Back to the Future: Circuit-testing TS & OCD

Abstract A decade before the rise of optogenetics, the first behavioral “circuit-test” – transgenically modulating the output of a genetically-specified brain circuit element to examine its effect on behavior – was performed. The behaviors emulated in those mice were comorbid tics and compulsions, elicited by a gene borrowed from cholera bacteria and tailored to intracellularly neuropotentiate glutamatergic somatosensory cortical and limbic output neurons of cortico/amygdalo-striato-thalamo-cortical (CSTC) loop circuits. Two decades later, cutting-edge chemogenetic and optogenetic methods are again being devoted to further characterize the circuits thought to trigger, mediate, aggravate, or ameliorate TS & OCD symptoms. These tour de force studies support essential roles in tics and compulsions for topographically-parallel corticostriatal and amygdalar glutamatergic output neurons; their target dorsal striatal & ventral striatal (nucleus accumbens) medium spiny neurons (MSNs) of the direct striatothalamic (urge & motor activating) vs. indirect striatopallidal (urge & motor suppressing) output pathways; and their converging modulatory dopaminergic and histaminergic afferents. Going “back to the future” to circuit-map tics and compulsions will give us precision targets for future psychological, drug, medtech, and gene therapies; look for “dopamine bypasses” on your next trip in the DeLorean.