Michael Tadross

Mice are widely used in neuroscience experiments, which often require head-fixation and attachment of skull-mounted hardware. For many experiments, these components must remain intact over weeks to months, ideally with animals group housed. Many labs have designed ad-hoc head-fixation systems, which is an inefficient process. For example, when reinventing these solutions in our lab, we faced challenges with group housing, wherein mice would chew and damage implanted cannulas and electrodes of their cage mates. We performed several non-trivial design iterations to solve this problem, and present the most successful designs as an open-source collection. The designs include a standard mounting headbar compatible with most skull-mounted hardware, a snap-on protective mouse hat (headhat) to prevent mice from chewing the hardware, and a head-fixation station to facilitate common experimental procedures. We provide 3D-printing files, detail vendors and software used to make the components of the system, and provide editable design files for maximum flexibility to individual lab requirements.

Extinction learning is an essential form of cognitive flexibility, which enables obsolete reward associations to be discarded. Its downregulation can lead to perseveration, a symptom seen in several neuropsychiatric disorders. This balance is regulated by dopamine from VTADA (ventral tegmental area dopamine) neurons, which in turn are largely controlled by GABA (gamma amino-butyric acid) synapses. However, the causal relationship of these circuit elements to extinction and perseveration remain incompletely understood. Here, we employ an innovative drug targeting technology, DART (drug acutely restricted by tethering), to selectively block GABAA receptors on VTADA neurons as mice engage in Pavlovian learning. DART eliminated GABAA mediated pauses; brief decrements in VTADA activity canonically thought to drive extinction learning. However, contrary to the hypothesis that blocking VTADA pauses should eliminate extinction learning, we observed the opposite: accelerated extinction learning. Specifically, DART eliminated the naturally occurring perseveration seen in half of control mice. We saw no impact on Pavlovian conditioning, nor on other aspects of VTADA neural firing. These findings challenge canonical theories, recasting GABAA-mediated VTADA pauses from presumed facilitators of extinction to drivers of perseveration. More broadly, this study showcases the merits of targeted synaptic pharmacology, while hinting at circuit interventions for pathological perseveration.