Cell-type specific asynchronous modulation of PKA by dopamine during reward based learning

Lee, Suk Joon; Lodder, Bart; Chen, Yao; Patriarchi, Tommaso; Tian, Lin; Sabatini, Bernardo L.

doi:10.1101/839035

Cited by 19 publications

(18 citation statements)

References 56 publications

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“…However, if the CBF were to convey a signed, value-based signal it would imply the existence of cortical mechanisms for interpreting and distinguishing positive and negative neuromodulator fluctuations. Cortex contains no obvious counterpart to the segregated type 1 and 2 DA receptor-expressing 25 populations of spiny projection neurons shown to serve this function within striatum (22). By contrast, a valence-free reinforcement prediction error would provide an alerting signal appropriate to the modular and functionally heterogeneous organization of cortex yet necessitate separate pathways for distinguishing reward and punishment.…”

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confidence: 99%

Basal forebrain-derived acetylcholine encodes valence-free reinforcement prediction error

Sturgill

Hegedűs

et al. 2020

Preprint

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Acetylcholine (Ach) is released by the cholinergic basal forebrain (CBF) throughout the cortical mantle and is implicated in behavioral functions ranging from arousal to attention to learning. Yet what signal ACh provides to cortex remains unresolved, hindering our understanding of its functional roles. Here we demonstrate that the CBF signals unsigned reinforcement prediction error, in contrast to dopamine (DA) neurons that encode reward 25 prediction error. We show that both CBF neuronal activity and acetylcholine (ACh) release at cortical targets signal reinforcement delivery, acquire responses to predictive stimuli and show diminished responses to expected outcomes, hallmarks of a prediction error. To compare ACh with DA, we simultaneously monitored the activity of both neuromodulators during a serial reversal learning task. ACh tracked learning as swiftly as DA during acquisition but lagged 30 slightly during extinction, suggesting that these neuromodulators play complementary roles in reinforcement as their patterns of innervation, cellular targets, and signaling mechanisms are themselves complementary. Through retrograde viral tracing we show that the cholinergic and dopaminergic systems engage overlapping upstream circuits, accounting for their coordination during learning. This predictive and valence-free signal explains how ACh can proactively and 35 retroactively improve the processing of behaviorally important stimuli, be they good or bad.

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confidence: 99%

Basal forebrain-derived acetylcholine encodes valence-free reinforcement prediction error

Sturgill

Hegedűs

et al. 2020

Preprint

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“…Measuring FRET by fluorescence lifetime could circumvent some of the challenges described above. Photometry systems based on time-correlated single photon counting have previously been described 32 and it was recently shown that this approach could be used to measure PKA activity in the nucleus accumbens using a FRET biosensor optimized for lifetime-based detection 16,70 . As for the imaging techniques described previously, the main drawback of lifetime approaches are the increased equipment costs and complexity of the technique.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

Jones-Tabah

Mohammad

Hadj-Youssef

et al. 2020

Sci Rep

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As with many G protein-coupled receptors (GPCRs), the signalling pathways regulated by the dopamine D1 receptor (D1R) are dynamic, cell type-specific, and can change in the face of disease or drug exposures. In striatal neurons, the D1R activates cAMP/protein kinase A (PKA) signalling. However, in Parkinson's disease (PD), alterations in this pathway lead to functional upregulation of extracellular regulated kinases 1/2 (ERK1/2), contributing to l-DOPA-induced dyskinesia (LID). In order to detect D1R activation in vivo and to study the progressive dysregulation of D1R signalling in PD and LID, we developed ratiometric fiber-photometry with Förster resonance energy transfer (FRET) biosensors and optically detected PKA and ERK1/2 signalling in freely moving rats. We show that in Parkinsonian animals, D1R signalling through PKA and ERK1/2 is sensitized, but that following chronic treatment with l-DOPA, these pathways become partially desensitized while concurrently D1R activation leads to greater induction of dyskinesia. G protein-coupled receptors (GPCRs) play pivotal roles in mediating neuronal communication in the brain. In fact, 90% of non-olfactory GPCRs are found in the brain 1 , where they regulate neuronal activity by engaging a variety of distal downstream effectors which include second messenger producing enzymes, ion channels, monomeric GTPases and protein kinases. Many GPCRs are pharmacologically targeted in the treatment of neurodegenerative and neuropsychiatric disease. Thus it is critical to understand how these receptors regulate intracellular signalling, and how this in turn regulates circuit function and ultimately, behavior. In cell culture models, these signalling pathways have been dissected extensively, through the use of genetically-encoded fluorescent and bioluminescent biosensors. Some of these biosensors have recently been used in the in vivo context, to link specific signalling patterns with behavioral outcomes 2-6. Many intracellular signalling biosensors utilize changes in Förster resonance energy transfer (FRET) between two fluorescent proteins 7 to report levels or activity of second messengers, protein kinases, GTPases, posttranslational modifications and protein-protein interactions 8-11. These tools have been widely used to dissect signaling pathways in cultured cells and have recently begun to be applied in vivo, aided by recent technological developments in intravital imaging 10,12 , microendoscopy 3 , 2-photon microscopy 13-15 and fluorescence lifetime measurement 16. Here we report a ratiometric fiber-photometry approach for real-time recording of geneticallyencoded FRET biosensors in freely moving rodents. We apply this approach to investigate alterations in striatal GPCR signalling in a rat model of Parkinson's disease and l-DOPA induced dyskinesia. The dopamine D1 receptor (D1R) is a Gα s/olf coupled GPCR expressed throughout the forebrain. As for many GPCRs, several factors can impact D1R signalling, including the properties of specific ligands, the cellular context, interac...

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“…Measuring FRET by fluorescence lifetime could circumvent some of the challenges described above. Photometry systems based on time-correlated single photon counting have previously been described 7 and it was recently shown that this approach could be used to measure PKA activity in the nucleus accumbens using a FRET biosensor optimized for lifetime-based detection 4,64 . Like the imaging techniques described previously, the main drawback of lifetime approaches are the increased equipment costs and complexity of the technique.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

Jones-Tabah¹,

Mohammad²,

Hadj-Youssef³

et al. 2020

Preprint

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Like many G protein-coupled receptors (GPCRs), the signalling pathways regulated by the dopamine D1 receptor (D1R) are dynamic, cell-type specific, and can change in response to disease or drug exposures. In striatal neurons, the D1R activates cAMP/protein kinase A (PKA) signalling. However, in Parkinson’s disease (PD), alterations in this pathway lead to activation of extracellular regulated kinases (ERK1/2), contributing to L-DOPA-induced dyskinesia (LID). In order to detect D1R activation in vivo and to study the progressive dysregulation of D1R signalling in PD and LID, we developed ratiometric fiber-photometry with Förster resonance energy transfer (FRET) biosensors and optically detected PKA and ERK1/2 signalling in freely moving rats. We show that in Parkinsonian animals, D1R signalling through PKA and ERK1/2 is sensitized, but that following chronic treatment with L-DOPA, these pathways become partially desensitized while concurrently D1R activation leads to greater induction of dyskinesia.

show abstract

Cell-type specific asynchronous modulation of PKA by dopamine during reward based learning

Cited by 19 publications

References 56 publications

Basal forebrain-derived acetylcholine encodes valence-free reinforcement prediction error

Basal forebrain-derived acetylcholine encodes valence-free reinforcement prediction error

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

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