A chemogenetic approach for dopamine imaging with tunable sensitivity

Abstract

Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches.

Immunometabolic state modulation of sequential decision making in patch-foraging mice

“…Acute increases in dopamine may be important for facilitating food-directed exploitative behaviour during foraging 116,117 . Of note, dopaminergic responses are sensitive to metabolic state, with mesoaccumbens dopamine opposingly enhanced by hunger 14,15,118,119,120,121,122,123 and suppressed by inflammation 22,73,124,125,126 . Striatal dopamine signalling may be involved in adjudicating energetic resources to meet survival priorities, which can be conceptualized in a resource allocation decision framework 127 .…”

Immunometabolic state modulation of sequential decision making in patch-foraging mice

“…Acute increases in dopamine may be important for facilitating food-directed exploitative behaviour during foraging 116,117 . Of note, dopaminergic responses are sensitive to metabolic state, with mesoaccumbens dopamine opposingly enhanced by hunger 14,15,118,119,120,121,122,123 and suppressed by inflammation 22,73,124,125,126 . Striatal dopamine signalling may be involved in adjudicating energetic resources to meet survival priorities, which can be conceptualized in a resource allocation decision framework 127 .…”

The nucleus accumbens shell regulates hedonic feeding via a rostral hotspot

“…A 3-min period at the beginning of all sessions with no stimuli was observed, and the data for these 3 min was removed before analysis. MedNAcSh responses to reward consumption or to aversive stimuli were quantified using custom in-house Matlab scripts as done previously ( Labouesse et al, 2024 ; Labouesse et al, 2023 ). Events were identified using TTLs within the software.…”

“…Please cite this paper upon usage of the code. No new MATLAB code was developed but the original code can be found in Labouesse et al, 2024 ; Labouesse et al, 2023 .…”

3-Hydroxybenzeneboronic Acid Enables Stable and Sensitive Dopamine Detection by Inhibiting Target Self-Polymerization

“…12 Labouesse et al reported a human D1 receptor positive allosteric modulator to realize the detection of tonic and phasic DA. 13 It has been reported that resorcinol (Res) can react with DA to form fluorescent azamonardine compounds. 14,15 Recently, we found that the Res-like molecules and Res-motif contained molecules can also specifically bind to DA to form azamonardine-like compounds and can be used to construct fluorometric DA probes.…”

“…To further verify the structure of azamonardine-like compounds, we have isolated and purified the fluorescent product. The detailed molecular weight of the product was studied by ESI-MS. As shown in Figure 2a, a m/ 13 C NMR characterization was further performed to verify the generated product. In addition, the FT-IR spectra were obtained (Figure S3, Supporting Information).…”

Immunometabolic state modulation of sequential decision making in patch-foraging mice

“…Acute increases in dopamine may be important for facilitating food-directed exploitative behaviour during foraging 116,117 . Of note, dopaminergic responses are sensitive to metabolic state, with mesoaccumbens dopamine opposingly enhanced by hunger 14,15,118,119,120,121,122,123 and suppressed by inflammation 22,73,124,125,126 . Striatal dopamine signalling may be involved in adjudicating energetic resources to meet survival priorities, which can be conceptualized in a resource allocation decision framework 127 .…”

The nucleus accumbens shell regulates hedonic feeding via a rostral hotspot

“…A 3-min period at the beginning of all sessions with no stimuli was observed, and the data for these 3 min was removed before analysis. MedNAcSh responses to reward consumption or to aversive stimuli were quantified using custom in-house Matlab scripts as done previously ( Labouesse et al, 2024 ; Labouesse et al, 2023 ). Events were identified using TTLs within the software.…”

“…Please cite this paper upon usage of the code. No new MATLAB code was developed but the original code can be found in Labouesse et al, 2024 ; Labouesse et al, 2023 .…”

3-Hydroxybenzeneboronic Acid Enables Stable and Sensitive Dopamine Detection by Inhibiting Target Self-Polymerization

“…12 Labouesse et al reported a human D1 receptor positive allosteric modulator to realize the detection of tonic and phasic DA. 13 It has been reported that resorcinol (Res) can react with DA to form fluorescent azamonardine compounds. 14,15 Recently, we found that the Res-like molecules and Res-motif contained molecules can also specifically bind to DA to form azamonardine-like compounds and can be used to construct fluorometric DA probes.…”

“…To further verify the structure of azamonardine-like compounds, we have isolated and purified the fluorescent product. The detailed molecular weight of the product was studied by ESI-MS. As shown in Figure 2a, a m/ 13 C NMR characterization was further performed to verify the generated product. In addition, the FT-IR spectra were obtained (Figure S3, Supporting Information).…”

Immunometabolic state modulation of sequential decision making in patch-foraging mice

“…Acute increases in dopamine may be important for facilitating food-directed exploitative behaviour during foraging 116,117 . Of note, dopaminergic responses are sensitive to metabolic state, with mesoaccumbens dopamine opposingly enhanced by hunger 14,15,118,119,120,121,122,123 and suppressed by inflammation 22,73,124,125,126 . Striatal dopamine signalling may be involved in adjudicating energetic resources to meet survival priorities, which can be conceptualized in a resource allocation decision framework 127 .…”

The nucleus accumbens shell regulates hedonic feeding via a rostral hotspot

“…A 3-min period at the beginning of all sessions with no stimuli was observed, and the data for these 3 min was removed before analysis. MedNAcSh responses to reward consumption or to aversive stimuli were quantified using custom in-house Matlab scripts as done previously ( Labouesse et al, 2024 ; Labouesse et al, 2023 ). Events were identified using TTLs within the software.…”

“…Please cite this paper upon usage of the code. No new MATLAB code was developed but the original code can be found in Labouesse et al, 2024 ; Labouesse et al, 2023 .…”

3-Hydroxybenzeneboronic Acid Enables Stable and Sensitive Dopamine Detection by Inhibiting Target Self-Polymerization

“…12 Labouesse et al reported a human D1 receptor positive allosteric modulator to realize the detection of tonic and phasic DA. 13 It has been reported that resorcinol (Res) can react with DA to form fluorescent azamonardine compounds. 14,15 Recently, we found that the Res-like molecules and Res-motif contained molecules can also specifically bind to DA to form azamonardine-like compounds and can be used to construct fluorometric DA probes.…”

“…To further verify the structure of azamonardine-like compounds, we have isolated and purified the fluorescent product. The detailed molecular weight of the product was studied by ESI-MS. As shown in Figure 2a, a m/ 13 C NMR characterization was further performed to verify the generated product. In addition, the FT-IR spectra were obtained (Figure S3, Supporting Information).…”