activity without affecting the light activation ratio. The molecular characterization and modification will aid in developing ideal light-regulated phosphodiesterase tools in the future.

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Section: Discussionmentioning

confidence: 99%

Characterization and Modification of Light-Sensitive Phosphodiesterases from Choanoflagellates

et al. 2022

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“…Very recently, three genetically encoded cAMP indicators (single FP-based Pink Flamindo and cADDis, FRET-based cAMPFIRE-L) have been used for two-photon imaging of cAMP in behaving mice [41][42][43] , building up the relationship between cAMP signaling and animal behavior. Given its high performance, G-Flamp1 would be an alternative and better choice for in vivo cAMP imaging.…”

Section: Discussionmentioning

confidence: 99%

A high-performance genetically encoded fluorescent indicator for in vivo cAMP imaging

Wang

Peng

et al. 2022

Preprint

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cAMP is a key second messenger that regulates diverse cellular functions including neural plasticity. However, the spatiotemporal dynamics of intracellular cAMP in intact organisms are largely unknown due to low sensitivity and/or brightness of current genetically encoded fluorescent cAMP indicators. Here, we report the development of the new circularly permuted GFP (cpGFP)-based cAMP indicator G-Flamp1, which exhibits a large fluorescence increase (a maximum ΔF/F0 of 1100% in HEK293T cells), relatively high brightness, appropriate affinity (a Kd of 2.17 μM) and fast response kinetics (an association and dissociation half-time of 0.20 s and 0.087 s, respectively). Furthermore, the crystal structure of the cAMP-bound G-Flamp1 reveals one linker connecting the cAMP-binding domain to cpGFP adopts a distorted β-strand conformation that may serve as a fluorescence modulation switch. We demonstrate that G-Flamp1 enables sensitive monitoring of endogenous cAMP signals in brain regions that are implicated in learning and motor control in living organisms such as fruit flies and mice.

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“…For inquiries regarding cADDis plasmid and virus generated during this study, please contact Montana Molecular. mKate2-biPAC plasmid DNA generated during this study and another study (Zhang et al, 2021) will be deposited to Addgene [catalog # 169127].…”

Section: Materials Availabilitymentioning

confidence: 99%

Dopamine-dependent cAMP dynamics in basal amygdala glutamatergic neurons

Lutas

Fernando

Zhang

et al. 2021

Preprint

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Dopaminergic inputs to basal amygdala (BA) instruct learning of motivational salience. Here, we investigated the dynamics of dopamine release and downstream signaling during multiple salient events occurring within tens of seconds. We established in vitro and in vivo real-time tracking and manipulation of cAMP - a key intracellular plasticity signal downstream of dopamine receptor activation. Optogenetically-evoked release of dopamine drove proportional increases in cAMP in almost all BA glutamatergic neurons, suggesting widespread actions of dopamine across neurons preferring positive or negative valence. These cAMP responses decayed more slowly than dopamine release, potentially extending the window of plasticity. cAMP levels accumulated following direct photostimulation of cAMP but not repeated stimulation of dopamine axons, due to potent depression of dopamine release. cAMP and protein kinase A (PKA) responses to repeated appetitive or aversive stimuli also exhibited pronounced depression. Thus, history-dependent dynamics of dopamine and cAMP may regulate learning of temporally clustered, salient stimuli.

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Hypothalamic dopamine neurons motivate mating through persistent cAMP signalling

Cited by 89 publications

References 62 publications

Characterization and Modification of Light-Sensitive Phosphodiesterases from Choanoflagellates

Characterization and Modification of Light-Sensitive Phosphodiesterases from Choanoflagellates

A high-performance genetically encoded fluorescent indicator for in vivo cAMP imaging

Dopamine-dependent cAMP dynamics in basal amygdala glutamatergic neurons

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