Optogenetic pharmacology of neuromodulatory receptors

A major goal of neuroscience is to understand how neuromodulatory systems regulate core processes of brain and behavior, from motor function and learning to reward, aversion, attention, and sleep. These systems go awry in schizophrenia and disorders of mood, motor control and cognition. Treatment for these conditions often turns to pharmacological manipulation of neuromodulators and their receptors. Understanding of neuromodulatory circuits has advanced considerably thanks to optogenetics and chemogenetics. But neuromodulation is difficult to crack. A major obstacle is that a single neuromodulator may play many diverse roles (e.g. dopamine functions in motor control, reward, aversion, attention, appetite and more). There are several reasons for this complexity: i) each neuromodulator has multiple receptor subtypes, and these may couple to distinct G proteins, and, even when coupled to the same G protein, may activate distinct effectors, ii) a particular receptor may have different functions in different cell locations (e.g. axons versus dendrites, and different micro-domain signaling complexes), and iii) a particular receptor may have different functions in different cells within a circuit.

We will describe a new approach that overcomes these limitations by controlling native, full-length neuromodulatory receptors at their natural cellular locations with photoswitchable orthogonal remote tethered ligands (PORTLs): a breakthrough of precise, receptor-, cell type- and brain region-selective switchable pharmacology.