A chemogenetic approach for dopamine imaging with tunable sensitivity

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Genetically-encoded dopamine (DA) sensors are crucial for imaging DA release.
• Sensor limitations in detecting a wide range of DA levels, particularly tonic vs. phasic release, stem from intrinsic affinity.
• Existing methods lack flexibility in tuning sensor sensitivity for diverse experimental needs.

Purpose of the Study:

• To develop a method for enhancing the sensitivity of genetically-encoded DA sensors.
• To investigate the use of a positive allosteric modulator (PAM) to boost sensor affinity on-demand.
• To reveal multi-modal DA signaling (tonic and phasic) across different experimental preparations and imaging techniques.

Main Methods:

• Utilized a human-selective dopamine receptor PAM (DETQ) to modulate sensor affinity.
• Tested PAM efficacy across in vitro, ex vivo, and in vivo preparations using one-photon and two-photon imaging.
• Employed in vivo photometry to detect optogenetically-evoked DA release and assess PAM effects on behavior.

Main Results:

• The PAM significantly enhanced DA detection sensitivity across all tested preparations and imaging modalities.
• DETQ administration provided a stable 31-minute potentiation window without observable behavioral changes.
• The PAM enabled the detection of region-specific and metabolic state-dependent tonic DA levels.
• Enhanced single-trial detection of behavior-evoked phasic DA release in the cortex and striatum was achieved.

Conclusions:

• A chemogenetic strategy using a PAM can potently and flexibly tune DA imaging sensitivity.
• This approach allows for the revelation of multi-modal (tonic/phasic) DA signaling.
• The method is applicable across various experimental preparations and imaging approaches, advancing DA research.